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To pilot the use of the Multimedia Application/website AboutMyOp.org. To collect the largest PROMs (Patient Reported Outcome Measures) dataset in adult patients undergoing elective Laparoscopic Cholecystectomy for symptomatic gallstones in the UK, and to aid the informed consent process.

Summary:
Patients referred with gallstone disease necessitating surgery (laparoscopic cholecystectomy) will be invited to
engage with our on-line interactive website. This will allow a two-way exchange of information in a secure environment (N3 compliant) to inform the patient about the risks, benefits, alternatives to surgery (cholecystectomy), and postoperative expectations. Furthermore, it will inform clinicians about the patient’s symptoms and history, and record a pre-operative Patient Reported Outcome Measure (PROM). The patient’s understanding of the facts required for
informed consent will be measured and a “Patient Health & Understanding Report” generated for hospital clinicians. This will form part of the electronic patient record, and will be a medico-legal document.

As with current practice patients will still attend their initial outpatient clinic appointment where they will meet a surgeon who will determine the appropriateness of surgery. Informed consent for surgery (cholecystectomy) will be obtained at this initial consultation facilitated by the information obtained from the “Patient Health & Understanding Report”. The patient will then continue to interact with the on-line platform before and after their operation to ensure they are well informed and to monitor their post-operative progress.

7 days after surgery the patient will be prompted to interact with the website to answer questions about their progress and recovery. This will replace the existing telephone follow-up interaction. Any problems identified will trigger a protocol driven interaction between the hospital and the patient.

At 1, 3 and 6 months after surgery a post-operative PROMs questionnaire will be answered by the patient allowing comparison of pre- and post-operative PROMs. This study will lead to the largest PROMs assessment of the effectiveness of laparoscopic cholecystectomy, will study the feasibility of our multimedia platform application in assisting with the process of informed consent, and will determine whether telephone follow-up can be safely replaced by a protocol driven online system.

Inclusion criteria:
INCLUSION CRITERIA:
– Male or female.
– Adults: aged 18 to 85 years.
– Be referred for consideration for an elective laparoscopic cholecystectomy for symptomatic gallstones based on their GPs diagnosis and referral to a general surgeon.
– Patients initially listed for laparoscopic cholecystectomy but subsequently converted to open cholecystectomy or subsequently have a more complex ‘biliary’ procedure (including but not exclusive to bile duct exploration, biliary drain insertion, biliary bypass procedure).

EXCLUSION CRITERIA:
– Patients unable to, or those choosing not to engage with the multimedia process – including patients lacking mental capacity, patients who do not have access to a multimedia device (including but not exclusive to a computer, tablet or multimedia/smart phone), patient who are unable to use a multimedia device unassisted.
– Patients who are unable to read or communicate in English without the presence of a translator (as this is a pilot study it is not possible to offer every language option yet, however we will have voice-over options, sign-language videos, and animations, and the whole system is designed to be screen-reader compliant. In the future hopefully there will be options for additional languages).
– Patients undergoing another major non-biliary operation during the same operation as their cholecystectomy.

Exclusion criteria:
Patients unable to, or those choosing not to engage with the multimedia process – including patients lacking mental capacity, patients who do not have access to a multimedia device (including but not exclusive to a computer, tablet or multimedia phone), patients who are unable to use a multimedia device unassisted.

Patients who are unable to read or communicate in English without the presence of a translator.

Patients undergoing another major non-biliary operation during the same operation as their cholecystectomy.

Principal Investigator for this trial: Dr Prita Daliya

Research Ethics Committee Reference: 16/SW/0088

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

To pilot the use of the Multimedia Application/website AboutMyOp.org. To collect the largest PROMs (Patient Reported Outcome Measures) dataset in adult patients undergoing elective Laparoscopic Cholecystectomy for symptomatic gallstones in the UK, and to aid the informed consent process.

Summary:
Patients referred with gallstone disease necessitating surgery (laparoscopic cholecystectomy) will be invited to
engage with our on-line interactive website. This will allow a two-way exchange of information in a secure environment (N3 compliant) to inform the patient about the risks, benefits, alternatives to surgery (cholecystectomy), and postoperative expectations. Furthermore, it will inform clinicians about the patient’s symptoms and history, and record a pre-operative Patient Reported Outcome Measure (PROM). The patient’s understanding of the facts required for
informed consent will be measured and a “Patient Health & Understanding Report” generated for hospital clinicians. This will form part of the electronic patient record, and will be a medico-legal document.

As with current practice patients will still attend their initial outpatient clinic appointment where they will meet a surgeon who will determine the appropriateness of surgery. Informed consent for surgery (cholecystectomy) will be obtained at this initial consultation facilitated by the information obtained from the “Patient Health & Understanding Report”. The patient will then continue to interact with the on-line platform before and after their operation to ensure they are well informed and to monitor their post-operative progress.

7 days after surgery the patient will be prompted to interact with the website to answer questions about their progress and recovery. This will replace the existing telephone follow-up interaction. Any problems identified will trigger a protocol driven interaction between the hospital and the patient.

At 1, 3 and 6 months after surgery a post-operative PROMs questionnaire will be answered by the patient allowing comparison of pre- and post-operative PROMs. This study will lead to the largest PROMs assessment of the effectiveness of laparoscopic cholecystectomy, will study the feasibility of our multimedia platform application in assisting with the process of informed consent, and will determine whether telephone follow-up can be safely replaced by a protocol driven online system.

Inclusion criteria:
INCLUSION CRITERIA:
– Male or female.
– Adults: aged 18 to 85 years.
– Be referred for consideration for an elective laparoscopic cholecystectomy for symptomatic gallstones based on their GPs diagnosis and referral to a general surgeon.
– Patients initially listed for laparoscopic cholecystectomy but subsequently converted to open cholecystectomy or subsequently have a more complex ‘biliary’ procedure (including but not exclusive to bile duct exploration, biliary drain insertion, biliary bypass procedure).

EXCLUSION CRITERIA:
– Patients unable to, or those choosing not to engage with the multimedia process – including patients lacking mental capacity, patients who do not have access to a multimedia device (including but not exclusive to a computer, tablet or multimedia/smart phone), patient who are unable to use a multimedia device unassisted.
– Patients who are unable to read or communicate in English without the presence of a translator (as this is a pilot study it is not possible to offer every language option yet, however we will have voice-over options, sign-language videos, and animations, and the whole system is designed to be screen-reader compliant. In the future hopefully there will be options for additional languages).
– Patients undergoing another major non-biliary operation during the same operation as their cholecystectomy.

Exclusion criteria:
Patients unable to, or those choosing not to engage with the multimedia process – including patients lacking mental capacity, patients who do not have access to a multimedia device (including but not exclusive to a computer, tablet or multimedia phone), patients who are unable to use a multimedia device unassisted.

Patients who are unable to read or communicate in English without the presence of a translator.

Patients undergoing another major non-biliary operation during the same operation as their cholecystectomy.

Principal Investigator for this trial: Dr Prita Daliya

Research Ethics Committee Reference: 16/SW/0088

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Deferred consent gives crucial recruitment push for major obstetrics trial

WOMAN is a randomised trial to see whether a medicine called tranexamic acid can help mothers who bleed heavily after giving birth. The drug is already widely used to treat heavy periods, so we know it’s safe. We also know that it works for non-pregnant patients bleeding for other reasons. But we are not sure if it does more good than harm in pregnancy. Only a randomised trial in many thousands of women can answer the question. Continue reading

ACCEPT – A phase Ib/II combination trial of acalabrutinib with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) (for patients with Diffuse Large B-Cell lymphoma)

Summary:
Diffuse large B-cell lymphoma (DLCBL) is the commonest of the non-Hodgkin’s lymphomas. Whilst the majority of
patients will respond well to conventional immunochemotherapy (R-CHOP), a significant number of patients will either
fail to respond to initial therapy or relapse after completion of therapy. Bruton’s tyrosine kinase (BTK) is an enzyme
dysregulated in numerous B-cell malignancies, including DLCBL. Acalabrutinib is an orally active BTK-inhibitor. It is
hypothesised that the addition of acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of
patients with DLCBL.
The proposed study is a phase Ib/II clinical trial to determine a suitable tolerated dose and efficacy of acalabrutinib in
combination with standard R-CHOP immunochemotherapy to treat patients with DLBCL.
The main aims of this clinical study are to find out:
-The maximum dose of acalabrutinib that can safely be given to patients
-More about the potential side effects of acalabrutinib and how they can be managed
-The effect the combination of R-CHOP and acalabrutinib has on DLBCL
Approximately 6-24 patients with DLBCL will be entered into the dose-escalation phase, and a further 15 patients will
be recruited to a dose expansion cohort. The final number will depend on the number of dose escalations required.

Inclusion criteria:
1. Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to a
central laboratory for gene expression profiling and pathology review
2. Measurable disease of at least 15mm
3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative
intent
4. Stage IAX (bulk defined as lymph node diameter >10cm) to stage IV disease and deemed to require a full course of
chemotherapy. Patients with non-bulky IE disease are not eligible
5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma
6. Adequate bone marrow function with platelets > 100×109/L; neutrophils > 1.0×109/L at study entry, unless lower
figures are attributable to lymphoma
7. Measured or calculated creatinine clearance > 30mls/min, (calculated using the formula of Cockcroft and Gault
[(140-Age) x Mass (kg)x(1.04 (for women)or 1.23 (for men))/Serum Creatinine (umolL)]
8. Serum bilirubin 3 months
12. Aged 16 years or above
13. Willing and able to participate in all required evaluations and procedures in this study protocol including
swallowing capsules without difficulty
14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent

Exclusion criteria:
1. Previous history of treated or untreated indolent lymphoma. However newly diagnosed patients with DLBCL who are
found to also have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be
eligible
2. Diagnosis of primary mediastinal lymphoma
3. Diagnosis of primary Central Nervous System lymphoma.
4. History of stroke or intracranial haemorrhage in preceding 6 months
5. History of bleeding diathesis (eg. haemophilia, von Willebrand disease)
6. Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg. phenprocoumon) within 7 days of
first dose of acalabrutinib. However patients using therapeutic low molecule weight heparin or low dose aspirin will be
eligible
7. Prior exposure to a BCR inhibitor(eg. BtK inhibitors, phosphoinositide-3 kinase (PI3K), or SyK inhibitors) or BCL-2
inhibitor (eg. ABT-199)
8. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
9. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole,
rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to short-acting H2-receptor
antagonists or antacids are eligible for enrolment into this study.
10. Uncontrolled systemic infection
11. Major surgery in the preceding 4 weeks of first dose of study drug. If a subject had major surgery, they must have
recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
12. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or
myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York
Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening.
13. Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, prior to initiation of
immunochemotherapy, the results of hepatitis serology should be known prior to commencement of therapy.
– Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients
with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients
who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible.
– Positive test results for hepatitis C virus (HCV) antibody serology will not be eligible.
14. Women who are sexually active and can bear children must agree to use highly effective forms of contraception
during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are
defined in Section 4.7
14. Breastfeeding or pregnant
15. Men who are sexually active and can potentially father children must agree to use highly effective forms of
contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of
contraception are defined in Section 4.7
16. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug.
17. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give
informed consent
18. Prior malignancy (other than DLBCL), except for adequately treated basal cell or squamous cell skin cancer, in situ
cervical cancer, or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit
survival to Principal Investigator for this trial: Dr Andrew McMillan

Research Ethics Committee Reference: 16/SC/0657

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Phase I-II study of Vinblastine in Combination with Nilotinib in Children, Adolescents, and Young Adults with Refractory or Recurrent Low-Grade Glioma

Summary:
Low grade gliomas (LGG) are the most frequent brain tumour in children. More than 50% of these tumours will
progress within the first 5 years and need further treatment. As most patients are young, the risks of radiotherapy to the
developing brain are high, further medical treatment options are urgently needed.
Vinblastine is an effective chemotherapy drug for LGG and has been shown to improve survival.
Nilotinib is type of biological therapy called a tyrosine kinase inhibitor.
Vinblastine and Nilotinib have different antiangiogenic mechanisms, limited and non-overlapping toxicities, and are
thought to play an interesting role in the treatment of paediatric LGG.
The phase I part of the trial has already been completed and identified the recommended doses (RD) of each agent
when given in combination.
The main objective of the phase II part is to evaluate the efficacy of vinblastine in combination with nilotinib at the RD,
as compared to vinblastine alone, in children, adolescents, and young adults with refractory or recurrent LGG.
This is an open label, randomised, study of the combination of nilotinib and vinblastine versus vinblastine alone
122 patients with LGG will be randomised to receive either:
• Vinblastine and nilotinib OR
• Vinblastine only
Vinblastine will be given as an intravenous injection on days 1, 8, 15 and 22 of each 28 day cycle. Nilotinib will be
taken as a capsule orally twice a day on each day of the cycle. Patients will receive up to 12 cycles of treatment in the
trial as long as they are benefitting from it and are well.
This trial is being funded in the UK by Cancer Research UK (including funding from the Brain Tumour Charity).
Nilotinib is being provided free of charge by Novartis.
This trial will open at 6 sites in the UK plus others within Europe.
The Sponsor of this international study is Gustave Roussy, France

Inclusion criteria:
• Written informed consent signed by the patient, or parents or legal representative and assent of the minor child
where appropriate.
• Age: 6 months to 12 years of age, or Lansky score ≥70% for patients ≤12
years of age, including patients with motor paresis due to disease.
• Life expectancy ≥ 3 months.
• Administration of stable dose of steroids for at least one week
• Adequate organ function:
– Adequate hematopoietic function: neutrophils 1.0 x 109/L, platelets 100 x 109/L; hemoglobin 8 g/dL
– Adequate renal function: serum creatinine 1.5 ULN according to age, Glomerular filtration rate or creatinine clearance
has to be > 70ml/min/1.73m2 or > 70% of the expected value.
– Adequate electrolytes levels: potassium, magnesium, phosphor phosphate, total calcium ≥ Lower Limit of Normal
(LLN)
– Adequate hepatic function: total bilirubin ≤1.5 x ULN; AST and ALT ≤2.5 x ULN.
– Absence of peripheral neuropathy ≥ grade 2 (Common Toxicity Criteria Adverse Event, NCI CTCAE v4.0)
• Adequate cardiac function:
– Shortening Fraction (SF) ≥ 28% (35% for children 450 msec on baseline ECG, using the QTcF formula) or other clinically significant
ventricular or atrial arrhythmia
• Wash-out period of at least
– 3 weeks in case of preliminary chemotherapy,
– 6 weeks in case of nitrosourea-containing chemotherapy,
– 2 weeks in the case of treatment with vincristine only
– 6 weeks in case of radiation therapy
• Possibility of receiving the therapeutic schedule as indicated in the protocol
• Patients with reproductive potential must use effective/acceptable birth method control (as defined per CTFG
guidelines) during their treatment and for up to 90 days after the last dose. Females with reproductive potential must
have a negative pregnancy test Exclusion criteria:
Concomitant anti-tumor treatment
• Not recovered to 450 msec on baseline ECG. If QTc >450 msec and electrolytes are not within normal ranges, electrolytes
should be corrected and then the patient re-screened for QTc.
– Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled
hypertension).
– History of or presence of clinically significant ventricular or atrial tachyarrhythmias (including congenital long QT
syndrome or a known family history of congenital long QT syndrome)
• Positive test for Hepatitis B virus surface antigen

Principal Investigator for this trial: Professor Richard Grundy

Research Ethics Committee Reference: 16/YH/0452

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A PROSPECTIVE INTERNATIONAL MULTICENTRE RANDOMISED CONTROLLED SINGLE BLIND CLINICAL INVESTIGATION OF MAGNETICALLY ENHANCED DIFFUSION FOR ACUTE ISCHAEMIC STROKE (MEDIS-INTERNATIONAL)

Summary:
Most strokes result from a blood clot blocking an artery in the brain, starving tissue of oxygen and nutrients (“ischemic
stroke”) and resulting in permanent damage. Prompt treatment with clot-dissolving drugs (“thrombolysis”) improves
the chances of recovering, but this treatment has only a limited effect when a major blood vessel is blocked by a large
clot. These major blood vessel blockages cause extensive brain damage and commonly result in death or permanent
disability.
Recent studies of devices that remove clots directly after being fed through the arteries to the brain have confirmed that
opening the blocked vessel significantly improves the chances of recovery. Unfortunately, this procedure requires
highly specialised facilities and is not available to most patients. Alternative approaches to restoring blood flow are
therefore needed.
This study will test a device, the MED system, designed to improve the chances of opening a blocked artery in these
severely affected patients. The system uses two components: an intravenous injection of iron-based particles (“microbeads”)
that circulate in the bloodstream; and a magnetic device placed next to the patient’s head to concentrate the
micro-beads at the site of the blockage, and cause them to rotate. This rotation improves both the speed and
effectiveness of clot breakdown by circulating the clot-dissolving drug more effectively at the site of the blockage.
The study will involve patients with stroke caused by a large vessel occlusion who are being treated with the clotdissolving
drug tPA, randomly allocating participants to the MED system injection or a placebo injection, and looking at
the effect on opening the blocked blood vessel 30-90 minutes after treatment.
The study is a multi-centre, randomised, controlled trial that will enrol up to 120 patients at approximately 15 sites over
27 months.

Inclusion criteria:
1. *Age ≥18 and ≤ 85
2. *Clinical signs consistent with acute ischaemic stroke
3. *Prestroke functional independence (prestroke Modified Rankin Score ≤2)
4. *NIHSS 4-25 at the time of randomisation
5. *Initiation of IV tPA within the locally approved time window from stroke symptom onset (onset time is defined as the
last time when the subject was witnessed to be at baseline), with investigator or designee verification that the subject
has received I is receiving the correct IV tPA dose for the estimated weight prior to randomisation.
6. (*) Arterial Occlusive Lesion (mAOL ≤1) in the M1 or M2 segments of the MCA or carotid terminus confirmed by CT
angiography.
7. (*) Subject is able to start the MED procedure within 15 ±10 minutes) from the t-PA IV infusion, and complete 60
minutes of MED procedure treatment.
8. Subject or subject’s legally authorised representative has signed and dated an Informed Consent Form according
to country regulations, ethics committee, andlor IRB requirements.
9. It is the enrolling Investigator’s or designee’s opinion based upon the knowledge of the Subject’s condition as well
as the features of the MED device, that the Subject is an appropriate candidate for stroke management utilising MED.
*Asterisks indicate entry criteria that can be evaluated during prescreening without obtaining informed consent form as
they are part of standard of care in stroke management. Asterisks in parentheses indicate entry criteria that can be
evaluated during prescreening without obtaining informed consent form at sites that routinely perform multimodal CT
or MRI as part of standard of care in stroke management.

Exclusion criteria:
1. *The subject is likely to receive intra-arterial (IA) intervention.
2. *Standard exclusions for thrombolysis according to the approved label and local institutional protocols.
3. *Female who is pregnant or lactating or has a positive pregnancy test at time of admission.
4. *Rapid neurological improvement prior to study randomisation suggesting resolution of the occlusion.
5. *Known hyper-sensitivity to radiographic contrast agents.
6. (*) Known hyper-sensitivity to iron-based agents.
7. *Current participation or participation in the last 4 weeks in another investigational drug or device treatment study.
8. *Life expectancy of less than 90 days due to other medical condition.
9. *Subject with a pre-existing neurological or psychiatric disease that would confound the neurological and functional
evaluations.
10. (*) Subject has contraindications to MR (examples include, but are not limited to, an implantable cardioverter
defibrillator, pacemaker, clipped or coiled aneurysm, neurostimulator).
11. (*)Subject has recently (within 30 days) received iron replacement therapy or iron based MR contrast.
12. *Subject has known or suspected liver disease, including hepatitis andlor cirrhosis.
Imaging Exclusion Criteria:
These exclusion criteria will be determined by local radiology interpretation of the imaging data at the time of subject
evaluation.
1. *Computed tomography (CT) evidence of haemorrhage on presentation.
2. *Exclusion: Large core of ischemia defined as NCCT ASPECTS 4 or less.
3. *CT or MRI evidence of intra-cranial tumour (except small meningioma).
4. *CTA evidence of carotid dissection or complete cervical carotid occlusion.
*Asterisks indicate entry criteria that can be evaluated during prescreening without obtaining informed consent form as
they are part of standard of care in stroke management. Asterisks in parentheses indicate entry criteria that can be
evaluated during prescreening without obtaining informed consent form at sites that routinely perform multimodal CT
or MRI as part of standard of care in stroke management.

Principal Investigator for this trial: Professor Phillip M W Bath

Research Ethics Committee Reference: 16/SC/0566

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A Phase III, Randomized, Double-blind Study to Evaluate Pembrolizumab plus Chemotherapy vs Placebo plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (TNBC)

Summary:
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women.
Breast cancer that tests negative for oestrogen receptors, progesterone receptors and human epidermal growth
factor receptor-2 is known as triple-negative breast cancer (TNBC). TNBC represents 15-20% of all breast cancers.
Treatment of TNBC is challenging and represents an area of unmet medical need, as these tumours lack therapeutic
targets, and become rapidly resistant to chemotherapy upon local recurrence and/or metastasis.
Programmed cell death 1 (PD1) is a protein present on the surface of immune (attacking) cells which fight cancer.
When immune cells come upon cancer cells, PD1 becomes activated by programmed cell death ligands 1 and 2
(PDL1 and PDL2) which are proteins on the surface of cancer cells. Interaction between these ligands and the
receptors present on the immune cells prevents the immune cells from attacking the cancer cells. The study drug
pembrolizumab has been developed to block PD1/PDL1 interaction, thereby increasing the immune attack on
cancers.
This Phase III study will last approximately 8 years and will recruit 855 adult men/women over the age of 18. Each
participant will take part in the trial for approximately 67 weeks from the time they sign the Informed Consent Form
through completion of study treatment.
The primary purpose of this study is to compare the rate of pathological complete response (pCR) and event-free
survival in treatment with pembrolizumab plus chemotherapy versus placebo plus chemotherapy as neoadjuvant
(preoperative) therapy and pembrolizumab versus placebo as adjuvant (post-surgery) therapy for TNBC. Secondary
outcomes test the use of tumour PD-L1 as a biomarker (a biological parameter indicating a biological condition) for
correlation to pembrolizumab response.

Inclusion criteria:
1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future
Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical
Research.
2.Be a male or female subject >18 years of age on day of signing informed consent.
3.Have centrally confirmed TNBC, as defined by the most recent ASCO/CAP guidelines.
4.Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary
tumor (T) and regional lymph node (N) staging per AJCC for breast cancer staging criteria version 7 as assessed by
the investigator based on radiological and/or clinical assessment: T1c, N1-N2, T2, N0-N2, T3, N0-N2,T4a-d, N0-N2
5.Provide a core needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to
the central laboratory.
6.Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of
treatment initiation.
7.Demonstrate adequate organ function as defined in the protocol. All screening labs should be performed within 10
days of treatment initiation.
8.Have left ventricular ejection fraction (LVEF) of ≥50% or ≥ institution lower limit of normal (LLN) as assessed by
echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
9.Males and female subjects of childbearing potential must be willing to use an adequate method of contraception.
Contraception, for the course of the study through 12 months after the last dose of study medication for subjects who
have received cyclophosphamide, and 6 months after the last dose of study medication for subjects who did not.
10.(Female subject of childbearing potential) Have a negative urine or serum pregnancy test within 72 hours prior to
receiving the first dose of study medication. If the urine test is positive or borderline a serum pregnancy test will be
required.

Exclusion criteria:
1.Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal
cell or squamous cell skin cancer or in situ cervical cancer.
2. Has received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another
co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137) or has previously participated in MK-3475 clinical trials.
4. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or
device within 4 weeks of the first dose of treatment in this current trial.
5.Has received a live vaccine within 30 days of the first dose of study treatment.
6.Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease
modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of
systemic treatment.
7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
8. Has a known history of Human Immunodeficiency Virus (HIV) (HIV
1/2 antibodies).
9. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
10. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
11. Has an active infection requiring systemic therapy.
12.Has significant cardiovascular disease, such as:
a) History of myocardial infarction, acute coronary syndrome or coronary
angioplasty/stenting/bypass grafting within the last 6 months
b) Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV
13. Has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might expose
the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject’s participation
for the full duration of the trial.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements
of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with
the screening visit through 12 months after the last dose of trial treatment for subjects who have received
cyclophosphamide, and for 6 months after the last dose of study medication for subjects who have not.
16. Has a known hypersensitivity to the components of the study therapy or its analogs.
17. Has a known history of active TB (Bacillus Tuberculosis)

Principal Investigator for this trial: Dr Stephen Y Chan

Research Ethics Committee Reference: 17/LO/0347

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

COMPLEEMENT-1: An open-label, multicenter, Phase IIIb study to assess the safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease

Summary:
This study (CLEE011A2404) is an open-label, single arm, Phase IIIb study to evaluate the overall safety, tolerability and
efficacy of ribociclib (LEE011) in combination with letrozole. The patients treated will be men and postmenopausal
women with Hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer who have not had
previous hormone treatment for their advanced disease. Approximately 3,000 patients will be enrolled in this study
globally.
Recent results from the MONALEESA-2 (NCT01958021) Phase III study show that the combination of ribociclib and
letrozole slows down the growth of HR+,HER2- advanced breast cancers more than the standard treatment of
letrozole alone. These results will be presented at the European Society of Medical Oncology (ESMO) 7th-11th October
2016.
The purpose of this study (CLEE011A2404) is to collect additional safety and efficacy data for the combination of
ribociclib and letrozole in a broad population of patients. While MONALEESA-2 did not include patients who had
received previous chemotherapy or male patients, CLEE011A2404 will include these patients as well as the groups
eligible for MONALEESA-2.
Study treatment will be provided until disease progression, physician’s decision, or until the end of study, whichever
event occurs first. There will be a 28 day screening phase, followed by a study treatment phase, during which time
patients will attend the hospital monthly, then an end of treatment and safety follow up visit.

Inclusion criteria:
1. Patient is an adult, male or female ≥ 18 years old at the time of informed consent
Note: Sexually active males should use a condom during intercourse while taking drug
and for 21 days after stopping medication and should not father a child in this period. A condom is required to be used
also by vasectomized men in order to prevent delivery of the drug via seminal fluid
2. Advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
3. In the case of women, patient is postmenopausal. Postmenopausal status is defined either by:
Prior bilateral oophorectomy
Age ≥60
Age 50 mL/min
In absence of liver metastases, alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) should be below 2.5 × ULN. If the patient has liver
metastases, ALT and AST should be Exclusion criteria:
1. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole
2. Patient who received any CDK4/6 inhibitor
3. Patient who received any prior systemic hormonal therapy for advanced breast cancer; no more than one prior
regimen of chemotherapy for the treatment of metastatic disease is permitted
Note:
Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior neo (adjuvant) therapy
included letrozole or anastrozole the disease free interval must be > 12 months from the completion of treatment until
study entry.
Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease are eligible.
Any prior (neo) adjuvant anti-cancer therapy or prior chemotherapy for metastatic
disease must be stopped at least 5 half-lives or 7 days, before study entry.
4. Patient is concurrently using other anti-cancer therapy.
5. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side
effects.
6. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 4.03
Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk, at investigator’s discretion).
7. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to
randomization, and who has not recovered to grade 1 or better from related side effects of such therapy (with the
exception of alopecia) and/or from whom ≥ 25% of the bone marrow was irradiated.
8. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of
adequately treated, basal or squamous cell carcinoma, nonmelanomatous skin cancer or curatively resected cervical
cancer.
9. Patient with central nervous system (CNS) metastases unless they meet ALL of the
following criteria:
At least 4 weeks from prior therapy for CNS disease completion (including radiation and/or surgery) to starting the
study treatment.
Clinically stable CNS lesions at the time of study treatment initiation and not
receiving steroids and/or enzyme-inducing anti-epileptic medications for the
management of brain metastases for at least 2 weeks.
10. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of the study drugs
11. Patient has a known history of HIV infection (testing not mandatory)
12. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s
judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise
compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal,
bacterial or viral infections, etc.)
13. Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormalities, including any of the following:
History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 6 months prior to screening
History of documented congestive heart failure
Documented cardiomyopathy
Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade
AV block
Long QT syndrome or family history of idiopathic sudden death or congenital long
QT syndrome, or any of the following:
i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia
or hypomagnesemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia.
ii.Concomitant use of medication(s) with a known risk to prolong the QT interval
and/or known to cause Torsades de Pointe that cannot be discontinued (within 5
half-lives or 7 days prior to starting study drug) or replaced by safe alternative
medication
iii. Inability to determine the QT interval on screening (QTcF, using Fridericia’s
correction)
Systolic blood pressure (SBP) >160 mmHg or Principal Investigator for this trial: Dr Stephen Y Chan

Research Ethics Committee Reference: 16/EE/0463

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TEST-IT – Point Of Care Testing For Sepsis In ICU Patients: A Diagnostic Accuracy Study

Summary:
Sepsis is the term used to describe serious infections. It is caused by microbes, such as bacteria, and one of the most important things in treating patients with sepsis is to give them effective antibiotics as soon as possible to treat the underlying infection.
Many different microbes can cause sepsis. Currently, the usual way to find out for sure which one to target in any particular patient is to wait for it to grow in a laboratory from a sample of their blood, or other samples. As it takes at
least 24-48 hours to grow in the laboratory, doctors choose ‘best guess’ antibiotics that can treat a lot of different microbes before they know which one would be the most effective. These are not always the best antibiotics for that particular individual, and sometimes patients only get the most effective treatment after a result from the laboratory becomes available.
Randox Ltd has recently developed a new bedside device based on technology that is able to identify bacteria in patients’ blood within just one hour. Looking only for characteristic fragments of over 40 different microbes means that doctors’ decisions about which treatment to give patients will not need to wait for over a day for the microbe to grow in a laboratory. This will allow treatments to be better targeted from a much earlier stage.
We will evaluate the new test in at least 15 intensive care units (ICUs) across the UK and on 4501 blood samples from patients. Whenever a blood sample is taken for culture as part of routine care, a sample will also be taken for analysis with the new test. Results will be compared to the laboratory culture each time to permit an assessment of how accurate the new test is.

Inclusion criteria:
Patients with suspected sepsis undergoing blood sampling for culture in the course of routine care.

Exclusion criteria:
1. Patients aged Principal Investigator for this trial: Dr Daniel Harvey

Research Ethics Committee Reference: 16/SC/0277

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Hartmann’s procedure versus intersphincteric APE: a prospective study (The HiP Study)

Summary:
More than 41 000 new cases of bowel cancer are diagnosed annually in the UK with one third occurring in the rectum.
Standard treatment for rectal cancer is an operation that removes the section of bowel containing the tumour,
reconnecting healthy bowel to the anal canal. This reconstructive approach allows patients to defecate normally, but is associated with a relatively high rate of perioperative complications (40%) and poor bowel function (50%). Where these
risks are unacceptably high (frail patients, multiple comorbidities, poor pelvic floor/anal canal function) alternative nonreconnecting
strategies are substituted.
Hartmann’s procedure (HP) has been regarded as the nonreconnecting
operation of choice and is technically quite
straightforward. Alternatively, another operation called IAPE completely removes all of the rectum and anal canal which
is thought to significantly reduce the incidence of serious pelvic infection that may with HP. Some surgeons are
reluctant to perform this procedure due to the slightly increased operating time and the risk of the local wound failing to
heal.
It is unclear which is the best procedure, and there are no prospective data to guide surgeons. This is a prospective
observational study of patients undergoing these two procedures, a formal RCT is not possible at the present time due
to uncertainty over patient numbers and feasibility of randomisation.
The primary objectives are to establish the use of each procedure and determine the surgical complication rate
associated with each. This prospective data may be sufficient to determine the optimal procedure, if not it will be used
to inform the design of a larger prospective randomised trial. We will also assess whether patients and surgeons
would be willing to recruit to such a study also. The study will incorporate centres from across the UK as well as
European and worldwide centres who are also interested in answering this question.

Inclusion criteria:
Locally curative rectal cancer (systemic metastases or recurrent cancer not contraindicated as long as primary tumour
is locally curable)
Histologically proven adenocarcinoma
Full MRI staging of primary tumour
Aged over 18
Able to provide fully informed consent
Primary anastomosis not appropriate
Fit for major resectional surgery

Exclusion criteria:
Cancer of the lower rectum that requires en bloc excision of the pelvic floor to achieve oncological clearance
(extrasphincteric or extralevator APE)
Pregnant patients
Patients unable to provide fully informed consent
Suspicion of tumour perforation
Patient not fit for major resectional surgery
Palliative resection

Principal Investigator for this trial: Mr David Humes

Research Ethics Committee Reference:

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BioImpedance Spectroscopy to Maintain Renal Output: The BISTRO Trial

Summary:
Background: Most patients who develop kidney failure choose unit-based haemodialysis treatment. Dialysis removes
waste products and excess fluid from the blood when the kidneys stop working properly. Haemodialysis involves
diverting blood to a machine to be cleaned.
One of the main functions of dialysis is to control the amount of fluid in the body. Too much fluid can lead to raised
blood pressure that damages the heart and increases the risk of stroke, and may cause fluid to collect in the lungs
leading to breathing difficulties. Too little fluid causes dehydration, cramps and low blood pressure and more rapid or
complete loss of any remaining kidney function. Bioimpedance is a simple, bedside measurement giving information
about body composition, specifically how much excess fluid is present. Clinicians can use this to guide how much
fluid should be removed from the body with the normal clinical assessment of the amount of fluid in the body, but it is
not known if this results in better decisions and outcomes for patients.
Research aims: To test whether taking regular measurements with a bioimpedance device, which gives information
about body composition, improves outcomes for people who have newly started haemodialysis treatment for kidney
failure. In particular, the study aims to see if this helps patients maintain their remaining kidney function, as this is
associated with improved survival, fewer symptoms of kidney failure, fewer side effects of dialysis treatment and a
better quality of life including confidence in managing their health, and cost benefit analysis.
Design and methods: People starting haemodialysis as an outpatient with some remaining kidney function will be
invited to participate in a clinical trial that compares current best practice with the same but additionally guided by
regular bioimpedance measurements. The study will randomise 516 patients from 30 dialysis units across the UK.

Inclusion criteria:
– Adults aged >18 years commencing centre-based maintenance haemodialysis due to advanced kidney disease
CKD stage 5, planned or unplanned, via arterio-venous fistula, graft or central venous catheter (i.e. with or without
permanent vascular access)
– Commencing dialysis on any regimen, including having incremental dialysis initiation
– Residual kidney function:
a) For patients who have not yet started dialysis treatment they should have a daily urine volume > 500ml/day and/or a
or a measured mean urea and creatinine clearance greater or equal 3ml/min/1.72m2 determined from a 24 hour
collection;
b) For patients already on dialysis they should have a urine volume >500ml during the short inter-dialytic period and/or
a measured mean urea and creatinine clearance greater or equal 3ml/min/1.72m2, determined from the same timed
inter-dialytic urine collections and an average of the post- and pre-dialysis plasma urea and creatinine concentrations.

Exclusion criteria:
-Unable or unwilling to give informed consent
-Unable to comply with trial procedures, e.g. collection of urine output
-Likely survival prognosis or planned modality transfer Principal Investigator for this trial: Dr Linda Bisset

Research Ethics Committee Reference: 16/NS/0094

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Refining Ovarian Cancer Test Accuracy Scores: A test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer.

Summary:
Our research project will identify and confirm tests that can help hospital doctors and GP’s make a better diagnosis of
ovarian cancer.
NICE has issued guidelines to GP’s, to test women if they have certain symptoms of bloating/tummy discomfort with a
blood test CA125 and then a pelvic ultrasound if the CA125 test result is abnormal. However published literature
shows GPs refer patients if they have symptoms or if either test is abnormal. In fact the blood test CA125 can be
raised in lots of other innocent conditions e.g. during menstrual periods. Also in younger women, noncancerous
cysts
on the ovary are very common. Conversely CA125 is only raised in half the women with early ovarian cancer. This
means that many women are referred who actually have a very low risk of cancer, and others are not referred until their
cancer has reached a more advanced stage.
By identifying better tests for ovarian cancer, we may be able to diagnose more women with ovarian cancer early but also reduce unnecessary tests, hospital visits and distress in women who don’t have cancer. We also know that
women with ovarian cancer who undergo thorough surgery by a gynaecological cancer specialist have the best
outcomes, so improved testing in hospital after referral may also help to identify the patients who will need this.
Rockets study is a part of a large complex project that will first look at all the published papers on new blood tests,
scan scoring and symptom scores. We will then use that information to test existing stored blood samples and data
from previous large studies conducted by our collaborators, to finetune
tests and create new scoring systems (risk
prediction models) which can be used to diagnose patients by GPs and after referral in hospital. We will then compare
our new risk prediction model against the current prediction score (RMI) in a study of 2450 newly presenting patients
with suspected ovarian cancer. This study will assess symptoms, scans and blood test results. Finally we will use all
of this information to set out best pathways for GP’s and hospital specialists to follow in women with suspected
ovarian cancer. This ethics application is for the prospective study only.

Inclusion criteria:
Pre and postmenopausal women with symptoms of suspected OC and either raised Ca125 or abnormal USG.

Exclusion criteria:
USG reveals nonovarian
pathology e.g. fibroids or simple ovarian cysts Principal Investigator for this trial: Mr Ketankumar B Gajjar

Research Ethics Committee Reference: 14/WM/1241

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Evaluation of the impact of care experience prior to undertaking NHS funded education and training

Summary:
What is the impact of care experience prior to undertaking NHS-funded education and training, on pre-registration
nursing students’ skills, values, behaviours and service users’ experiences of care?
Nursing care quality was criticised in England following the failings in care identified by the Mid Staffordshire inquiry.
Findings included shortcomings in nurses’ values and attitudes, and emphasised the need for staff to prioritise
compassion. Regarding pre-registration nursing, the inquiry report recommended that nursing applicants undertake
Health Care Assistant training and experience before commencing nurse training.
In 2013 the Department of Health (DH) introduced a pilot programme providing nursing applicants with hands-on care
experience, prior to training, in the hope that they would acquire real-life experience of the reality of healthcare and
provide employers with opportunities to ensure that individuals had relevant values and behaviours, before
commencing study.
There is little evidence that this response will adequately address concerns highlighted. This DH-funded study aims to
investigate the impact of care experience prior to entering nurse training, on nursing students’ caring skills, values and
behaviours. This phase of research seeks to explore patient experiences of care provided by student nurses (both
with and without prior care experience), during their hospital-based placements in 2017, at four NHS Trusts. It invites
patients to complete a questionnaire evaluating the care received from a student nurse participant. The study aims to
recruit 43 adult branch student nurse participants from the University of Nottingham, University of Huddersfield and
Anglia Ruskin University and up to 5 patient participants per student nurse participant, totalling 215 patient
participants.
The research will inform policy makers, the NHS, clinicians and educators about the effect of prior experience on
students’ caring skills, values, behaviours, and the best model of providing experience, so that individuals can deliver
the best care to patients upon graduation and beyond.

Inclusion criteria:
To be assessed by the student nurse participant’s mentor/senior nurse/nurse who the student nurse participant has
been working with.
1. A patient whom a student nurse participant has been involved in caring for, on at least one occasion, on the day of
recruitment, or on a previous day
2. A patient who is considered to possess the mental capacity to understand the requirements of participation and
provide (implied) informed consent to participate in the research
3. A patient who is considered to be well enough to participate in the research, and for whom participation would not
delay clinical treatment, intervention, or discharge
4. A patient who is at least 18 years of age
5. A patient who is proficient in written and spoken English

Exclusion criteria:
To be assessed by the student nurse participant’s mentor/senior nurse/nurse who the student nurse participant has
been working with.
1. A patient whom a student nurse participant has not been involved in caring for, on at least one occasion, on the day
of recruitment, or on a previous day
2. A patient who is not considered to possess the mental capacity to understand the requirements of participation
and provide (implied) informed consent to participate in the research
3. A patient who is not considered to be well enough to participate in the research, and for whom participation would
delay clinical treatment, intervention, or discharge
4. A patient who under 18 years of age
5. A patient who is not proficient in written and spoken English

Principal Investigator for this trial: Mr Patrick Callaghan

Research Ethics Committee Reference: 17/LO/0279

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Prospective Clinical Investigation for a Randomized, Controlled, Multicenter Non-inferiority Study Comparing Standard Wound Closure Technique with Drains (control) to Standard Wound Closure Techniques with TissuGlu® and No Drains (test) in Mastectomy

Summary:
The TissuGlu® Mastectomy Study is a prospective, randomized, controlled, multicenter non-inferiority study comparing
standard wound closure technique with drains (control) to standard wound closure techniques with TissuGlu® and no
drains (test) in mastectomy.
The objective of the study is to compare groups based on the number of Post-Operative Clinical Interventions, where
Clinical Intervention is defined as one of the following events:
1. Removal of an in-dwelling drain (As defined in the Protocol);
2. Needle aspiration to remove fluid from a Clinically-Relevant Seroma (As defined in the Protocol);
3. Invasive action to the drain or drain wound such as repositioning or re-attaching the drain retention sutures;
4. Reinsertion or insertion of a drain postoperatively;
5. Surgical procedures due to wound healing complications related to wound management
84 Patients with Mastectomy with or without SLNB only (42 test and 42 control) will be enrolled in the UK and
Germany. Patients will be randomly assigned to one of the two groups and will be enrolled for 90 days from day of
Surgery. It is expected that it will take 6-9 months for the full duration of the study including the 90 day follow up period.
During the follow-up period, patients will be physically examined, the surgical site is evaluated and a patient
questionnaire should be completed.

Inclusion criteria:
1. ≥ 18 years of age;
2. Provide signed and dated informed consent form;
3. Willing to comply with all study procedures, schedules and be available for the follow-up evaluations for the duration
of the study;
4. Willing to follow instructions for incision care and follow guidelines related to resumption of daily activities;
5. Agree not to schedule any additional elective surgical procedures that involve an incision until their participation in
this study is complete;
6. In good general health in the opinion of the Investigator with no conditions that would significantly impact wound
healing as determined by medical history, and review of recent concomitant medications;
7. Requiring a mastectomy (standard, modified, modified radical) with or without sentinel node biopsy;
8. ≤ ASA 3 – American Society of Anesthesiologists Physical Classification System

Exclusion criteria:
1. Pregnancy or lactation;
2. Known medical condition that results in compromised blood supply to tissues;
3. Known or suspected allergy or sensitivity to any test materials or reagents;
4. Any condition known to affect wound healing, such as collagen vascular disease;
5. Receiving antibiotic therapy for pre-existing condition or infection;
6. Planned immediate breast reconstruction;
7. Concurrent use of fibrin sealants or other internal wound care devices;
8. Unable to understand questions, instructions or the informed consent presentation in the language of the
investigators performing the study;
9. Requiring a mastectomy with ALND (as determined at time of surgery);
10. Be participating in any conflicting medical device clinical trial within 30 days of enrollment in this study

Principal Investigator for this trial: Miss Lisa Whisker

Research Ethics Committee Reference: 17/EM/0014

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Magnetic resonance imaging of Abdominal Lymph nodes (MAL)

Summary:
Inflammatory diseases are likely to cause enlargement of the abdominal lymph nodes which could potentially act as
biomarkers of inflammation. MRI can image lymph nodes non-invasively. We are interested in collecting pilot image
data, particularly a water diffusion MRI scans as diffusion MRI scans show enlarged lymph nodes. To this effect we are
proposing a one hour MRI scan to collect images of enlarged lymph nodes. We will collect data from approximately 60
patients diagnosed with one of the following: chronic viral hepatitis B or C infection, symptomatic coeliac disease,
symptomatic Crohn’s disease, Diverticulitis, active Helicobacter pylori infection or liver cirrhosis

Inclusion criteria:
Inclusion criteria
• 60 patients diagnosed with one of the following:
o chronic viral hepatitis B or C infection,
o symptomatic coeliac disease,
o Symptomatic Crohn’s disease,
o Diverticulitis,
o Active Helicobacter pylori infection,
o Clinical, radiological or histological diagnosis of liver cirrhosis
• Aged 18-65
• Male or female
• Able to give informed consent
• Able to schedule the first MRI scan (Visit 2 of the study) within 2 months of the screening visit

Exclusion criteria:
Exclusion criteria
• Pregnancy declared by candidate
• Contraindications for MRI scanning i.e. metallic implants, pacemakers, history of metallic foreign body in eye(s) and
penetrating eye injury
• Inability to lie flat or exceed scanner limits of weight Principal Investigator for this trial: Dr Gordon Moran

Research Ethics Committee Reference: 17/LO/0370

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A Phase 2, Open-Label, Single-Agent, Multicenter Study to Evaluate the Efficacy and Safety of INCB054828 in Subjects With Metastatic or Surgically Unresectable Urothelial Carcinoma Harboring FGF/FGFR Alterations

Summary:
The purpose of this study is to evaluate the efficacy, safety, and tolerability of INCB054828 in subjects with
advanced/nonresectable or metastatic urothelial carcinoma with Fibroblast growth factor / Fibroblast growth factor
Receptor(FGF/FGFR) alterations. Cancers have several common characteristics that can be observed across
numerous tumour types. One common characteristic is the uncontrolled growth and survival of cells and their ability to
become invasive throughout the body. Fibroblast growth factor (FGF) signaling produces cell division (mitogenic),
survival (anti-apoptotic), and formation of new blood cells (angiogenic) responses in cells, which leads to a
deregulated state. The study drug INCB054828 is an inhibitor of the FGF/FGFR family of receptor tyrosine kinases that
is proposed for the treatment of Cancers. This is an open-label monotherapy study of INCB054828 in subjects with
metastatic or surgically unresectable urothelial cancer harbouring FGF/FGFR alterations.
Potential subjects may be identified based on local genomic sequencing but must be screened for the FGF/FGFR
alteration through the sponsor’s central laboratory; if positive, the subject will then undergo screening to meet the rest
of the inclusion/exclusion criteria. Once a subject has completed screening and has enrolled into the study, treatment
will start on Day 1.
Subjects will receive INCB054828 at a once-daily, starting dose of 13.5 mg on a 2-weeks-on-therapy and 1-week-offtherapy
schedule. Subjects will be eligible if they have a known FGF/FGFR alteration and have either 1) failed at least
1 previous treatment for their metastatic or surgically unresectable urothelial carcinoma (ie, chemotherapy,
immunotherapy) or 2) are platinum ineligible. Subjects may have undergone cystectomy(surgical removal of all or part
of the bladder).
Subjects will undergo regular safety assessments during treatment as well as regular efficacy assessments.
Subjects will be allowed to continue receiving study drug in 21-day cycles until documented disease progression or
unacceptable toxicity is reported.

Inclusion criteria:
1.Men and women, aged 18 or older.
2.Histologically documented metastatic or surgically unresectable urothelial carcinoma (Stage IIIB or IV per the
American Joint Committee on Cancer (AJCC 2010); may include primary site from ureters, upper tract, renal pelvis,
and bladder.
3.Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
4.Life expectancy ≥ 12 weeks.
5.Radiographically measurable or evaluable disease per RECIST v1.1.
6.Known FGF/FGFR alteration from the sponsor’s central laboratory and have either
a) have failed at least 1 previous treatment for their metastatic or surgically unresectable urothelial carcinoma (ie,
chemotherapy, immunotherapy) or b)have not received chemotherapy for metastatic or surgically unresectable
urothelial carcinoma due to poor performance status (ECOG performance status of 2) and insufficient renal function
(creatinine clearance Exclusion criteria:
1.Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications
within 21 days or 5 half-lives (whichever is longer) before first dose of study drug. Subjects must have recovered
(Grade ≤ 1 or at pre-treatment baseline) from AEs from previously administered therapies.
2.Untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed (eg,
evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases).
Subjects with previously treated and clinically stable brain/CNS metastases and who are off all corticosteroids for ≥ 4
weeks are eligible.
3.Known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the
cervix, or other non-invasive or indolent malignancy that has undergone potentially curative therapy.
4.Are pregnant or lactating.
5.Prior receipt of a selective FGFR inhibitor.
6.Abnormal laboratory parameters:
a.Total bilirubin ≥ 1.5 × upper limit of normal (ULN; ≥ 2.5 × ULN if Gilbert syndrome or metastatic disease involving liver).
b. AST and ALT > 2.5 × ULN (AST and ALT > 5 × ULN in the presence of liver metastases).
c.Creatinine clearance ≤ 30 mL/min based on Cockroft-Gault. d. Serum phosphate > institutional ULN.
e.Serum calcium outside of the institutional normal range or serum albumin-corrected calcium outside of the
institutional normal range when serum albumin is outside of the institutional normal range.
7.History of calcium/phosphate homeostasis disorder.
8.History of human immunodeficiency virus infection.
9.Evidence of hepatitis B virus or hepatitis C virus active infection or risk of reactivation.
10.History or presence of an abnormal ECG that in the investigator’s opinion is clinically meaningful. A screening QTcF
interval > 450 milliseconds is excluded.
11.History of clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial
infarction, New York Heart Association Class III or IV congestive heart failure, or arrhythmia requiring therapy. Subjects
with a pacemaker and well-controlled rhythm for at least 1 month before first dose will be allowed.
12.Have undergone major surgical procedure other than for diagnosis within 28 days before Cycle 1 Day 1.
13.Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
14.Pregnant or nursing women or subjects expecting to conceive or father children within the projected duration of the
study, starting with the screening visit through completion of safety follow-up visit.
15.Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy,
hormonal therapy, investigational therapy, or tumour embolization).
16.Received prior radiation therapy administered within 4 weeks of first dose of study drug. Subjects must have
recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A
2-week washout is permitted for palliative radiation to non-CNS disease.
17.History and/or current evidence of ectopic mineralisation/calcification, including but not limited to soft tissue,
kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon
calcification.
18.Current evidence of corneal disorder/keratopathy, including but not limited to bullous/band keratopathy, corneal
abrasion, inflammation/ulceration, keratoconjuctivitis, etc, confirmed by ophthalmologic examination.
19.Current use of prohibited medication as described in Section 5.6.2.
20.Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is shorter) before the first
dose of study drug.
21.Known hypersensitivity or severe reaction to INCB054828 or excipients of INCB054828 study drug (refer to the IB).
22.Inability or unlikeliness to comply with the dose schedule and study evaluations, in the opinion of the investigator.
23.Inability to comprehend or unwilling to sign the informed consent form (ICF).
24.Inability or unwillingness to swallow INCB054828 or significant gastrointestinal disorder(s) that could interfere with
the absorption, metabolism, or excretion of INCB054828.
25.Subjects who require haemodialysis.
26.Any condition that would, in the investigator’s judgment, interfere with full participation in the study, including
administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with
interpretation of study data.
27. Subjects with history of hypovitaminosis D requiring supraphysiologic doses to replenish the deficiency. Subjects
receiving vitamin D food supplements are allowed.

Principal Investigator for this trial: Dr Santhanam Sundar

Research Ethics Committee Reference: 16/EM/0465

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ATLANTIS: An adaptive multi-arm phase II trial of maintenance targeted therapy after chemotherapy in metastatic urothelial cancer

Summary:
Metastatic urothelial cancer (MUC), including bladder and upper urinary tract cancers, is the eighth most common
cause of cancer death in the UK. The standard treatment for MUC is chemotherapy, given for a defined period of time
(often 2-4 months), to control the tumour and maintain a good quality of life for as long as possible. After completion
of chemotherapy, the cancer would start to grow again and may spread to other parts of the body, often referred to as
‘relapse’ of the cancer. The outcome once relapse has occurred is very poor, with average life expectancy around 8
months.
Patients will have trial treatment selected based on the presence or not of particular molecules (biological
markers/biomarkers) in their cancer tissue. Depending on which ‘biomarkers’ are present within the cancer, the
patient will be matched to a drug subgroup in the main trial. Patients will be randomly allocated to the trial treatment or
placebo (non-active tablet). ATLANTIS will investigate whether treatment matched to the biomarker given after initial
chemotherapy delays the time to the cancer growing in patients with MUC.
The target population includes patients with cancer affecting the bladder, including upper urinary tract which has
spread elsewhere (metastatic) and is usually treated with chemotherapy. Patients in the study must have had
chemotherapy (between 4-8 cycles) and their cancer should have responded or not worsened during this period. The
testing for tumour biomarkers will be done on tissue removed at the time of the original cancer diagnosis.
Patients will continue to receive trial treatment until their cancer worsens, they have significant side effects, are
recommended to start further anti-cancer therapy, patient withdraws consent or if it is no longer in the best interests of
the patient to continue with the trial treatment. Patients will be followed up for information on further anti-cancer
treatments they receive after stopping trial therapy as well as information about how long patients survive after the trial.

Inclusion criteria:
Inclusion criteria for ATLANTIS are as follows:
1 – Previously diagnosed stage IV urothelial cancer (UC) (T4b, Nany, Many; Tany, N1-3, M0; Tany, Nany, M1).
Histologically confirmed urothelial cancer. This includes cancers of the urinary bladder, ureter, renal pelvis or urethra
with transitional and/or squamous histology. A component of either or both of these histologies is adequate for entry.
2 – Able to commence the trial treatment within 10 weeks of completing chemotherapy.
3 – Adequate tissue for biomarker testing. Testing will occur centrally.
4 – Patients must have received between 4 and 8 cycles of first line chemotherapy for Metastatic/advanced UC to be
eligible. Previous adjuvant or neoadjuvant chemotherapy does not count as a line of therapy.
5 – Adequate organ function as defined in drug specific appendices.
6 – ECOG performance status 0-2.
7 – Age ≥ 16 years.
8 -Female patients of childbearing potential must agree to comply with effective contraceptive measures, have been
using adequate contraception since the last menses, will use adequate contraception during the trial, and have a
negative pregnancy test within one week of trial entry.
9 -Male patients with partners of child-bearing potential must agree to take measures not to father children by using
one form of highly effective contraception, effective at the first administration of IMP and throughout the trial.
10 – Written informed consent prior to admission to this trial.
11 -Meets all inclusion criteria for the relevant component subgroup listed in the appendices for each specific IMP.

Exclusion criteria:
Exclusion creiteria for ATLANTIS are as follows:
1 – Progression during first-line chemotherapy for metastatic disease. This should be based on a radiological
comparison between the pre-chemotherapy CT and end of treatment CT (local review). Patients may be permitted to
enter the trial if their end of chemotherapy scans shows response or stable disease (local assessment using RECIST
1.1) when compared to their latest pre-chemotherapy scan, even if there is progression when compared to a nadir
scan performed during chemotherapy. These patients should be discussed with the trial team.
2 – Do not currently require second line chemotherapy in the opinion of the investigator.
3 – More than one line of chemotherapy for metastatic or locally advanced disease (where the regimen is changed
during first-line treatment without evidence of progression (for example the patient changes from cisplatin to
carboplatin due to toxicity) this will constitute a single line of chemotherapy). Prior adjuvant / neoadjuvant
chemotherapy is permitted in addition.
4 – Patients receiving radical/curative surgery or radiotherapy at the end of first line treatment (palliative radiotherapy is
allowed).
5 – Patients receiving less than 4 or more than 8 cycles of chemotherapy before randomisation and initiation of trial
intervention (excluding any chemotherapy given as neo-adjuvant / adjuvant).
6 – Treatment with any other investigational agent within 28 days prior to first dose of trial medication within ATLANTIS
7 – Less than 3 or more than 10 weeks since the last infusion of first-line chemotherapy for advanced/metastatic UC at
time of initiation of trial interventions.
8 – History of another malignancy in the last 2 years (other than treated squamous/basal cell skin cancer, treated early
stage cervical cancer or treated / biochemically stable, organ confined prostate cancer not requiring on-going
androgen deprivation therapy).
9 – Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or
interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder).
10 – Positive pregnancy test for females.
11 – Inadequate organ function as defined in drug specific appendices.
12 – Ongoing therapy with prohibited medication which cannot be discontinued prior to starting trial specific
intervention (as defined in drug specific appendices). 13 – Major surgery or any radiotherapy within 4 weeks prior to
trial entry (palliative radiotherapy within >2 weeks is permitted).
14 – Significant comorbidity or serious intercurrent medical or psychiatric illness, including serious active infection
which, in the opinion of the investigator would make it inappropriate for the patient to enter the trial.
15 – Women who are breast feeding.
16 – Meets any of the exclusion criteria listed in the relevant component subgroup specific appendix.

Principal Investigator for this trial: Dr Santhanam Sundar

Research Ethics Committee Reference: 16/WS/0197

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Efficacy and Safety Assessment of T1580 versus Vehicle in Dry Eye Disease Treatment

Summary:
This study will involved menopausal patients with moderate to severe keratitis caused by dry eye disease (DED) which
has not improved despite treatment with tear substitutes.
This study will include around 450 patients in several countries (in Europe and outside Europe) in multiple sites. The
purpose of this study is to evaluate the efficacy of T1580 versus a vehicle for the treatment of moderate to severe
keratitis caused by dry eye disease. The vehicle corresponds to a placebo, which is the same eye drop as T1580, but
without ciclosporin. The study is designed to also evaluate the safety of T1580.
The study duration will be 1 year: in the first 6-month period, the patient will receive either T1580 or vehicle with 2
parallel groups followed by a 6-month treatment period during which all patients will receive T1580

Inclusion criteria:
– Informed consent signed and dated
– Menopausal woman
– Patient with BILATERAL persistent DED having required continuous tear substitute for the last 2 years at Screening
visit.
– Patient with at least ONE eye with:
a. Schirmer test without anaesthesia scored ≥ 2 mm/5 min, and 32 dots AND corresponding to a grade 3 or a grade 4
on the Oxford scale at Baseline visit (please, refer to Oxford scale).
– Patient with Ocular Surface Disease Index (OSDI) ≥ 23 (i.e., at least moderate symptomatology of DED) at Baseline
visit.

Exclusion criteria:
– Presence of an active condition :
a. Ocular rosacea, uveitis,
b. Abnormal eye lid anatomy, blinking, or naso-lachrymal drainage system,
c. Ocular hypertension or glaucoma requiring an ophthalmic medicinal product,
d. Infectious conjunctivitis, severe blepharitis, and/or progressive pterygium.
– Major corneal hypoaesthesia value ≤ 20 mm as measured with a Cochet-Bonnet aesthesiometer.
– Far best corrected visual acuity (BCVA) worse than or equal to + 0.7 LogMar.
– Any history of, or active, relevant ocular disorder condition other than those listed above which is likely to interfere with
the study results as judged by the investigator at Screening or Baseline visits. Any ophthalmic disease likely to change
the assessment of fluctuating blurred vision linked to dry eye disease or may result in a visual acuity deterioration in
the following year.

Principal Investigator for this trial: Professor Harminder S Dua

Research Ethics Committee Reference: 16/LO/1458

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High Or Low Dose Syntocinon® for delay in labour: the HOLDS trial

Summary:
About a third of women become delayed in their first labours and are given a drug (oxytocin) widely used in maternity
care in the belief that it increases the number of spontaneous vaginal births(SVB). Currently about 40% of these
women will have a SVB, 40% will have an instrumental birth and 20% a caesarean section(CS). The latter two are
associated with more health related problems and health service costs.
The NICE Intrapartum Care Guideline challenged the use of standard dose regimen of oxytocin by finding it was
associated with shorter labour but no change in the mode of birth. The recent Cochrane systematic review suggested
that high dose regimen of oxytocin decreases the numbers of women having a CS but not enough is known about the
effect on the baby and on women’s birth experience for it to be recommended.
We have designed a randomised controlled trial to compare standard and high dose regimens of oxytocin for women
with confirmed delay in the first stage of labour. This application is for a definitive trial, following on from a pilot study
undertaken in 2009/10.
Our proposed trial will randomise 1500 women across approximately 30 maternity units to standard or high dose
regimens of oxytocin, and measure differences in rates of CS, as well as collecting information about the birth and
safety of mother and baby.
This trial will provide best evidence to answer this important clinical question. If effective this relatively inexpensive
intervention has potential to reduce resource and health implications associated with CSs.

Inclusion criteria:
Inclusion criteria – eligible women will include:
– nulliparous women who are able and willing to give informed consent
– singleton pregnancy of 37-42 weeks gestation
– confirmed delay in labour (using NICE intrapartum care guideline)
– ruptured membranes
– decision to prescribe syntocinon for augmentation of labour

Exclusion criteria:
• Multiparous women
• Nulliparpous women undergoing induction of labour
• Nulliparpous women with a BMI >40 at booking
• Nulliparpous women who have a multiple pregnancy
• Nulliparpous women who have existing cardiac disease, bleeding disorders, diabetes (either pre-existing or
gestational), scarred uterusprevious uterine surgery,
• Nulliparpous women with significant antepartum haemorrhage
• Women are under 16 years of age
• Women who have a known contra-indication to oxytocin therapy as listed in the Summary of marketing Product
Characteristics (SmPC)

Principal Investigator for this trial: Dr George Bugg

Research Ethics Committee Reference: 16/WM/0014

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Stroke: an evaluation of Thrombectomy in the Ageing Brain – [including] where IV thromboLysis IS contraindicated

Summary:
Most strokes are caused by a clot blocking a blood vessel in the brain. These can often be treated with a “clotbusting” (“thrombolytic”) drug. A “clotbusting”
drug is less likely to open the blocked blood vessel if the clot is larger.
Some people have medical conditions that mean it is not safe to give them a clot busting drug.
Medical devices that can remove clots (clot pullers or retrievers) may be used as an additional treatment to
thrombolysis or instead of no active treatment where thrombolysis cannot safely be given called
thrombectomy. Such
devices are more likely to open up the blocked blood vessel, but are more complicated to use. There is no evidence
they have any more risk than thrombolytic drugs.
We are doing a study to investigate whether treatment using a purpose designed new clotretrieval
device is at least as
safe and effective in unblocking the occluded blood vessel after an acute stroke as existing devices. The new device
has design features that may be particularly useful in elderly patients.
We will investigate whether additional brain imaging would be helpful in acute stroke patients treated with clot pullers
by:
1) examining whether analysis of blood vessels on the scans taken before treatment starts can predict who will or will
not do well, and see if there is any link to age.
2) detailed MRI brain scan 24h after treatment to see if scan findings at that stage can predict long term outcome,
identify complications not appreciated on routine CT and see whether these are linked to patient age.

Inclusion criteria:
• Clinical diagnosis of acute ischaemic stroke
• Male or nonpregnant
female ≥50 years of age
• Clinically significant neurological deficit and NIHSS score 10 or greater.
• Enrolment, randomisation and procedure commencement (groin puncture) possible within 90 minutes of the
imaging (CT/CTA) confirmed diagnosis of LVO (AND maximum 5h after stroke onset anterior circulation, 8.5h for
posterior circulation).
• Occlusion of the MCA trunk, MCA bifurcation or intracranial internal carotid artery (including carotidT),
M1 or ≤2
proximal M2 branches; intracranial vertebral/basilar/P1 PCA demonstrated on CTA, MRA, or DSA.
• Interventional device delivery (guide catheter placed in target artery beyond aortic arch and angio obtained) can be
achieved within 6 hours of onset of the stroke (9h for posterior circulation occlusions).
• Consent of patient or assent of appropriate representative.
• Independent prior to the stroke (estimated mRS 02).
• Expected to be able to be followed up at 12 months.

Exclusion criteria:
• CT evidence of ICH, or evidence of extensive established hypodensity on CT(defined as >1/3 MCA territory or
ASPECTS score ≤7). In posterior circulation strokes pcASPECTS
1/3 of territory.
• Clinical history suggestive of subarachnoid haemorrhage even if CT normal.
• Eligible for an academic “treatment policy” (i.e. phase III trial) RCT of stroke thrombectomy in that institution & willing
to be randomised into such
• Vascular access contraindications e.g. bilateral femoral bypass surgery, tight ipsilateral carotid or vertebral stenosis
(if judged not readily amenable to acute intervention by Interventional Neuroradiologist [INR]who would carry out the
procedure), unsuitable proximal vascular anatomy likely to render endovascular catheterisation difficult, unsafe or
impossible (as judged by INR who would carry out the procedure).
• Extracranial: chronic/atherosclerotic ipsilateral ICA or dominant vertebral artery occlusion
• Alternative intracranial pathology potentially responsible for the new symptoms
• Medical comorbidities
which would preclude safe cerebral vessel catheterisation or which are expected to limit life
expectancy to Principal Investigator for this trial: Dr Ganesh Subramanian

Research Ethics Committee Reference: 14/NE/0113

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Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure with Reduced Ejection Fraction

Summary:
Heart failure affects approximately 38 million people worldwide and continues to be a major cause of death,
hospitalisation, and poor quality of life. Dapagliflozin reduces glucose reabsorption from the kidney back into the
bloodstream, resulting in less glucose circulating in the blood, which has been shown to lead to a reduction in body
weight and blood pressure, which are known risk factors for the progression of heart failure. It is thought that
dapagloflozin therefore provides protection for the heart.
AstraZeneca are evaluating the effect of dapagliflozin in this event-driven study, lasting approximately 33 months, to
see whether type II diabetic and non-diabetic patients with an established diagnosis of chronic heart failure, and at
high risk of cardiovascular death or heart failure events, have a reduction in the worsening of their condition during the
study. We will also be looking at the safety and tolerability of dapagliflozin. Patients will be automatically assigned to
either the dapagliflozin tablets or placebo (sugar) tablets at the start of the study and the treatment each patient
receives will not be known to AstraZeneca or their doctor. After providing written consent, study patients will have their
medical history reviewed, have an ECG, blood tests and vital signs taken, complete quality of life questionnaires and
have physical examinations performed to check on their overall health and wellbeing. Following enrolment into the
study, visits will be completed at 14 days, 60 days, 120 days, 240 days, 360 days and then every 4 months thereafter
until the study closes.

Inclusion criteria:
1. Provision of signed informed consent prior to any study specific procedures
2. Male or female, aged ≥18 years at the time of consent
3. Established documented diagnosis of symptomatic HFrEF (NYHA functional class
II-IV), which has been present for at least 2 months and is optimally treated with
pharmacological and/or device therapy, as indicated
NB: Patients in which additional pharmacological or device therapy is contemplated, or should be considered, must
not be enrolled until therapy has been optimized and is stable for ≥1 month.
4. LVEF≤40% (echocardiogram, radionuclide ventriculogram, contrast angiography or
cardiac MRI ) within the last 12 months prior to enrolment (Visit 1. If there is more than one assessment of LVEF the
value from the most recent measurement should be used in assessing eligibility. Patients undergoing coronary
revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)), valve
repair/replacement or implantation of a cardiac resynchronization therapy device (CRT) or any other surgical, device or
pharmacological intervention (eg initiation of a beta-blocker) that might improve LVEF must have a measurement of
LVEF at least 3 months after the intervention in order to be eligible. NB: Patients with known HFrEF but without a recent
(≤12 months) assessment of LV function will undergo a local echocardiogram at the time of enrolment.
5. NT-proBNP >600 pg/ml (or if hospitalized for heart failure within the previous 12
months, NT-proBNP ≥400 pg/ml) at enrolment (visit 1). If concomitant atrial fibrillation at Visit 1, NT-proBNP must be
≥900 pg/ml (irrespective of history of heart failure hospitalization)
6. Patients should receive background standard of care for HFrEF and be treated
according to locally recognized guidelines with both drugs and devices, as appropriate. Guideline-recommended
medications should be used at recommended doses unless contraindicated or not tolerated. Therapy should have
been individually optimized and stable for ≥4 weeks (this does not apply to diuretics – see NB below) before visit 1 and
include (unless contraindicated or not tolerated):
an ACE inhibitor, or ARB or sacubitril/valsartan
and
a beta-blocker
and
if considered appropriate by the patient’s treating physician; a mineralcorticoid
receptor antagonist (MRA)
NB: Most patients with heart failure require treatment with a diuretic to control
sodium and water retention leading to volume overload. It is recognized that
diuretic dosing may be titrated to symptoms, signs, weight and other information
and may thus vary. Each patient should, however, be treated with a diuretic regimen aimed at achieving optimal
fluid/volume status for that individual.
7. eGFR ≥30 ml/min/1.73 m2 (CKD-EPI formula) at enrolment (visit 1)

Exclusion criteria:
1. Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or
previous intolerance of an SGLT2 inhibitor
2. Type 1 diabetes mellitus (T1D)
3. Symptomatic hypotension or systolic BP 3x the upper limit of normal [ULN]; or total bilirubin >2x ULN at time of enrolment)
14. Known blood-borne diseases such as specified in Appendix B (category A and B)
15. Severe (eGFR Principal Investigator for this trial: Dr John Walsh

Research Ethics Committee Reference: 17/WS/0069

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A case-control study to investigate whether occupational asbestos exposure is an under-recognized cause of idiopathic pulmonary fi-brosis (IPF) using an interview to measure previous asbestos exposure and a blood test to investigate genetic susceptibility

Summary:
Idiopathic pulmonary fibrosis (IPF) is a scarring lung disease. It damages the air sacs that allow oxygen to be
transferred into the blood and transported to vital organs. These changes make people with IPF cough and feel short
of breath. We don’t know what causes the damage. People who get IPF are usually older than 40; it’s a very serious
illness that cannot be cured and gets worse over time. Statistics show that IPF is becoming more common in the UK
but it’s not known why. It can be difficult for doctors to tell if someone has IPF or another disease called asbestosis.
Asbestosis is like IPF but different because we know that breathing in asbestos dust has caused the lung damage.
Our study will help to find out how much IPF is due to breathing in asbestos at work. This will help us to understand
IPF, make sure people get the right treatment and compensation they are entitled to, and make sure that the rules
about asbestos dust at work are right so that we protect workers and prevent disease in the future.
We will recruit men with new diagnoses of IPF (cases) from several hospitals across England and Wales. For
purposes of comparison a group of men of the same age attending the same hospitals at about the same time for
other conditions (controls) will be recruited, in a ratio of 1:1; the total number of participants will be 920. Participants
will complete a telephone interview and will be invited to provide a blood sample to investigate how genetics and
asbestos exposure interact in IPF.

Inclusion criteria:
Cases:
Male
New diagnosis of IPF between February 2017 and October 2019
Controls:
Male
New outpatient department attendee between February 2016 and October 2019

Exclusion criteria:
Cases:
Unable to give informed consent
Ever worked outside of the UK
Controls:
Unable to give informed consent
Ever worked outside of the UK
Diagnosis of IPF

Principal Investigator for this trial: Dr Gauri Saini

Research Ethics Committee Reference: 17/EM/0021

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A case-control study to investigate whether occupational asbestos exposure is an under-recognized cause of idiopathic pulmonary fi-brosis (IPF) using an interview to measure previous asbestos exposure and a blood test to investigate genetic susceptibility

Summary:
Idiopathic pulmonary fibrosis (IPF) is a scarring lung disease. It damages the air sacs that allow oxygen to be
transferred into the blood and transported to vital organs. These changes make people with IPF cough and feel short
of breath. We don’t know what causes the damage. People who get IPF are usually older than 40; it’s a very serious
illness that cannot be cured and gets worse over time. Statistics show that IPF is becoming more common in the UK
but it’s not known why. It can be difficult for doctors to tell if someone has IPF or another disease called asbestosis.
Asbestosis is like IPF but different because we know that breathing in asbestos dust has caused the lung damage.
Our study will help to find out how much IPF is due to breathing in asbestos at work. This will help us to understand
IPF, make sure people get the right treatment and compensation they are entitled to, and make sure that the rules
about asbestos dust at work are right so that we protect workers and prevent disease in the future.
We will recruit men with new diagnoses of IPF (cases) from several hospitals across England and Wales. For
purposes of comparison a group of men of the same age attending the same hospitals at about the same time for
other conditions (controls) will be recruited, in a ratio of 1:1; the total number of participants will be 920. Participants
will complete a telephone interview and will be invited to provide a blood sample to investigate how genetics and
asbestos exposure interact in IPF.

Inclusion criteria:
Cases:
Male
New diagnosis of IPF between February 2017 and October 2019
Controls:
Male
New outpatient department attendee between February 2016 and October 2019

Exclusion criteria:
Cases:
Unable to give informed consent
Ever worked outside of the UK
Controls:
Unable to give informed consent
Ever worked outside of the UK
Diagnosis of IPF

Principal Investigator for this trial: Dr Gauri Saini

Research Ethics Committee Reference: 17/EM/0021

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Clinical Trials currently recruiting at Nottingham University Hospitals NHS Trust 2017-06-08 01:00:00

Summary:
Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), affecting over 5 million
people worldwide, and in the UK is estimated to account for 26% of legal blindness. The incidence of GA increases
exponentially with age and there is currently no treatment.
The disease impact on the patient, caregiver and society due to GA is not being well understood. The purpose of this
observational study is to assess the clinical details and health-related quality of life of patients with GA compared to
patients without GA.
This study also aims to describe the healthcare costs associated with GA and collect data from caregivers of patients
with GA in order to understand the effect on the caregiver’s life due to caring for a patient with this condition.
Patients with and without GA meeting the study criteria for eligibility will be invited to participate in the study by the
treating physician or research nurse. Information on the study will be provided to the patient.
If patients consent to participate, the physician or a member of the research team will collect data regarding their
medical history and other relevant data onto an electronic case report form (eCRF). Patients will be invited to complete
questionnaires providing information on patient-reported outcomes (PRO) at time of the visit. In addition, if the GA
patient has a caregiver, the caregiver will be invited to complete questionnaires providing information on caregiverreported
outcomes following informed consent.
The study is expected to last approximately 12 months from when the first patient provides informed consent (i.e.
signs the consent form).

Inclusion criteria:
GA patients:
– Bilateral symptomatic GA patients (physician confirmed).
– Aged 70 years and older at study inclusion.
– Provision of informed consent allowing contribution of patient data into the study.
Non-GA controls:
– Patients with no ophthalmic condition that in the opinion of the investigator affects visual function. Example
conditions that may be included in the study include, but are not limited to, the following: early/intermediate AMD, dry
eye, choroidal nevus, epiretinal membrane, a history of cataract surgery, etc.
– Age 70 and older at study inclusion.
– Provision of informed consent allowing contribution of patient data into the study.
Caregivers of GA patients:
– Anyone, paid or unpaid, who provides assistance to the enrolled GA patient in terms of daily activities.
– Aged 18 years and older at study inclusion.

Exclusion criteria:
GA patients:
– Participated in an interventional study during 12 months prior (i.e. ≤12 months) to study inclusion date.
– Participated in the Genentech Mahalo study (Study number CFD4870g).
– Participating in the Roche Chroma/Spectri (Study numbers GX29176 and GX29185, respectively) or Proxima A/B
studies (Study numbers GX29633 and GX29639).
– History of choroidal neovascularisation (CNV), diabetic macular edema (DME) and/or retinal vein occlusion (RVO).
– Decreased cognitive function such that the patient would be unable to understand an interview at time of visit (in the
opinion of physician/research nurse).
Non-GA controls:
– Participated in an interventional study during 12 months prior (i.e. ≤12 months) to study inclusion date.
– History of GA, CNV, DME and/or RVO.
– Decreased cognitive function such that the patient would be unable to understand an interview at time of visit (in the
opinion of physician/research nurse).
Caregivers of GA patients:
– Anyone who just accompanies the enrolled GA patient to a visit without providing assistance to the enrolled GA
patient in terms of daily activities.

Principal Investigator for this trial: Mr Winfried M Amoaku

Research Ethics Committee Reference: 16/NI/0260

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A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Sofosbuvir/Velpatasvir for 12 Weeks in Subjects with Chronic HCV Infection Who are on Dialysis for End Stage Renal Disease

Summary:
This study is a Phase 2, open label multicentre study evaluating the efficacy and safety of treatment of Epclusa®
(sofosbuvir 400mg/velpatasvir 100mg) a fixed-dosed combination tablet, in patients with chronic HCV infection who
are on dialysis for end stage renal disease (ESRD).
Hepatitis C is a disease caused by a virus (known as HCV) which has infected the liver. A virus is a very small
organism that invades healthy cells and forces them to make copies of the virus. The body tries to fight the virus, but it
can resist the body’s defenses. Some people can clear the virus on their own, but in others the virus cannot be
cleared. Those people have chronic or long-term HCV infections. Curing HCV infection is associated with numerous
health benefits including more than 70% and 90% reductions in the risk of liver cancer and liver-related mortality
respectively.
Epclusa® is already approved in the US, EU and other regions for the treatments of chronic HCV infections, but there
is no dosing recommendation for those with severe renal impairment such as ESRD. The unmet medical need
provides a strong rationale for this study as the data obtained will address gaps in knowledge.
The purpose of this study is therefore to assess the safety and efficacy of Epclusa® given once daily for 12 weeks in
participants with chronic HCV infection who are on dialysis for EDSR. The study aims to enroll approximately 100 male
and female participants over the age of 18 at approximately 35 sites in Australia, Canada, New Zealand, Spain, Israel
and the United Kingdom. Participants will be enrolled for around 9 months with at least 9 clinic visits falling during and
after the treatment periods. Participants will also have the option to partake in future pharmacokinetic and genomic
research related to chromic HCV infection.

Inclusion criteria:
1) Willing and able to provide written informed consent
2) Male or female age ≥ 18 years
3) Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ LLOQ at screening
5) End stage renal disease (ESRD) requiring peritoneal dialysis (PD) or haemodialysis (HD)
6) The most recent HCV treatment must have been completed at least 8 weeks prior to screening
7) Participants must have a determination of treatment experience (treatment naïve vs. treatment experienced).
Treatment naïve is defined as having never been exposed to an approved or experimental HCV-specific direct acting
antiviral agents or prior treatment of HCV with interferon or ribavirin. All other patients will be considered treatment
experienced.
8) Participants must have appropriate testing for determination of cirrhosis status.
a) Presence of cirrhosis is defined as any one of the following:
i) Fibroscan with a result of > 12.5 kPa
ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥ 5)
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score ≥0.75 at screening
b) Absence of cirrhosis is defined as any one of the following:
i) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day 1
ii) Liver biopsy performed within 2 years of Screening showing absence of cirrhosis
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score 100 cells/mm3 prior to Screening.
Participants with an isolated or unconfirmed HIV RNA >50 copies/mL (or >LLOQ if the local laboratory assay’s LLOQ is
50≥ copies/mL) are not excluded
ii) On a stable ARV regimen for ≥ 8 weeks prior to Screening and is expected to continue the current ARV regimen
through the end of study (See exclusion criteria 7).
11) A negative serum pregnancy test is required for female Participants (unless permanently sterile or greater than two
years post-menopausal).
12) Male participants and female participants of childbearing potential who engage in heterosexual intercourse must
agree to use protocol specified method(s) of contraception as described in Appendix 4.
13) Lactating females must agree to discontinue nursing before the study drug is administered.
14) Participants must be able to comply with the dosing instructions

Exclusion criteria:
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV, HIV, and kidney disease or co-morbidities associated with ESRD
except as noted below) any other major medical disorder that may interfere with subject treatment, assessment or
compliance with the protocol; subjects currently under evaluation for a potentially clinically significant illness (other
than HCV or ESRD) are also excluded.
b) Current or prior history of significant cardiac disease including or resulting in:
– Hospital admission for significant cardiovascular disease (myocardial infarction, unstable angina, heart failure,
hypertensive emergency) or has had a cardiovascular procedure (e.g CABG or PTCA), within 6 months of Screening
– Cardiomyopathy with ejection fraction 10 X the upper limit of normal (ULN)
b) AST > 10 X ULN
c) Direct bilirubin > 1.5 X ULN. For subjects receiving ritonavir boosted atazanavir regimen, a direct bilirubin > 1.5 x
ULN will be allowed if 9%
f) Hemoglobin 1.5 x ULN unless subject has known haemophilia or is stable on an anticoagulant regimen affecting INR
i) Hepatitis B surface antigen positive
9) Prior exposure to any HCV NS5A inhibitor.
10) Male with pregnant female partner.
11) Females who may wish to become pregnant and/or plan to undergo egg harvesting during the course of the study
and up to 30 days of the last dose of study drug
12) Males who may wish to donate sperm during the course of the study until at least 30 days after the last dose of
study drug
13) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug screen will exclude
subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by
the investigator.
14) Use of any prohibited concomitant medications as described in Section 5.4.
15) Subjects with HIV-1 coinfection cannot be receiving an ARV regimen containing efavirenz (EFV)
16) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent > 10 mg/day).
17) Known hypersensitivity to the VEL, SOF, the metabolites, or formulation excipient.
18) For participants with HIV-1 co-infection only:
– HIV-1 RNA >50 copies/mL
– CD4 T-cell count Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 17/LO/0089

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A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Sofosbuvir/Velpatasvir for 12 Weeks in Subjects with Chronic HCV Infection Who are on Dialysis for End Stage Renal Disease

Summary:
This study is a Phase 2, open label multicentre study evaluating the efficacy and safety of treatment of Epclusa®
(sofosbuvir 400mg/velpatasvir 100mg) a fixed-dosed combination tablet, in patients with chronic HCV infection who
are on dialysis for end stage renal disease (ESRD).
Hepatitis C is a disease caused by a virus (known as HCV) which has infected the liver. A virus is a very small
organism that invades healthy cells and forces them to make copies of the virus. The body tries to fight the virus, but it
can resist the body’s defenses. Some people can clear the virus on their own, but in others the virus cannot be
cleared. Those people have chronic or long-term HCV infections. Curing HCV infection is associated with numerous
health benefits including more than 70% and 90% reductions in the risk of liver cancer and liver-related mortality
respectively.
Epclusa® is already approved in the US, EU and other regions for the treatments of chronic HCV infections, but there
is no dosing recommendation for those with severe renal impairment such as ESRD. The unmet medical need
provides a strong rationale for this study as the data obtained will address gaps in knowledge.
The purpose of this study is therefore to assess the safety and efficacy of Epclusa® given once daily for 12 weeks in
participants with chronic HCV infection who are on dialysis for EDSR. The study aims to enroll approximately 100 male
and female participants over the age of 18 at approximately 35 sites in Australia, Canada, New Zealand, Spain, Israel
and the United Kingdom. Participants will be enrolled for around 9 months with at least 9 clinic visits falling during and
after the treatment periods. Participants will also have the option to partake in future pharmacokinetic and genomic
research related to chromic HCV infection.

Inclusion criteria:
1) Willing and able to provide written informed consent
2) Male or female age ≥ 18 years
3) Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ LLOQ at screening
5) End stage renal disease (ESRD) requiring peritoneal dialysis (PD) or haemodialysis (HD)
6) The most recent HCV treatment must have been completed at least 8 weeks prior to screening
7) Participants must have a determination of treatment experience (treatment naïve vs. treatment experienced).
Treatment naïve is defined as having never been exposed to an approved or experimental HCV-specific direct acting
antiviral agents or prior treatment of HCV with interferon or ribavirin. All other patients will be considered treatment
experienced.
8) Participants must have appropriate testing for determination of cirrhosis status.
a) Presence of cirrhosis is defined as any one of the following:
i) Fibroscan with a result of > 12.5 kPa
ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥ 5)
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score ≥0.75 at screening
b) Absence of cirrhosis is defined as any one of the following:
i) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day 1
ii) Liver biopsy performed within 2 years of Screening showing absence of cirrhosis
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score 100 cells/mm3 prior to Screening.
Participants with an isolated or unconfirmed HIV RNA >50 copies/mL (or >LLOQ if the local laboratory assay’s LLOQ is
50≥ copies/mL) are not excluded
ii) On a stable ARV regimen for ≥ 8 weeks prior to Screening and is expected to continue the current ARV regimen
through the end of study (See exclusion criteria 7).
11) A negative serum pregnancy test is required for female Participants (unless permanently sterile or greater than two
years post-menopausal).
12) Male participants and female participants of childbearing potential who engage in heterosexual intercourse must
agree to use protocol specified method(s) of contraception as described in Appendix 4.
13) Lactating females must agree to discontinue nursing before the study drug is administered.
14) Participants must be able to comply with the dosing instructions

Exclusion criteria:
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV, HIV, and kidney disease or co-morbidities associated with ESRD
except as noted below) any other major medical disorder that may interfere with subject treatment, assessment or
compliance with the protocol; subjects currently under evaluation for a potentially clinically significant illness (other
than HCV or ESRD) are also excluded.
b) Current or prior history of significant cardiac disease including or resulting in:
– Hospital admission for significant cardiovascular disease (myocardial infarction, unstable angina, heart failure,
hypertensive emergency) or has had a cardiovascular procedure (e.g CABG or PTCA), within 6 months of Screening
– Cardiomyopathy with ejection fraction 10 X the upper limit of normal (ULN)
b) AST > 10 X ULN
c) Direct bilirubin > 1.5 X ULN. For subjects receiving ritonavir boosted atazanavir regimen, a direct bilirubin > 1.5 x
ULN will be allowed if 9%
f) Hemoglobin 1.5 x ULN unless subject has known haemophilia or is stable on an anticoagulant regimen affecting INR
i) Hepatitis B surface antigen positive
9) Prior exposure to any HCV NS5A inhibitor.
10) Male with pregnant female partner.
11) Females who may wish to become pregnant and/or plan to undergo egg harvesting during the course of the study
and up to 30 days of the last dose of study drug
12) Males who may wish to donate sperm during the course of the study until at least 30 days after the last dose of
study drug
13) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug screen will exclude
subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by
the investigator.
14) Use of any prohibited concomitant medications as described in Section 5.4.
15) Subjects with HIV-1 coinfection cannot be receiving an ARV regimen containing efavirenz (EFV)
16) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent > 10 mg/day).
17) Known hypersensitivity to the VEL, SOF, the metabolites, or formulation excipient.
18) For participants with HIV-1 co-infection only:
– HIV-1 RNA >50 copies/mL
– CD4 T-cell count Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 17/LO/0089

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A 24-week double blind treatment and 24-week follow up, randomized, multi-center, placebo-controlled, phase IIa/IIb study to evaluate the safety and efficacy of i.v. bimagrumab on total lean body mass and physical performance in patients after surgical treatment of hip fracture

Summary:
Muscle loss (atrophy) is commonly seen in elderly people at risk of a hip fracture. When these people undergo surgery
to fix their fracture further muscle loss can be expected because of immobility and delayed rehabilitation. This can vary
depending on age, gender, and the presence of other conditions.
Approximately one third of patients with hip fracture are readmitted to the hospital within the first 6 months (Bockvaar et
al 2003), a considerable portion due to infections (21%), blood clots complications (3%) and injurious falls/fractures
(8%). This highlights the need for effective treatment to speed up mobility.
Antibodies are normally made by your body’s immune system to fight infections. In recent years, a number of
antibodies have been designed to work as drugs. Bimagrumab is a human antibody designed to attach to a receptor in
muscle. This will stop a molecule which interferes with normal muscle growth. If this molecule is blocked by
bimagrumab, muscle cells can increase in size. Since people who undergo hip surgery lose muscle, treatment with
bimagrumab could slow or stop this. Treatment with bimagrumab might increase muscle mass and might improve a
person’s strength.
This is a multicentre study where neither patients nor doctors know what treatment a patient is receiving so results are
objective. Patients included in the study must have undergone hip fracture surgery. Around 210 men and women (aged
65 years old or above) from across the world, will be added into one of 3 possible study arms (bimagrumab 10 mg/kg,
3 mg/kg or placebo as an intravenous infusion every 4 weeks). Each subject will enter a screening period between 728
days, after a hip surgery, followed by a 52 week treatment period.
This study is being conducted by Novartis Pharma AG.

Inclusion criteria:
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed;
2. Males and postmenopausal
females ≥ 65 years (as defined in Section 6.5.9);
3. Patient must have had successful surgical treatment of the hip fracture (medial, lateral and pertrochanteric proximal
femoral fracture, AO Classification 31 AC
(AO Foundation 2013);
4. Patient must be mentally competent at screening, to have scored at least ≥ 21 on the Folstein Mini Mental State
Examination (MMSE);
5. Patient must be able to complete a 4 m gait speed test at screening, between days 728
after fracture surgery;
6. Patient must be able to understand and follow the requirements and procedures for the study, be committed to
participate in rehabilitation training as outlined in Section 5.1.2 and be willing to participate for approximately 56 weeks;
7. Patients must weigh at least 35 kg and must have a body mass index (BMI) within the range of 16 – 35 kg/m2 at
screening;
8. Two to four weeks after surgery (prior to randomization): Successful surgical
intervention for fracture repair defined as 1) implantation according to manufacturer’s instructions AND 2) completed
surgical wound healing.

Exclusion criteria:
Must
not have a chronic active infection (e.g., HIV, hepatitis B or C, tuberculosis, etc);
Orthopedic history:
• History of repeated hip fracture, subtrochanteric
fractures,or any other lower limb fracture in the 6 months prior to
screening
Conditions countering muscle increase or causing muscle wasting:
• History or ongoing disease known to cause malabsorption of protein
Conditions interfering with muscle function assessments:
• severe Vitamin D deficiency (25OHvitamin
D 180 or
100 or Principal Investigator for this trial: Professor Opinder Sahota

Research Ethics Committee Reference: 14/LO/1064

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A Phase 2, Double Blind, Randomized Study Evaluating the Safety, Tolerability, and Efficacy of GS-4997 in Combination with Prednisolone versus Prednisolone Alone in Subjects with Severe Alcoholic Hepatitis (AH)

Summary:
Alcoholic Hepatitis (AH) is an inflammatory condition of the liver caused by consuming too much alcohol over an
extended period of time. When alcohol gets processed in the liver, it produces toxic chemicals which can injure the
liver cells. This injury results in inflammation and leads to AH. Corticosteroids, like prednisolone are the current
standard of care for helping reduce the inflammatory process. However, the limited benefits, combined with the often
high rates of infection in participants with AH, make it clear that safer and more effective therapies are needed. GS-
4997 has been shown to block chemical pathways in the liver that lead to inflammation of the liver cells. Its
mechanism of action is complimentary to prednisolone.
In this study approximately 120 participants will be enrolled at multiple sites across the world to see if GS-4997 in
combination with prednisolone is safer and more effective in treating AH than prednisolone alone.
Participants will be randomly assigned to one of the following treatment groups:
-Treatment Group A: GS-4997 18 mg once daily + prednisolone 40 mg once daily
-Treatment Group B: GS-4997 placebo once daily + prednisolone 40 mg once daily
To assess the safety and effectiveness of GS-4997 eligible participants will attend a screening period that can last up
to 14 days, a treatment period of 4 weeks, and a follow-up period of 20 weeks after their last dose of study medication.
The treatment period is a total of 26 weeks. There will be an option to enrol in a PK-sub study to measure changes in
the amount of study medication in participants’ blood over the course of one day.

Inclusion criteria:
1) Males and non-pregnant, non-lactating females between 18-70 years of age, inclusive based on the date of the
screening visit;
2) Willing and able to give informed consent prior to any study specific procedures being performed. In participants
with hepatic encephalopathy (HE), which may impair decision-making, consent will be obtained per hospital
procedures (e.g., by legal Authorised
Representative);
3) Clinical diagnosis of severe AH based on all of the following:
a) History of excessive alcohol consumption during the past 3 months (average of >40 g/d of alcohol for women and
>50 g/d for men);
b) Aspartate aminotransferase (AST) > 50 U/L;
c) Aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT) >1.50;
d) Onset of jaundice within the past 3 months;
e) Maddrey’s DF ≥ 32 at screening;
4) All female participants of childbearing potential must agree to use a highly effective method of contraception during
intercourse from the screening visit throughout the study period and for 90 days following the last dose of study
medication. If females utilise hormonal agents as one of their contraceptive methods, the same hormonal methods
must have been used for at least
3 months before study dosing. Females on hormonal methods must also utilise a barrier method as another form of
contraception;
5) Male participants must refrain from sperm donation from screening through at least 90 days following the last
dose of study medication;
6) Male participants must agree to use condoms during intercourse from screening through study completion and for
90 days following the last dose of study medication;
7) Female participants must refrain from egg donation or harvest for 90 days after last dose of study medication;
8) Willing and able to comply with scheduled visits, medication administration plan, laboratory tests, other study
procedures, and study restrictions

Exclusion criteria:
Participants who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Pregnant or lactating females;
2) Other causes of liver disease including chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive), chronic
hepatitis C (HCV RNA positive), acetaminophen hepatotoxicity, biliary obstruction, and autoimmune liver disease;
3) Serum AST >400 U/L or ALT >300 U/L;
4) MELD >30 at screening;
5) Maddrey’s DF >60 at screening;
6) Grade 4 Hepatic Encephalopathy (HE) by West Haven criteria;
7) Concomitant or previous history of hepatocellular carcinoma;
8) History of liver transplantation;
9) HIV Ab positive;
10) Uncontrolled sepsis;
11) Uncontrolled gastrointestinal (GI) bleeding or controlled GI bleeding within 7 days of screening that was
associated with shock or required transfusion of more than 3 units of blood;
12) Type 1 hepatorenal syndrome (HRS) or renal failure defined as a serum creatinine >221 μmol/L (> 2.5 mg/dL) or
the requirement for renal replacement therapy;
13) Participants dependent on inotropic (e.g., epinephrine or norepinephrine) or ventilatory support (i.e. endotracheal
intubation or positive-pressure ventilation);
14) Portal vein thrombosis;
15) Acute pancreatitis;
16) Cessation of alcohol consumption for more than 2 months before baseline/Day 1;
17) Severe associated disease (e.g., cardiac failure, acute myocardial infarction, severe cardiac arrhythmias, severe
pulmonary disease, neurologic disease,) that may lead to premature mortality within the study period;
18) Malignancy within the 2 years prior to screening, with the exception of specific cancers that have been cured by
surgical resection (basal cell skin cancer, etc.). Participants under evaluation for possible malignancy are not eligible.
19) Positive urine screen for amphetamines, cocaine or opiates (i.e., heroin, morphine) at screening.
Participants on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening
may be included in the study. Participants with positive cannabis medication screen may be included in the study.
Participants with a positive urine medication screen due to prescription opioid-based medication are eligible if the
prescription and diagnosis are reviewed and approved by the investigator;
20) Treatment with immunosuppressive medications [e.g., systemic corticosteroids (inhaled and topical steroids are
allowed), budesonide, tacrolimus, sirolimus, cyclosporine, azathioprine, mycophenolate
mofetil, and methotrexate], pentoxifylline, or N-acetylcysteine (NAC) within 6 month of screening;
21) Use of the following CYP3A4 inhibitors (clarithromycin, conivaptan, grapefruit juice,
itraconazole, ketoconazole, nefazodone, posaconazole, bupenorphine/naloxone, telithromycin,
voriconazole) or CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St. John’s Wort) within 2 weeks of baseline;
22) Active ocular herpes simplex;
23) Any laboratory abnormality or condition that, in the investigator’s opinion, could adversely affect the safety of the
participant or impair the assessment of study results;
24) Participation in another investigational study of a medication or device within 1 month prior or within 5 half-lives of
the prior investigational agent (whichever is longer) prior to screening;
25) Concurrent participation in another therapeutic clinical study;
26) Known hypersensitivity to the study medications (GS-4997 and prednisolone), the metabolites, or formulation
excipient;
27) Presence of any condition that could, in the opinion of the investigator, compromise the participant’s ability to
participate in the study, such as history of substance abuse other than alcohol use or a psychiatric or medical
condition;
28) Unavailable for follow-up assessment or concern for participant’s compliance with the protocol procedures

Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 16/LO/1891

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Nucleoside withdrawal in HBe Ag negative hepatitis B virus infection to promote HBsAg clearance (Nuc-B)

Summary:
Hepatitis B virus (HBV) causes infection of the liver, either a severe infection with a shorter duration (acute) or a
persistent longer term infection (chronic). Worldwide there are 350 million people with chronic HBV infection. Two
types of treatment for chronic HBV infection are available: interferons or nucleoside/nucleotide analogues. Interferons
are used for a finite period of time and treatment rarely results in elimination of the virus ie a cure. The majority of
patients therefore choose to be treated instead with nucleos(t)ide analogues – tablets taken every day that cause no
side effects, however, once started the majority of patients will need to continue taking them for the rest of their life.
There is evidence from a recent clinical trial that if treatment with nucleos(t)ide analogues is stopped after a few years
of treatment/viral suppression some patients may be able to eliminate the virus. We therefore want to confirm the
findings from this trial, following patients for at least three years after cessation of treatment and in addition use
interferon in some of the patients at the time that the nucleos(t)ide analogue treatment is withdrawn to increase the
immune response against the virus. Elimination of the virus is important because it represents cure of infection so all
treatment can be safely discontinued.
We anticipate three outcomes for the trial patients. 1. Viral elimination (a cure), 2 A sustained virological response
(their immune system can keep the virus at a low level) or 3. They might relapse and restart their nucleos(t)ide
analogues. In future it will be important to be able to predict which patients have which outcome so as part of this trial
we will measure a number of variables by testing patients’ liver and blood samples to predict which patients are most
likely to benefit from which treatment.

Inclusion criteria:
• Age ≥ 18
• Chronic HBV infection
• HBeAg negative
• Nucleos(t)ide analogues treatment for ≥3 years
• HBV DNA Exclusion criteria:
• Cirrhosis at any time
• HBeAg to anti-HBe seroconversion within the last 3 years
• Interferon use in the last 3 years
• Contraindications to interferon use
• Participation in HBV-specific therapeutic vaccine studies within 12 months
• HCV, HDV or HIV co-infection
• Immunosuppressant use
• Clinically significant comorbidities that, in the opinion of the investigator, render the patient unsuitable

Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 16/LO/1318

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StartRight: Getting the right classification and treatment from diagnosis in young adults with diabetes

Summary:
The treatment of Type 1 and Type 2 diabetes is very different. People with Type 1 diabetes rapidly stop making their
own insulin, so need insulin injections from diagnosis. People with Type 2 diabetes can keep making their own
insulin but it may not work as well as it should, so they can be treated with diet or tablets. While they may eventually
need insulin treatment it is usually not until many years after diagnosis.
It is often difficult for doctors to tell which kind of diabetes a person has, particularly in younger adults where both Type
1 and Type 2 diabetes are common. Because of this, sometimes (in about 15-20% of young adults) people are given
the wrong diagnosis. This can have a huge impact as it means they could receive the wrong treatment. A person
incorrectly diagnosed with Type 1 diabetes will be prescribed unnecessary insulin injections and miss out on other
helpful therapies. A person incorrectly diagnosed with Type 2 diabetes may develop severely high glucose and
become unwell with a condition called Diabetic Ketoacidosis if they do not receive insulin treatment.
This study aims to improve this situation by helping doctors more accurately tell the type of diabetes a person has
when they are first diagnosed. We will recruit 1000 participants who have recently been diagnosed with diabetes
between the ages of 18 and 50. We will record clinical features and measure blood tests that may help us determine
diabetes type at diagnosis and follow participants for 3 years to see whether they stop producing their own insulin and
need insulin treatment, which confirms Type 1 diabetes. We will assess whether clinical features and blood tests can
help us tell if a patient needs rapid insulin treatment and should be initially treated as Type 1 or Type 2 diabetes.
We will combine results from this study and existing previous studies to produce a calculator, called a clinical
probability model that will allow doctors and patients to combine information from clinical features and (where
necessary) blood tests to accurately diagnose what type of diabetes a person has and therefore give the correct
treatment. This will be freely available to doctors and patients as a website calculator and smartphone app.

Inclusion criteria:
• Adults diagnosed with diabetes within the previous 12 months.
• Aged ≥18 and ≤50 at the time of diabetes diagnosis*
• Able and willing to provide informed consent.
* Clinical diagnosis of diabetes mellitus. Biochemical diagnosis confirmed from healthcare records post recruitment.

Exclusion criteria:
• Gestational diabetes
• Known secondary diabetes (diabetes considered likely due to medication, cystic fibrosis, pancreatitis, pancreatic
cancer, pancreatic surgery, hemochromatosis or Cushing’s syndrome).

Principal Investigator for this trial: Dr Peter Mansell

Research Ethics Committee Reference: 16/SW/0130

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Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication

Summary:
Biomede is an international, multicenter, randomised, open-label, adaptive, phase II trial of treatment for Diffuse
Intrinsic Pontine Glioma (DIPG). This trial mandates a biopsy of the tumour to obtain the biological profile of the
tumour. The allocation of treatment in each patient will be based on the specific biological tumour profile. Recruitment
target is 80 patients in the UK, 250 in the EU with DIPG over 4 years. The initial agents to be studied based on
biomarkers profile are; Dasatinib, Erlotinib and Everolimus as single agents combined with standard radiotherapy.

Inclusion criteria:
Eligibility criteria for the BIOMEDE study (pre-screening for the randomised subtrials)
– Diagnosis of DIPG (clinical and radiological, or histological in case the biopsy was performed before study entry)
– DIPG at diagnosis: no prior chemotherapy for the present cancer; no prior cerebral radiation therapy
– NB : Metastatic disease allowed. Patient with metastatic disease are eligible for the study (including the randomised
trial if diagnosis of DIPG confirmed). In this situation, radiotherapy will have to start within three weeks after the biopsy
while targerted treatment will start at the end of the irradiation
– Age > 6 months and 12 weeks after the start of study treatment
– Karnofsky performance status scale or Lansky Play Scale > 50%. The PS should not take the neurologic deficit per
se into account. NB: Children and young adults with a worse performance status due to glioma-related motor paresis
can be included.
– Absolute neutrophil count > 1.5 x 109/l, Platelets > 100 x 109/l
– Total bilirubin 1,5 ULN, creatinine clearance must be > 70 ml/min/1,73
m² (EDTA radioisotope GFR or 24 hours urines collection)
– Normal coagulation tests: prothrombin rate (prothrombin time = PT), TCA (PTT), fibrinogen
– No current organ toxicity > grade 2 according to the NCI-CTCAE version 4.0 especially cardiovascular, pulmonary or
renal disease (including but not limited to: congenital long QT syndrome, nephrotic syndrome, glomerulopathy,
uncontrolled high blood pressure despite adequate treatment, interstitial lung disease, pulmonary arterial
hypertension).In case of known or possible cardiac disease, a cardiological advice will be required prior to the
inclusion in the randomized trial as a preexisting cardiopathy represents a contra-indication to dasatinib.
– Effective and appropriate contraception for patients (male and female) of reproductive potential during their entire
participation in the study and during 6 months after the end of treatment. Effective contraception are defined in CTFG
Guidelines “Recommendations related to contraception and pregnancy testing in clinical trials”
– Negative pregnancy test (serum beta-HCG) evaluated in the last week in females of reproductive potential
– Written informed consent given by patient and/or parents/legal representative for treatment and randomization
Eligibility criteria for the subtrials
Eligibility criteria for the different subtrials will be mainly based on biomarkers assessment as detailed in the table
above. In addition, contra-indication and precautions for use to specific drugs will be considered.

Exclusion criteria:
Non eligibility criteria for the study
– Massive intratumour bleeding
– Any other concomitant anti-cancer treatment not foreseen by this protocol
– Any other cancer during the last 5 years
– Uncontrolled intercurrent illness or active infection
– Any other co-morbid condition that in the investigator’s opinion would impair study participation
– Unable for medical follow-up (geographic, social or mental reasons)
– Patient not fulfilling one of the previous eligibility criteria.
– Patient previously treated with irradiation on the brainstem for another neoplasm
– Patient with congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
– Patient not covered by a social security agreement accepted in the treating country if national requirement.
– Pregnant or breast feeding women
– NB: A patient with known hypersensitivity for one the drug or its excipients could still participate to the study and
receive one of the other drug(s)

Principal Investigator for this trial: Professor Richard Grundy

Research Ethics Committee Reference: 16/LO/2141

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PANORAMA – Real World Molecular Testing, Treatment Patterns, and Clinical Outcomes in Patients with Locally Advanced or Metastatic NSCLC

Summary:
This study will assess molecular testing, treatment patterns, and associated clinical outcomes among patients with
Epidermal Growth Factor Receptor(EGFR) mutation-positive locally advanced or metastatic Non Small Cell Lung
Cancer (NSCLC) who have progressed while on or after receiving EGFR- Tyrosine Kinase inhibitor(TKI) therapy
(primary cohort).
Additionally, the study also aims to evaluate molecular testing, treatment patterns, and associated clinical outcomes in
a secondary cohort of newly diagnosed patients with locally advanced or metastatic NSCLC who are treatment naïve
or patients who were diagnosed at an earlier stage but have progressed to metastatic NSCLC during the selection
period.
This study is descriptive in nature and does not attempt to test any specific a priori hypotheses.

Inclusion criteria:
Primary Cohort:
Adult male or female patients (according to age of majority/adulthood as defined
by local regulations)
• Patients who have progressed on or after front-line EGFR-TKI therapy within the
patient selection period
o Note: Patients should have received front-line EGFR-TKIs (e.g., gefitinib,
erlotinib, afatinib, or icotinib) in any of the prior lines of therapy and not
necessarily prior to enrolment in the study
• Patients with prior confirmed EGFR mutation-positive (both common and uncommon EGFR mutations) locally
advanced or metastatic NSCLC
Note: Patients who developed resistance to an EGFR-TKI due to any other
phenotypic/histologic transformations or other mutations at the index
date will be eligible for participation in this study as long as they have prior
confirmed diagnosis of EGFR mutation-positive (any mutations) locally
advanced or metastatic NSCLC
• Provision of written informed consent as per local regulations; patient consent
should be within 6 weeks of index date (defined as the date of progression as
ascertained by the physician on or after EGFR-TKI therapy)
Secondary Cohort
• Adult male or female patients (according to age of majority/adulthood as defined
by local regulations).
• Patients newly diagnosed with locally advanced or metastatic NSCLC who are
treatment naive or patients who were diagnosed at an earlier stage but have
progressed to metastatic NSCLC during the selection period.
• Provision of written informed consent as per local regulations; patient consent
should be within 6 weeks of the index date (defined as the date of NSCLC diagnosis).

Exclusion criteria:
• Enrolment in studies that prohibit any participation in this Observational Study
o Patients may be concurrently enrolled in unblinded clinical trials, but not
blinded clinical trials in which the treatment being administered is unknown

Principal Investigator for this trial: Dr Sarah Khan

Research Ethics Committee Reference: 16/LO/2128

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Exploring the Ethics of Ambulance Trials: a qualitative interview study of patients, relatives and paramedics

Summary:
We aim to explore experiences, perceptions and challenges reported by patients and/or their relatives and
paramedics regarding the ethics of recruiting patients to a trial in a prehospital ambulance setting.
Trials involving ambulance services are a rapidly developing field with increasing numbers and scale of studies. Our
aim reflects: the lack of evidence in this field; the need for early interventions in time-critical conditions such as out-ofhospital
cardiac arrest, myocardial infarction (‘heart attack’) and stroke; and the need to redesign emergency and
urgent care systems under pressure from increasing demand and new treatments.
Randomised Controlled Trials (RCTs) in ambulance settings pose particular challenges, including urgency of
conditions and treatment, and difficulties with recruitment, randomisation and informed consent with limited time or
impaired patient capacity. Trials have used the notion of ‘assent’ (agreement to participate by the patient, relative or
staff) followed by later full patient consent. This research environment is in its infancy compared to research in hospital
and primary care due to ethical and logistic barriers.
We will focus primarily on the ethical challenges for stakeholders (patients, public, healthcare organisations,
practitioners) and their solutions.

Inclusion criteria:
In order to be invited to take part in this study patients will have been previously recruited to an RCT (AIRWAYS2) and will fulfil the criteria for that study. They will be approached in the first instance by the research nurses from their initial trial and asked whether they would like to take part in this study. Only those patients that have the mental capacity and are well enough to participate in an interview will be approached. It is anticipated that patients will be over the age of 18 but no upper age limit will be applied. Both mail and female patients will be included.
Paramedic inclusion criteria
In order to be eligible to take part in this study paramedics must have been directly involved in randomising patients into the RCT (AIRWAYS2). Paramedics will be approached initially by the research teams at EMAS and given the opportunity to participate via a brief expression of interest form.

Exclusion criteria:
There are no other specific exclusion criteria for this study. Where a patients first language is not English a translator will be provided where possible, in the event a translator cannot be found this could result in exclusion from the study

Principal Investigator for this trial:

Research Ethics Committee Reference:

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Correlates of sedentary behaviour and physical activity in Rheumatoid Arthritis (RA) and Osteoarthritis (OA)

Summary:
Moderate-to-vigorous physical activity (MVPA) is recommended for people with Rheumatoid Arthritis (RA) and lower
limb Osteoarthritis (OA) in order to improve physical and psychological health, as well as to reduce the joint pain,
disease-related inflammation, and associated physical dysfunction symptomatic of these conditions. However, the
physical dysfunction resulting from RA and OA also means that most individuals living with these conditions do not
engage in sufficient levels of MVPA to experience these health benefits.
Reducing sedentary behaviour (e.g., time spent sitting, lying) may be perceived as more manageable than increasing
MVPA for people with RA and OA. Recent studies in older adults have suggested that reducing sedentary behaviour
might help to improve physical function, enhance psychological health, and lessen systemic inflammation. Importantly,
the positive health benefits of reducing sedentary behaviour are reported to occur regardless of levels of MVPA
participation.
Currently, we know little about the physical and psychological health implications of sedentary behaviour for RA and
OA, as well as factors predictive of both sedentary time and MVPA engagement. In addition, we do not know if the
possible health implications of sedentary behaviour are independent from the health benefits of MVPA engagement for
these individuals.
The primary aim of this research is therefore to investigate (and compare) the determinants and health consequences
of objectively measured MVPA and sedentary behaviour in RA and OA. The research will be conducted at Russells Hall
Hospital (Dudley). Patients who consent will be asked to participate in 2 ‘study weeks’, 6 months apart. At the start and
end of each study week, participants will be asked to complete questionnaires, provide a fasted blood sample (RA
only), and undertake assessments of height, weight, body composition, and blood pressure. Participants will also be
given an accelerometer to wear for 7 days during the study week.

Inclusion criteria:
Rheumatoid Arthritis:
1. Patients must be clinically diagnosed with RA (ACR Clinical Classification Criteria; Aletaha et al., 2010).
2. Aged 18 years old and above.
Osteoarthritis:
1. Adults above 45 years of age.
2. Physician-made diagnosis of hip or knee OA regardless of radiographic evidence (confirmed by the consultant or
research nurse who will introduce the study to the participant).

Exclusion criteria:
Rheumatoid Arthritis:
1. Patients unable to ambulate independently, or with the use of a walking aid (e.g., walking stick)
2. Individuals will also be excluded if they have been diagnosed with fibromyalgia, gout, or lupus
3. Presence of any mental illness that causes significant memory loss, for example, Alzheimer’s disease and
vascular dementia
Osteoarthritis:
1. Patients unable to ambulate independently, or with the use of a support or aid (e.g., walking stick).
2. Co-existence of other forms of arthritis such as rheumatoid arthritis, fibromyalgia, gout, lupus (self-reported).
3. Individuals will also be excluded if they have been diagnosed with any mental illness that causes significant
memory loss (e.g., Alzheimer’s disease and vascular dementia [self-reported]).
Other exclusion criteria relevant to main protocol sub-section (RA only):
1. Cortisol awakening response – Patients taking corticosteroid treatment will be excluded from the section of the study
protocol that concerns assessment of the cortisol awakening response (i.e., saliva samples – corticosteroids will
interfere with hormone secretion/regulation and confound measurement of cortisol in saliva)

Principal Investigator for this trial: Dr A Abhishek

Research Ethics Committee Reference: 16/WM/0371

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Randomised, phase II/III, 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA

Summary:
This is a clinical trial for patients diagnosed with early stage breast cancer i.e. that has not spread to other organs such
as the lungs, liver or bones, who have been advised to receive chemotherapy before surgery (neoadjuvant)
chemotherapy.
The trial investigates the safety and effectiveness of olaparib, a drug which targets part of the pathway that repairs
damaged DNA, in addition to platinumbased
neoadjuvant chemotherapy.
The trial is open to patients who have breast cancer caused by an inherited mutation (change from the normal DNA
sequence) in the BRCA 1 or BRCA 2 genes. In addition, it is open to patients who do not have hormoneresponsive
(oestrogen) breast cancer that also does not overexpress
a protein called HER2. These breast cancers are called
triple negative breast cancers (TNBC). BRCA–mutated (gBRCA) and TNBC are considered to have a higher risk of
disease recurrence after surgery and are usually treated with chemotherapy.
The chemotherapy to be given are drugs called paclitaxel (given weekly) and carboplatin (given once every 3 weeks)
followed by drugs called anthracyclines. Both of these drugs have been used in breast cancers of these types and
stage previously but not in combination with olaparib. However, they have been used in combination with olaparib in
women with more advanced breast cancers with good results.
So this trial investigates whether introducing olaparib at an earlier stage of breast cancer might produce more
shrinkage of the breast cancer before surgery, which may allow a better chance of avoiding mastectomy and may lead
to a better chance of avoiding recurrence of the breast cancer.

Inclusion criteria:
• Written informed consent.
• Aged between 16 and 70
• Histologically confirmed invasive breast cancer.
• Clinical stage T14
N02
(tumour or metastatic node diameter > 10mm)
• Confirmed ERnegative
and HER2negative.
or
• Germline BRCA mutation positive, irrespective of hormone status but HER2 negative.
• Performance Status 01

Exclusion criteria:
• T0 tumour in absence of axillary node > 10mm
• TNBC with a nonbasal
phenotype and overexpressing
Androgen Receptor
• Not suitable for neoadjuvant chemotherapy
• Distant metastases apparent prior to randomisation
• Prior history of invasive breast cancer within the last 5 years
• Previous PARP inhibitor use or any previous chemotherapy or targeted agent.
• Any previous chemotherapy or agent used for the treatment of cancer within the last 5 years.

Principal Investigator for this trial: Dr Stephen Y Chan

Research Ethics Committee Reference: 15/NW/0926

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A phase III double-blind randomised parallel group comparison of the efficacy and safety of FP-1201-lyo (recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome

Summary:
This study is Sponsored by Faron Pharmaceuticals Ltd. and explores a potential new treatment for Acute Respiratory
Distress Syndrome (ARDS). ARDS results in the leaking of fluid from lungs, inflammation and respiratory failure. This
is a serious condition which can be life-threatening.
There are currently no approved pharmacological treatments for ARDS and standard of care is currently management
of the condition with supportive care.
The treatment proposed in this research study is a pharmacological compound called FP-1201-lyo (recombinant
human interferon IFN beta-1a) which has already been investigated. Results from previous studies suggest this new
treatment would have beneficial effects in patients with ARDS in reducing leakage from the lungs.
The purpose of this study is to evaluate the safety and effectiveness of FP-1201-lyo in improving survival and reducing
the need for mechanical ventilation.
patients will be randomly assigned to one of two treatments – FP-1201-lyo or placebo. Treatments will be given in addition to receiving their standard of care. Patients included in the study will be given study medication once daily for 6 days by intravenous injection or through the in situ central/peripheral line. The patients will continue to be monitored daily from D7 to Day 28 or until they are discharged from Intensive Care Unit (ICU). Follow up visits will then take place at days, 90, 180 and 360 days.
Study assessments conducted will include , but not limed to: vital signs, physical examination, blood sampling and self-completed questionnaires. patients will also be provided the opportunity to join the pharmacogenetic portion of the study which involve an additional blood sample draw.
It is anticipated a total of 300 patients will be randomised in approximately 60 centres in 9 countries across Europe.

Inclusion criteria:
1. Patient has a diagnosis of moderate or severe ARDS according to the Berlin definition of ARDS:
1.1 Acute onset of respiratory failure within 1 week of a known clinical insult or new or worsening respiratory
symptoms
1.2 Respiratory failure associated with known ARDS risk factors and not fully explained by either cardiac failure or fluid
overload (an objective assessment of cardiac failure or fluid overload is needed if no risk factors for ARDS [moderate
or severe ARDS] are present)
1.3 Radiological abnormalities on chest X-ray or on computerised tomography scan, i.e., bilateral opacities, that are
not fully explained by effusions, nodules, masses or lobar/lung collapse
1.4 Hypoxaemia:
• Moderate ARDS: PaO2/FiO2 >100 mmHg (>13.3 kPa) to ≤200 mmHg (≤26.6 kPa) with positive end expiratory
pressure (PEEP) ≥5 cmH2O
• Severe ARDS: PaO2/FiO2 ≤100 mmHg (≤13.3 kPa) with PEEP ≥5 cmH2O
2. The radiological and hypoxaemia criteria (1.3 and 1.4) must be met within the same 24-hour period. The time of
onset of ARDS is when the last of the two specified ARDS criteria is met
3. Administration of the first dose of study drug must be planned to take place within 48 hours of first fulfilling the above
inclusion criteria
4. Patient is intubated and mechanically ventilated
5. A signed informed consent form from the patient or the patient’s personal legal representative or a professional
legal representative must be available
6. Patient is aged ≥18 years

Exclusion criteria:
1. Woman known to be pregnant, lactating or with a positive (urine or serum test) or indeterminate (serum test)
pregnancy test
2. Patient is simultaneously taking part in another pharmacotherapy protocol
3. Patient is not expected to survive for 24 hours
4. Patient has an underlying clinical condition where, in the opinion of the Investigator, it would be extremely unlikely
that the patient would come off ventilation, e.g., motor neurone disease, Duchenne muscular dystrophy, or rapidly
progressive interstitial pulmonary fibrosis
5. Patient has severe chronic obstructive pulmonary disease requiring long-term home oxygen therapy or mechanical
ventilation (non-invasive ventilation or via tracheotomy) except for continuous positive airway pressure (CPAP) or bilevel
positive airway pressure used solely for sleep-disordered breathing
6. Patient has congestive heart failure, defined as New York Heart Association class IV
7. Patient has acute left ventricular failure
8. Patient has liver failure (Child-Pugh grade C)
9. Patient has received any prior interferon
10. Patient has known hypersensitivity to natural or recombinant IFN beta or to any of the excipients
11. Patient is receiving renal dialysis therapy for chronic renal failure
12. Patient is receiving extra-corporeal membrane oxygenation, high-frequency oscillatory ventilation or any form of
extra-corporeal lung support
13. Patient has had any form of mechanical ventilation (invasive or non-invasive, excluding CPAP alone) for longer than
48 hours prior to the diagnosis of ARDS
Non-invasive ventilation has to be continuously applied for at least 12 hrs per day in these 48 hours
14. Patient has burns to ≥15% of their total body surface area

Principal Investigator for this trial: Dr Daniel Harvey

Research Ethics Committee Reference: 15/LO/2098

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Head & Neck 5000 Follow-up Study

Summary:
Head & Neck 5000 is a large observational study of people with head and neck cancer from across the United
Kingdom. The overall aim of the Head & Neck 5000 Follow-up Study is to describe the social, lifestyle and clinical
outcomes in people with head and neck cancer and relate these to information gained from the original Head & Neck
5000 study. In order to achieve this, participants who have taken part in Head & Neck 5000 for at least three years will
be sent an invitation to complete the Follow-up Study questionnaire. Data will be collected from the medical notes and
through linkage to national databases for all participants who consented to this.

Inclusion criteria:
1. Participants recruited to the original Head & Neck 5000 cohort
2. Participants who have been in the Head & Neck 5000 study for a minimum of 3 years

Exclusion criteria:
1. Participants who did not consent to be approached regarding further research
2. Participants withdrawn from the H&N5000 study
3. Participants who are now considered to meet the criteria for mental incapacity or vulnerability set out in the Mental
Capacity Act 2005

Principal Investigator for this trial: Dr Judith Christian

Research Ethics Committee Reference: 16/NI/0163

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A PROSPECTIVE, MULTICENTER, OBSERVATIONAL POST-AUTHORIZATION SAFETY STUDY TO EVALUATE THE LONG TERM SAFETY PROFILE OF LEMTRADA® (ALEMTUZUMAB) TREATMENT IN PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS

Summary:
This is a multicentre,
post authorisation, observational study to evaluate the long term safety profile of LEMTRADA
(alemtuzumab) treatment in patients wil relapsing forms of multiple sclerosis (RMS).
This is an observational study with no experimental intervention utilized. Enrolled patients will receive treatment and
evaluations for their MS as determined by their treating physicians in accordance with local standard of care. Visits will
be scheduled by the treating healthcare provider (HCP) according to patientspecific
needs and local clinical practice.
For purposes of this study, HCPs will be requested to record information on enrolled patients at the time of study
enrolment, and then to conduct followup
data entry on a semiannual
basis for a period of 5 years postenrolment.
The full study duration is expected to be approximately 9 years, including an approximate 4 year enrolment period.

Inclusion criteria:
A patient is eligible for the study if all of the following apply:
• Diagnosis of RMS, in accordance with the local label
• Initiated LEMTRADA treatment for the firsttime
within 8 weeks of study entry
• Able and willing to provide written informed consent for study participation

Exclusion criteria:
Current participation in a clinical study where LEMTRADA is being provided as an investigational product.

Principal Investigator for this trial: Dr Bruno Gran

Research Ethics Committee Reference: 15/YH/0276

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Clinical Trials currently recruiting at Nottingham University Hospitals NHS Trust 2017-06-08 01:00:00

Summary:
Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), affecting over 5 million
people worldwide, and in the UK is estimated to account for 26% of legal blindness. The incidence of GA increases
exponentially with age and there is currently no treatment.
The disease impact on the patient, caregiver and society due to GA is not being well understood. The purpose of this
observational study is to assess the clinical details and health-related quality of life of patients with GA compared to
patients without GA.
This study also aims to describe the healthcare costs associated with GA and collect data from caregivers of patients
with GA in order to understand the effect on the caregiver’s life due to caring for a patient with this condition.
Patients with and without GA meeting the study criteria for eligibility will be invited to participate in the study by the
treating physician or research nurse. Information on the study will be provided to the patient.
If patients consent to participate, the physician or a member of the research team will collect data regarding their
medical history and other relevant data onto an electronic case report form (eCRF). Patients will be invited to complete
questionnaires providing information on patient-reported outcomes (PRO) at time of the visit. In addition, if the GA
patient has a caregiver, the caregiver will be invited to complete questionnaires providing information on caregiverreported
outcomes following informed consent.
The study is expected to last approximately 12 months from when the first patient provides informed consent (i.e.
signs the consent form).

Inclusion criteria:
GA patients:
– Bilateral symptomatic GA patients (physician confirmed).
– Aged 70 years and older at study inclusion.
– Provision of informed consent allowing contribution of patient data into the study.
Non-GA controls:
– Patients with no ophthalmic condition that in the opinion of the investigator affects visual function. Example
conditions that may be included in the study include, but are not limited to, the following: early/intermediate AMD, dry
eye, choroidal nevus, epiretinal membrane, a history of cataract surgery, etc.
– Age 70 and older at study inclusion.
– Provision of informed consent allowing contribution of patient data into the study.
Caregivers of GA patients:
– Anyone, paid or unpaid, who provides assistance to the enrolled GA patient in terms of daily activities.
– Aged 18 years and older at study inclusion.

Exclusion criteria:
GA patients:
– Participated in an interventional study during 12 months prior (i.e. ≤12 months) to study inclusion date.
– Participated in the Genentech Mahalo study (Study number CFD4870g).
– Participating in the Roche Chroma/Spectri (Study numbers GX29176 and GX29185, respectively) or Proxima A/B
studies (Study numbers GX29633 and GX29639).
– History of choroidal neovascularisation (CNV), diabetic macular edema (DME) and/or retinal vein occlusion (RVO).
– Decreased cognitive function such that the patient would be unable to understand an interview at time of visit (in the
opinion of physician/research nurse).
Non-GA controls:
– Participated in an interventional study during 12 months prior (i.e. ≤12 months) to study inclusion date.
– History of GA, CNV, DME and/or RVO.
– Decreased cognitive function such that the patient would be unable to understand an interview at time of visit (in the
opinion of physician/research nurse).
Caregivers of GA patients:
– Anyone who just accompanies the enrolled GA patient to a visit without providing assistance to the enrolled GA
patient in terms of daily activities.

Principal Investigator for this trial: Mr Winfried M Amoaku

Research Ethics Committee Reference: 16/NI/0260

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

RASP bronchoscopy study

Summary:
Asthma is a very common disorder which causes a great deal of distress for patients, and occasionally results in
premature death. Approximately 10% of people with asthma have severe disease which is not helped by current
treatments; we need to find new treatments for these patients urgently. Patients with asthma are not all the same, but
have distinct features which characterise their asthma. We therefore hypothesise that asthma is not a single disease,
but a syndrome resulting from several distinct underlying disease processes known as endotypes. There are
approximately 30,000 genes in humans, and each gene is responsible for the production of a particular protein. Using
a technique called “whole genome expression profiling” we have undertaken a small study looking at the activity of all
30,000 genes in the airway tissue of people with asthma. This work has identified 3 mutually exclusive distinct
molecular patterns (endotypes) of severe asthma and has identified other potentially important molecular targets
(manuscripts in preparation).
In particular, we have found that 25-50% of patients have asthma associated with the activity of proteins called Th2
cytokines (Th2-high asthma). New treatments are in development that target this pathway. However, we do not know
what is driving severe asthma in patients who do not express these Th2 cytokines. The aim of this study is to
investigate in more detail the molecular mechanisms driving severe asthma in patients who do not express Th2
cytokines (Th2-low asthma), so that we can identify new targets for treatment in this group. To do this we will collect
airway tissue via a telescope (bronchoscope), and analyse gene and protein expression in the tissue. We will then
compare the molecular activity between patients with Th2-high and Th2-low asthma, and healthy control subjects
(data obtained from a parallel study).

Inclusion criteria:
Patients must meet the following criteria for study entry:
1. Ability and willingness to provide written informed consent and to comply with the study protocol
2. Age 18–65 years at the time of informed consent
3. Severe asthma (BTS treatment step 4/5) despite intensive follow-up by an asthma specialist for at least 3 months
4. Diagnosis of asthma at least 12 months prior to informed consent
5. Baseline post bronchodilator FEV1 > or equal to 40% of predicted
6. History of asthma treatment with high doses of inhaled glucocorticosteroids ( ≥ 1000 μg fluticasone propionate daily
or equivalent (Clenil [BDP] 2000 μg, Fostair [BDP] 800 μg, fluticasone furoate 192 μg, budesonide dry powder 1600 μg,
ciclesonide 640 μg), and LABA, with or without an additional controller, for at least 3 months prior to screening or
previous corticosteroid optimisation (RASP workstrand 1).
7. For patients using oral corticosteroids, adherence with oral prednisolone regimen, as demonstrated by detectable
serum prednisolone and evidence of suppressed cortisol within 6 hours of reported daily dose on at least one
occasion during the screening period
8. Assessment according to the standards of the BTS UK Difficult Asthma Network or equivalent
9. Chest X-ray or computed tomography (CT) scan obtained within 12 months prior to consent (Visit 1) or chest X-ray
during the screening period (prior to Visit 2) confirming the absence of other clinically significant lung disease
10. Documented history of bronchodilator reversibility response of ≥ 12% and ≥ 200 mL within the past 18 months,
as demonstrated by any of the following:
i) Documented airflow obstruction (FEV1/forced vital capacity [FVC] Exclusion criteria:
Patients who meet any of the following criteria will be excluded from study entry:
• Treatment with intravenous [IV], intramuscular [IM]) or intraarticular corticosteroids within 4 weeks prior to Visit 1 or
during the screening period for any reason, including an acute exacerbation event
• A severe asthma exacerbation requiring oral corticosteroids within 4 weeks. Such patients can be re-screened.
• Infection that meets any of the following criteria:
– Any infection that resulted in hospital admission for 24 hours within 4 weeks prior to Visit 1 or during screening
– Any infection that required treatment with IV or IM antibiotics within 4 weeks prior to Visit 1 or during screening
– Any active infection that required treatment with oral antibiotics within 2 weeks prior to Visit 1 or during screening
– Upper or lower respiratory tract infection within 4 weeks prior to Visit 1 or during screening
– Antibiotics include any antimicrobial therapy used to treat bacterial, fungal, parasitic, viral, or other infections.
Antibiotics prescribed for lung infection prophylaxis would also exclude the patient
• Active tuberculosis requiring treatment within 12 months prior to Visit 1
Patients who have completed treatment for tuberculosis at least 12 months prior to Visit 1 and have no evidence of
recurrent disease are permitted.
• Known immunodeficiency, including, but not limited to, HIV infection
• Evidence of acute or chronic hepatitis or known liver cirrhosis
• AST, ALT, or total bilirubin elevation > 2.0 the upper limit of normal (ULN) during screening
• Clinically significant abnormality on screening electrocardiogram (ECG) or laboratory tests (haematology, serum
chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk of bronchoscopy
• History of clinically significant lung disease other than asthma
• Known current malignancy or current evaluation for a potential malignancy
• Unable to safely undergo elective flexible fiberoptic bronchoscopy because of any one of the following:
– History of allergic reactions to local anesthetics to be used in the procedure
– History of a clinically significant clotting abnormality, including on Screening Coagulation Panel
– History of acute myocardial infarction, unstable angina, or other medical conditions that, in the opinion of the
investigator, may make the patient unsuitable for elective bronchoscopy
• Other clinically significant medical disease that is uncontrolled despite treatment, that is likely, in the opinion of the
investigator, to impact the patient’s ability to participate in the study
• Current smoker, former smoker with smoking history of 15 pack-years
A current smoker is defined as someone who has smoked at least one cigarette per day (or pipe, cigar, or marijuana)
for 30 days within the 12 months prior to Visit 1. A pack-year is defined as the average number of packs of
cigarettes per day times the number of years of smoking.
• Use of a licensed or investigational monoclonal antibody including anti–IL 13, anti-IL-4/IL-13, omalizumab, anti–IL-5,
or anti–IL 17, within 6 months or 5 drug half-lives prior to Visit 1 (whichever is longer) or during screening
• Use of a systemic immunomodulatory or immunosuppressive therapy (other than a monoclonal antibody or
corticosteroids [see separate exclusion]) within 3 months or 5 drug half-lives prior to Visit 1 (whichever is longer) or
during screening
• Use of other investigational therapy not described above within 4 weeks or 5 drug half-lives prior to Visit 1 (whichever
is longer) or during screening
Patients participating in a clinical trial that has not been unblinded should be assumed to have received the active
drug
• Initiation of or change in allergen immunotherapy within 3 months prior to Visit 1 or during screening
• Receipt of a live attenuated vaccine within 4 weeks prior to Visit 1 or during screening
• Pregnant or lactating
• History of bronchial thermoplasty

Principal Investigator for this trial: Dr Dominick Shaw

Research Ethics Committee Reference: 16/EM/0260

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

ENDOTHELIAL PROGENITOR CELLS: POTENTIAL BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF ISCHAEMIC STROKE

Summary:
Stroke is a life-threatening condition that occurs due to sudden disruption of blood supply to the brain. Although stroke
can happen in all age groups including children, the elderly are at a greater risk of having strokes. Indeed, threequarter
of all strokes are seen in people over the age of 65. Unfortunately, due to short therapeutic window (4.5 h of
stroke onset), only 5% of patients can receive the currently available single medical therapy with rt-PA, a clot-busting
agent. As recent studies show that bone marrow-derived endothelial progenitor cells may migrate to the site of injury
to repair the damaged brain vessels and tissue, it is possible that their numbers and functional capacity may
determine the clinical outcome of stroke patients i.e. severely disabled, moderately disabled or no signs at all. This
study will assess these parameters in elderly stroke patients compared to their age-matched stroke-free counterparts.
In addition to this, the study will also compare the level of these parameters between healthy elderly and healthy young
volunteers to discover the specific impact of aging on them. The proposed study will last for three years for which the
eligible patients will be recruited from these admitted to Nottingham University Hospitals stroke service. The
experiments will be conducted in the Division of Stroke, Clinical Neuroscience at the University of Nottingham.

Inclusion criteria:
Patients with anterior circulation ischaemic stroke and aged 65 years or older.
Independence prior to stroke (mRSExclusion criteria:
Patients with posterior circulation ischaemic stroke and aged below 65 years of age.
Patients with primary intracerebral haemorrhage, recent recurrent ischaemic stroke, transient ischaemic attack or who
had ischaemic stroke within the last 3 months will be excluded from the study.
Elderly Healthy Volunteers who are below 65 years of age and with previous history of stroke.
Young Healthy Volunteers who are below 18 years or above 65 years of age and with pevious history of stroke.

Principal Investigator for this trial: Dr Nikola Sprigg

Research Ethics Committee Reference: 16/WM/0304

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A randomised phase II trial of Imatinib alternating with Regorafenib compared to Imatinib alone for the first line treatment of advanced gastrointestinal stromal tumour (GIST).

Summary:
This is a prospective, randomised, open label phase II trial, stratified by participating site, previous adjuvant therapy
(prior vs none), and previous imatinib for metastatic disease for less than 21 days.
The study aims to determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety to
warrant further evaluation as a first line treatment for metastatic GIST.
The target population is adults with histologically confirmed, measurable metastatic GIST, who have received no prior
treatment for metastatic disease. Patients who are currently taking, and have had up to 21 days of uninterrupted
treatmentwith 400mg daily of imatinib are eligible to participate in this study.
Patients will be randomised to receive either:
Arm A – imatinib 400mg orally daily continuously (control arm);
or
Arm B – alternating 28‐day periods of imatinib 400mg orally daily for 21 to 25 days followed by a washout (drug free)
period of 3 to 7 days, then regorafenib 160mg orally daily for 3 weeks followedby a 7 day washout (drug free) period.
Treatment will continue until disease progression or prohibitive adverse events as detailed in the protocol.
Following endpoints are:
Progression free survival (Primary)
Objective tumour response rate
Clinical benefit rate
Complete response rate
Time ‐to‐treatment failure
Safety/Toxicity/Tolerability
Overall Survival

Inclusion criteria:
1. Adults (over 18 yrs) with histologically confirmed GIST. In CD‐117‐negative cases DOG‐1 must be positive or a
KIT/PDGFRA mutation must be present.
2. Unresectable, metastatic disease.
3. No prior TKI for metastatic disease, with the exception of those patients who have had up to 21 days of uninterrupted
treatment on 400mg daily of imatinib.
4. Imatinib therapy given as an adjuvant treatment and completed at least 3 months prior to entry into this trial is
permitted. Patients who have progression of GIST while on adjuvant therapy are not eligible for this trial.
5. ECOG performance status 0‐2
6. Measurable disease by RECIST version 1.1. (Note: Participants with only peritoneal disease will be eligible only if
they have lesions measurable in two dimensions and have at least 1 lesion which is ≥ 2 cm in size).
7. Adequate bone marrow function (Haemoglobin ≥ 9.0g/dL, platelet count ≥ 100 x 109/L, and absolute neutrophil
count ≥ 1.5 x 109/L).
8. Adequate liver function (Serum total bilirubin ≤1.5 x ULN, INR ≤ 1.5, and ALT, AST, ALP ≤2.5 x ULN (≤ 5 x ULN for
participants with liver metastases). Lipase level must be ≤ 1.5 x ULN.
9. Adequate renal function (Creatinine clearance > 50ml/min) based on either the Cockcroft Gault formula, 24 hour
urine or Glomerular Filtration Rate (GFR scan); and serum creatinine ≤ 1.5 x ULN.
10. Tumour tissue available for central review.
11. Willing and able to comply with all study requirements, including treatment timing and/or nature of required
assessments.
12. Study treatment both planned and able to start within 14 days of randomisation.
13. Signed, written informed consent.

Exclusion criteria:
1. Concurrent GI illness which may prevent absorption of imatinib or regorafenib – please note that prior gastrectomy
or bowel resection does not exclude patients from this study.
2. Use of other investigational drugs within 4 weeks prior to enrolment.
3. Known sensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
4. Participants receiving therapeutic doses of warfarin.
5. Presence of brain metastases.
6. The presence of PDGFR D842V mutation or other mutation known to cause imatinib resistance.
7. Inability to swallow tablets.
8. Arterial thrombotic or ischaemic events, such as cerebrovascular accident or pulmonary embolism within 6 months
prior to randomisation; or major venous thrombotic events requiring use of an anticoagulant such as warfarin within 6
months prior to randomisation.
9. Poorly controlled hypertension (systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite
optimal medical management).
10. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or non healing wound, ulcer or fracture.
11. Congestive cardiac failure (NYHA ≥ grade 2), unstable angina or new onset angina within the previous 3 months,
or AMI within the previous 6 months. Cardiac arrhythmias requiring antiarrhythmic
therapy (beta blockers or digoxin are permitted).
12. Haemorrhage or bleeding event ≥ Grade 3 according to CTCAE v4.0 within 4 weeks prior to randomisation.
13. Ongoing infection of > Grade 2 according to CTCAE v4.0.
14. Active hepatitis B or C or HIV, or chronic hepatitis B or C requiring treatment with antiviral therapy. Testing for these
is not mandatory unless clinically indicated.
15. Interstitial lung disease with ongoing signs and symptoms.
16. Persistent proteinuria of ≥ Grade 3 (>3.5g/24 hours) according to CTCAE v4.0
17. Other significant medical or psychiatric condition judged by the investigator to interfere with protocol requirements.
18. Use of biological response modifiers such as granulocyte colony stimulating factor (G‐CSF), within 3 weeks prior
to randomisation.
19. Patients taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg clarithromycin, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinovir, telithromycin, voriconazole) or strong CYP3A4
inducers (eg carbamazepine, phenobarbitol, phenytoin, rifampicin, St John’s wort).
20. History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated
carcinoma‐in‐situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional
cell carcinoma of the bladder are eligible.
Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5
years after definitive primary treatment.
21. Pregnancy, lactation, or inadequate contraception. Women must be post menopausal, infertile, or use a reliable
means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days
prior to registration. Women of childbearing potential and men must agree to use adequate contraception before
entering the trial until at least 8 weeks after the last study drug administration.

Principal Investigator for this trial: Dr Ivo Hennig

Research Ethics Committee Reference: 16/NE/0112

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NIV Outcomes Study in acute exacerbations of COPD

Summary:
Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) account for 12% of UK hospital admissions. During
an exacerbation, the lungs may be unable to adequately clear carbon dioxide (“waste gas”), and the blood becomes
more acidic as it accumulates (termed respiratory acidaemia). Respiratory acidaemia has a high mortality and noninvasive
ventilation (NIV) can be lifesaving. Clinicians currently lack a simple method to accurately predict outcome and
often overestimate the risk of death resulting in under-use of NIV. We aim to assist decision making by developing a
simple prognostic tool, and in turn challenge nihilism by providing objective outcome data. Our results can inform
discussions about treatment options with patients/families resulting in increased use of NIV in those who will benefit,
and enhanced palliative care provision in those who will not. A simple prognostic tool will have been derived by the
time the proposed study commences.
Patients who survive an episode of respiratory acidaemia have high rates of readmission and can experience a poor
quality of life. When assessing suitability for NIV, the clinician and patient are required to consider the likelihood of the
patient recovering to a quality of life acceptable to them. However, we lack robust data on quality of life recovery and
predictors of poor quality of life. Consequently this discussion is often ill-informed.
The proposed study has 2 facets that should be considered separately.
1) To validate the prognostic tool prospectively in at least 425 consecutively admitted patients both in the trust
where it was developed and in other trusts to ensure it retains predictive accuracy (internal and external validation).
2) Consenting patients surviving to discharge will be undergo a 12-month longitudinal assessment of life after NIV.
This will examine functional status, anxiety and depression, quality of life and willingness to undergo NIV again using
validated questionnaires.

Inclusion criteria:
1. Age 35 years or older.
2. Smoking history greater than or equal to 10 pack years.
3. Obstructive spirometry (FEV1/FVC 6.5 kPa).

Exclusion criteria:
1. Previous inclusion in the study.
2. Other illness likely to limit survival to less than 1 year

Principal Investigator for this trial: Dr Milind Sovani

Research Ethics Committee Reference: 16/NE/0213

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Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding trials(MAGPIE)

Summary:
Premature birth is associated with high rates of death, and worse outcomes in survivors. Over the last 20 years,
respiratory support has improved meaning more babies now survive. Now, the most common causes of serious
illness after the first week are due to gut complications or infections. Necrotising enterocolitis (NEC) is a serious gut
disease occurring in premature babies. NEC affects 1 in 10 babies born more than 8 weeks early; 1 in 3 of them
require major surgery or die. Infections affect 1 in 5 premature babies, may cause death, and doubles the risk of long
term problems such as cerebral palsy. Our group is already undertaking an NIHR funded study (ELFIN) to examine
whether the way we feed premature babies affects rates of infection, NEC and brain outcomes: ELFIN – Enteral
Lactoferrin in Neonates. That study will tell us whether lactoferrin is a useful treatement for all babies, but it does not
tell us how the treatment works. The MAGPIE study (Mechanisms Affecting the Gut of Preterm Infants in Enteral
Feeding Studies) will be run alongside ELFIN in a sub-set of babies (around 480 out of the total 2200 babies
anticipated to join ELFIN). Babies who have joined ELFIN will be eligible to join the MAGPIE study if they are cared for
in a participating hospital. The MAGPIE study simply involves collecting a daily specimen of stool and urine from the
baby during hospital stay, and analysing any residual gut tissue if an operation was needed. The samples will be
analysed to see if the pattern of gut bacteria affects gut function and will tell us how lactoferrin is working. The samples
collected are all non-invasive and pose no additional risk to the baby. They will not affect the conduct of the main ELFIN
study or usual medical treatments.

Inclusion criteria:
Preterm infants Exclusion criteria:
Lack of informed consent

Principal Investigator for this trial: Dr Jon Dorling

Research Ethics Committee Reference:

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A Phase 1, Open-Label, Randomised, Repeat Dose, Parallel Group Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Ferric Maltol at Three Dosage Levels in Paediatric Subjects aged 10-17 years of age with iron deficiency (with or without anaemia)

Summary:
There is an unmet need for an alternative oral (by mouth) treatment for iron deficiency in children and teenagers, and
too avoid the need for intravenous therapy. In children, iron deficiency anaemia (IDA) may cause the following
symptoms tiredness, restlessness, attention-deficit/hyperactivity disorder, irritability, growth retardation, and cognitive
and intellectual impairment. The existing scientific and clinical experience with ferric maltol in the treatment of IDA in
patients with inflammatory bowel disorder (IBD) supports its further investigation in the treatment of iron deficiency/IDA
in children and teenagers. Data from this pharmacokinetics study in children and teenagers will be used to select the
dose(s) for a subsequent Phase 3 paediatric study of Ferric Maltol in the treatment of IDA.
Ferric Maltol is being developed by Shield TX (UK) Ltd., as a new type of oral (by mouth) treatment for iron deficiency
treatment where the iron is surrounded by maltol molecules. Maltol is a natural sugar often used as a food additive.
Ferric maltol makes more iron available in the stomach and intestines. As there is more iron available in the system
for the body to absorb, the study drug can ease anaemia symptoms in iron deficiency anaemic patients.
The purpose of this study is to understand the absorption of iron and absorption and elimination (removal) of maltol in
children and teenagers. Thirty-six participants in the UK (males and females 10-17 years of age) with iron deficiency
will be recruited in the study.

Inclusion criteria:
1. Ability to understand the information given in the Independent Ethics Committee (IEC) approved Information Sheet
and Consent form. The parent or guardian of the study subject must sign and date the informed consent and
authorization to use protected health information (PHI) in accordance with national and local subject privacy
regulations prior to any study mandated procedure. Where appropriate the study participant will be asked to provide
their assent to participate in the study using the IEC approved Assent form.
2. Willing and able to comply with study requirements.
3. Age ≥ 10 to ≤17 years at the time of informed consent and throughout duration of the study.
4. A current diagnosis of iron deficiency (with or without anaemia); iron deficiency defined by ferritin Exclusion criteria:
1. Has untreated or untreatable severe malabsorption syndrome e.g., untreated coeliac disease.
2. Has received within 28 days prior to Screening intramuscular or intravenous (IV) injection or administration of depot
iron preparation.
3. Has received oral iron supplementation within 7 days prior to Screening.
4. Has received blood transfusion within 12 weeks prior to Screening or is scheduled to have blood transfusion or
donations during the study period.
5. Has concomitant disease that would significantly compromise iron absorption or absorbed iron utilisation such as
swallowing disorders and/or extensive small bowel resection.
6. Has chronic renal disease (eGFR 2.0 times
upper normal limit as measured at the Screening visit.
10. Active acute inflammatory disease, including IBD flare or disease exacerbation, which in the opinion of the
Investigator, is clinically significant.
11. Active chronic or acute infectious diseases requiring antibiotic treatment.
12. Pregnant or breast feeding.
13. Concomitant medical conditions with extensive active bleeding, other than menstrual cycles; subjects who suffer
from menorrhagia may be included at the Investigator’s discretion.
14. Scheduled or expected hospitalization and/or surgery during the course of the study
15. Participation in any other interventional clinical study within 28 days prior to Screening.
16. Cardiovascular, liver, renal, hematologic, psychiatric, neurologic, gastrointestinal, immunologic, endocrine,
metabolic, respiratory or central nervous system disease that, in the opinion of the Investigator, may adversely affect
the safety of the subject and/or objectives of the study drug or severely limit the lifespan of the subject.
17. Any other unspecified reason that, in the opinion of the Investigator or the Sponsor make the subject unsuitable for
enrolment.

Principal Investigator for this trial: Dr Jon Jin Kim

Research Ethics Committee Reference: 16/WM/0512

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The cystic fibrosis (CF) anti-staphylococcal antibiotic prophylaxis trial (CF START); a randomised registry trial to assess the safety and efficacy of flucloxacillin as a longterm prophylaxis agent for infants with CF

Summary:
CF START is a national UK trial that will determine the safest and most effective antibiotic strategy for infants
diagnosed with cystic fibrosis (CF). 480 CF infants will be randomly allocated either flucloxacillin prophylaxis (the
current UK standard of care) or antibiotics given in a more targeted manner. The primary outcome will be the age at
first growth of Pseudomonas aeruginosa from a respiratory culture (an important safety measure for families). All
outcomes will be recorded on a national CF Registry, including a number of secondary outcomes assessing
effectiveness and safety. Finally at 40-48 months, a measure of respiratory function will be undertaken in a central
laboratory, which will provide a clearer indication of the effectiveness of these two strategies.

Inclusion criteria:
1. A confirmed diagnosis of cystic fibrosis through one of the following three routes:
– Two CF-causing mutations are identified.
OR
– One or no CF- causing mutations identified and a sweat chloride test result greater than 59 mmol/L.
OR
– Two CFTR mutations (not known CF-causing mutations) and a sweat chloride test result greater than 29 mmol/L.
2. Age 70 days or less.
3. Consent for inclusion on the national UK CF Registry.
4. Consent for inclusion in the CF START trial.

Exclusion criteria:
1. An inconclusive diagnosis after newborn screening (NBS).*
2. A condition (non-CF) that, in the opinion of the recruiting investigator will impact on the long-term management and
outcome of a participant with CF.**
3. Previous growth of PsA from respiratory culture.
4. Infants with a history of hypersensitivity to β-lactam antibiotics (e.g. penicillins) or excipients
5. Infants with a history of flucloxacillin associated jaundice/hepatic dysfunction.
*Infants with an inconclusive diagnosis after NBS (termed ‘CF Screen Positive Inconclusive Diagnosis (CFSPID)’)
should not receive standard CF care and should not be recruited into CF START (Munck et al 2015).
The two situations that result in a diagnosis of CFSPID after NBS are;
• Two CFTR mutations recognised, one or both of which are not characterised as CF-causing and the sweat chloride
is less than 30 mmol/L
• The sweat chloride is repeatedly between 30-59 mmol/L and only one or no CFTR mutations are recognised
**Significant non-CF conditions might include chromosomal abnormality (for example, Down syndrome), cerebral
palsy, chronic lung disease (oxygen requirement) following pre-term birth and other significant congenital anomalies
(for example, severe cardiac disease, tracheo-oesophageal fistula, diaphragmatic hernia).

Principal Investigator for this trial: Professor Alan Smyth

Research Ethics Committee Reference: 16/NW/0629

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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and Safety of Elafibranor in Patients with Nonalcoholic Steatohepatitis (NASH) and fibrosis

Summary:
Nonalcoholic steatohepatitis (NASH) is a disorder that falls as a subgroup of Nonalcoholic fatty liver disease (NAFLD)
and occurs when there is excessive fat build-up in the liver causing damage to the cells and inflammation with or
without scarring (fibrosis).
Eventually, progression of the disease in the Liver will lead to advanced fibrosis, cirrhosis and other liver
complications that include liver failure and liver cancer.
The purpose of this study is to examine how safe and effective Elafibranor is in the treatment of NASH. Patients who
are found to be eligible for the study will be consented and they will follow an initial treatment phase of 72 weeks with
either Elafibranor or a Placebo and then to continue into a long term treatment phase for a total of approximately 72
months.
Participants will be randomised to receive either 120mg Elafibranor or placebo in a 2:1 ratio (Elafibranor:placebo) in a
blinded manner. Treatment groups will be balanced on entry depending on 3 factors: whether they have type 2
diabetes; Gender and their Fibrosis stage. Both elafibranor and the placebo will be provided as a white to off-white
round coated tablet with no printed inscription.
Patients will receive the drug they will require at every study visit once they are randomised onto the study and
instructed to take one tablet per day orally before breakfast with a glass of water each morning. During the first
treatment phase visits will be every 12 weeks and Clinical and biological evaluation will be performed during the First
Treatment Period.
This is a multicentre, multinational, randomised, double-blind study comparing the efficacy and safety of Elafibranor to
a placebo in patients with NASH
Study Sites: This study is to be conducted at approximately 220 study sites worldwide.

Inclusion criteria:
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the trial:
1. Males or females aged from 18 to 75 years inclusive at first Screening Visit.
2. Must provide signed written informed consent and agree to comply with the study protocol.
3. Body Mass Index ≤45 kg/m².
4. Females participating in the study must either not be of childbearing potential (hysterectomy, bilateral oophorectomy,
medically documented ovarian failure, or >50 years of age with cessation of menses for at least 12 months due to
ovarian failure) or using efficient double contraception: hormonal contraception (including patch, contraceptive ring,
etc), intra-uterine device, or other mechanical contraception method + condom or diaphragm or spermicide for the full
duration of the study and for 1 month after the end of treatment.
5. Histological confirmation of steatohepatitis on a diagnostic liver biopsy by central reading of the slides (biopsy
obtained within 6 months prior to Randomization or during the Screening Period) with at least 1 in each component of
the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3).
6. NAS score ≥4.
7. Fibrosis stage of 1 or greater and below 4, according to the NASH CRN fibrosis staging system. For patients with
fibrosis stage 1, only patients at high risk of progression will be included meaning with a NAS score ≥5 and 2 of the
following conditions: persistent elevated ALT, obesity defined by a BMI 30, metabolic syndrome (NCEP ATP III
definition), type 2 diabetes, or HOMA-IR >6.
8. Patients agree to have 1 liver biopsy during the Screening Period for diagnostic purpose (if no historical biopsy
within 6 months before Randomization is available), 1 liver biopsy after 72-weeks of treatment for assessment of the
treatment effects on NASH, as well as another in case of suspicion of cirrhosis (to have a histological confirmation),
and a final liver biopsy after approximately 4 years of treatment (visit V13), unless a biopsy has already been
performed within the year.
9. Stable dose of vitamin E (>400 IU/day), polyunsaturated fatty acids (>2 g/day), or ursodeoxycholic acid from at least 6
months prior to diagnostic liver biopsy.
10. For patients with type 2 diabetes, glycemia must be controlled. If glycemia is controlled by antidiabetic drugs, no
change in anti-diabetic therapy is allowed within 6 months prior to diagnostic liver biopsy, under the following
conditions:
o no change in dose for patients treated by glucagon-like peptide 1 agonist
o no qualitative change (i.e. implementation of a new anti-diabetic drug) for patients treated by metformin, dipeptidylpeptidase
4 inhibitors, sodium/glucose cotransporter 2 inhibitors, sulfamides, or insulin.

Exclusion criteria:
Patients who meet any of the following criteria will be excluded from entering the study:
1. Known heart failure (Grade I to IV of New York Heart Association classification).
2. History of efficient bariatric surgery within 5 years prior to Screening.
3. Uncontrolled hypertension during the Screening Period despite optimal antihypertensive therapy.
4. Type 1 diabetes patients.
5. Patients with decompensated diabetes (hemoglobin A1c [HbA1c] >9.0%). If abnormal at the first Screening Visit, the
HbA1c measurement can be repeated at the latest 2 weeks prior to Randomization. A repeated abnormal HbA1c
(HbA1c >9.0%) leads to exclusion.
6. Patients receiving thiazoledinediones (pioglitazone, rosiglitazone), unless the drug was discontinued at least 6
months before the diagnostic liver biopsy.
7. Patients with a history of clinically significant acute cardiac event within 6 months prior to Screening such as: acute
cardiovascular episode, stroke, transient ischemic attack, or coronary heart disease (angina pectoris, myocardial
infarction, revascularization procedures).
8. Weight loss of more than 5% within 6 months prior to Randomization.
9. Compensated and decompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, NASH
patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded.
10. Current or recent history (12
14. Where applicable, patients not covered by Health Insurance System and/or not in compliance with the
recommendations of National Law in force.
15. Patients who cannot be contacted in case of emergency.
16. Known hypersensitivity to the investigation product or any of its formulation excipients.
17. Patients with previous exposure to elafibranor.
18. Patients who are currently participating in, plan to participate in, or have participated in an investigational drug or
medical device trial within 30 days or five half-lives, whichever is longer, prior to Screening.

Principal Investigator for this trial: Professor Guruprasad P Aithal

Research Ethics Committee Reference: 16/NE/0147

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MEDI4736 combinations in metastatic renal cell carcinoma

Summary:
This study is being carried out to see if the drugs MEDI4736, savolitinib and tremelimumab can be used alone or in
combination to reduce the size of tumours in patients with kidney cancer.
The drugs being tested in this study have an anti-tumour effect and have been tested in pre-clinical and human
studies before. MEDI4736 and tremelimumab work with the immune system to help the body fight against tumour
cells with immune cells. Savolitinib works to correct a faulty signal which causes tumour growth.
There are strict inclusion and exclusion criteria for this trial. Broadly speaking, patients with histologically confirmed
advanced or metastatic renal cell cancer with a component of either clear cell cancer or papillary cancer are eligible.
If a patient is eligible for the study and decides to take part, they will be enrolled into one of 3 stages of the study.
-First stage: aims to find the optimal dose of MEDI4736+savolitinib.
-Second stage: patients with papillary cell cancer will be treated with MEDI4736+savolitinib. Patients with clear cell
cancer will be randomised to one of four treatment arms and receive MEDI4736, savolitinib, MEDI4736+savolitinib, or
MEDI4736+tremelimumab.
-Third stage: patients will be tested for biomarkers before enrolment, and depending on the results will be allocated to
one of 3 treatments (MEDI4736, savolitinib, or MEDI4736+tremelimumab) to see if certain biomarkers are linked to
drug efficacy.
All patients will have regular scans, blood tests, and reviews with the clinical team. Patients will be offered optional
tumour biopsies. The team will compare the patient’s results from before, during and after treatment in order to see
how well the drugs work and if they are safe. Treatment will stop after 12 months, or if the patient’s disease
progresses.
Patients will only be involved in one stage of the study.
The study is being carried out in hospitals in England, Scotland, Wales, France and Spain

Inclusion criteria:
150
-Written informed consent prior to performing any protocol-related procedures, including study specific screening
procedures
-Age ≥ 18 years at the time of study entry
-Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
-Life expectancy ≥12 weeks
-Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or metastatic (stage IV)
renal cell cancer with a component of either clear cell cancer or papillary cancer. Patients with a component of both
must be enrolled into the cohort with the predominant tumour type
—Clear cell renal cancer patients must have experienced progressive disease after exposure to VEGF targeted
therapy
—Papillary cell renal cancer patients must be considered to be VEGF treatment naive or treatment refractory to be
eligible
-Evidence of measurable disease (i.e., ≥1 malignant tumour mass that can be accurately measured in at least 1
dimension ≥ 20 mm with conventional computerized tomography CT Scan or Magnetic Resonance Imaging (MRI), or
≥10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites,
peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic
lesions, or irradiated lesions are not considered measurable
-Adequate normal organ, marrow and coagulation function as defined by the following criteria: —Haemoglobin ≥
9.0g/dL
—Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/uL) without growth factor support
—Platelet count ≥ 100 x 109 /L (≥100,000/uL)
—Total serum bilirubin ≤1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed
Gilbert’s syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of
haemolysis or hepatic pathology], who will be allowed only in consultation with their physician
—Serum transaminases (AST/ALT) ≤2.5 x the institutional ULN
—GFR ≥40mL/min as assessed using the standard methodology at the investigating sites (e.g. by Cockroft-Gault)
—International Normalisation Ration (INR) Exclusion criteria:
-Participation in another clinical study with an investigational product within 28 days prior to enrolment
-Any previous treatment with an anti−programmed death−1 (PD-1), or anti−PD-L1 therapeutic antibody, CD137
agonists, c-MET inhibitors or pathway-targeting agents, or CTLA-4. Patients with limited c-MET inhibitor exposure must
be discussed with the CI
-Receipt of the last dose of anti-cancer therapy within 2 weeks or five half-lives of the anti-cancer therapy prior to the
first dose of study drug, or radical radiotherapy within 4 weeks prior to the first dose of study drug
-Receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates which have a
narrow therapeutic range within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort)
-Currently receiving treatment with therapeutic doses of warfarin sodium
-Current or prior use of immunosuppressive medication within 21 days before the first dose of MEDI4736 or
tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at
physiological doses
-Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug, whichever is shorter,
prior to enrolment
-Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736 or
anticipation that such a live, attenuated vaccine will be required during the study
-Symptomatic or uncontrolled brain metastases requiring concurrent treatment, including surgery, radiation and/or
corticosteroids
-History of another primary malignancy other than RCC within 3 years prior to Cycle 1, Day 1 (see protocol for
exceptions)
-Mean resting QT interval corrected for heart rate >470ms calculated from triplicate ECGs
-Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or
interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or
superior vena cava syndrome)
-Any unresolved toxicity of CTCAE grade >2 from previous anti-cancer therapy. Patients with irreversible toxicity that is
not expected to be exacerbated by the IMP may be included
-Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any
unresolved irAE >Grade 1
-Active or prior documented autoimmune disease within the past 2 years including myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular
thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-
Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
-Active or prior documented inflammatory bowel or history of gastrointestinal disorders which may interfere with the
absorption of the study drug
-History of primary immunodeficiency
-History of allogeneic prior allogeneic stem cell or solid organ transplant
-History of hypersensitivity to MEDI4736, tremelimumab, or any excipient or history of severe allergic, anaphylactic, or
other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
-History of hypersensitivity to savolitinib and its excipients
-Uncontrolled intercurrent illness including, ongoing or active infection, symptomatic congestive heart failure,
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or any factors that increase the risk of QTc
prolongation, any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, active peptic
ulcer disease or gastritis, Type I diabetes mellitus, active bleeding diatheses including any subject known to have
evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or compromise the ability of the subject
to give written informed consent
-Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater),
myocardial infarction within 3 months prior to enrolment, Patients with a known left ventricular ejection fraction Principal Investigator for this trial: Professor Poulam Patel

Research Ethics Committee Reference: 15/SC/0640

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A PHASE Ib, BLINDED, RANDOMIZED,MULTICENTER, MULTIPLE-ASCENDING DOSESTUDY OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF UTTR1147A ADMINISTERED BY SUBCUTANEOUS INJECTION IN PATIENTS WITHNON-HEALING NEUROPATHIC DIABETIC FOOTULCERS

Summary:
Ulceration of the foot associated with diabetes mellitus is a common and disabling condition. Besides control of the
underlying diabetes, the current best standard of care (SOC) for Diabetic Foot Ulcers (DFUs) includes local ulcer care
with frequent cleaning and debridement, (removal of dead and hard skin, usually with a scalpel) control of any
infection, pressure-relieving strategies, and restoration of blood flow to the foot if needed.
The aim of this study is to test the safety of study drug UTTR1147A at different dose levels. UTTR1147A is a version of
a protein called interleukin-22 which helps to fight infection and repair tissue damage by encouraging the growth of
new tissue. There is currently only one ongoing study of UTTR1147A in healthy volunteers. Because the results are
blinded, not all of the side effects of this treatment are known.
This study is sponsored by Genentech Inc. About 66 – 90 patients, will take part in this double blind placebo
controlled study at approximately 15 sites in Europe. There will be at least 18 study visits if the patient’s ulcer remains
open through the duration of treatment. If the patient’s ulcer is still open at the end of the treatment period, the patient
will be followed weekly and SOC ulcer treatment will continue for 8 weeks in the observation period. If an ulcer is
confirmed closed at any time during the study, the patient may be followed every 4 weeks during the observation
period. Procedures involved include a physical examination, vital signs (pulse and blood pressure), blood tests,
ECGs, a foot X-Ray, tests for blood flow to the affected foot and DFU related assessments.
Based on the patient’s status of their DFU at the end of the 2-week run-in period (infected or not), patients will be
randomly assigned to one of 4 treatment cohorts (A. B, C or D) to receive either UTTR1147A or placebo. Cohorts A, B,
or D, will have a 2 to 1 chance of being treated with UTTR1147A. Group C have an equal chance of receiving either
UTTR1147A or placebo. Patients in Cohort D will undergo small biopsies from the edge of the ulcer in addition.
Neither the participant nor the study doctor will know what treatment was assigned.

Inclusion criteria:
• Signed Informed Consent Form
• Age ≥ 18 to ≤ 80 years
• Up to date on all age-appropriate cancer screenings per local standards or, if
not up to date or not sure about their status, document their understanding of the possible tumor-promoting risks of
UTTR1147A
• Have a diagnosis of Type 1 or Type 2 diabetes. Diagnosis may be established by medical records and history of
treatment or HbA1c ≥ 6.5%.
• Peripheral neuropathy that is confirmed by demonstrating loss of sensation with
use of a 10 g (5.07 Semmes-Weinstein) monofilament (IWGDF 2015)
• Have adequate circulation to the foot as documented by an Ankle Brachial
Index (ABI) > 0.7 AND at least one of the following:
Toe Brachial Index (TBI) ≥ 0.50
Doppler waveform in the posterior tibial or dorsalis pedis arteries at the
ankle consistent with adequate flow in the foot (biphasic or triphasic)
Transcutaneous oxygen pressure > 40 mmHg
• Have an ulcer area at screening (on Day 14) as follows for the index ulcer:
1−5 cm2 for Cohorts A, B, C
2−5 cm2 for Cohort D
• Have infection status of the index ulcer (per IDSA 2012 Guidelines) at the end of the run-in as follows:
No infection for Cohorts A and B
Mild infection for Cohorts C and D
• Have an index ulcer as follows:
Present for > 4 but ≤ 52 weeks at the initial screening visit
Located below the malleoli on the plantar or dorsal surface of the forefoot or midfoot
Extends into the dermis or SC tissue without evidence of exposed muscle,
tendon, bone, or joint capsule
• Able to comply with the study protocol, in the investigator’s judgment
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use
a method of contraception having a failure rate of 1 year but Exclusion criteria:
• Have an index ulcer that is as follows (as determined by the investigator or
designated staff):
A decrease in surface area > 20% during the run-in from Day − 14 to Day 1
An increase in surface area > 20% during the run-in from Day − 14 to Day 1
Of non-diabetic pathophysiology
On the heel
Over an active/acute Charcot deformity
Over 5 cm on its longest dimension as measured on Day 14
With maximum depth >1cm on Day −14
With either positive probe to bone (PTB) test or positive foot X-Ray for osteomyelitis
Necrotic areas remaining after extensive sharp debridement at initial screening
Have moderate or severe index ulcer infection as defined by the IDSA/IWGDF classification at the screening visit or
any time prior to randomization
In cases where the patient has more than one foot ulcer, these criteria will not apply to any ulcer other than the index
ulcer.
• Have current evidence of osteomyelitis, cellulitis, or evidence of systemic infection including fever or pus drainage
from the index ulcer site at the screening visit or any time prior to dosing Have current evidence of osteomyelitis,
cellulitis, or evidence of systemic infection including fever or pus drainage from the index ulcer site at the
screening visit or any time prior to dosing
• Have gangrene present on any part of the affected foot
• Known PAD requiring revascularization
• Any significant edema in the foot with the index ulcer that may interfere with drug administration or ulcer
assessments in the judgment of the investigator
• Pregnant or lactating, or intending to become pregnant any time until 56 days
after the last dose of study drug
• Women of childbearing potential who have a positive serum pregnancy test
result at screening on Day 7 or a positive urine pregnancy test on Day 1
•Use of an investigational drug or participation in an investigational study within
30 days or 5 half-lives before administration of study drug, whichever is greater
• Have a glycated hemoglobin A1c (HbA1c_ level of > 12% assessed at screening
• Are currently receiving dialysis
• Are receiving oral or parenteral corticosteroids, immunosuppressive, or cytotoxic agents
• Positive Fecal Immunochemical Test (FIT) at screening
• Have active malignancy or any history of a malignancy
• First degree relative or two second-degree relatives with gastrointestinal (e.g.,
colorectal) cancer
• Have a known or suspected allergy to primary or secondary dressing materials
used in this trial
• History of moderate or severe allergic or anaphylactic/anaphylactoid reactions
to chimeric, human, or humanized antibodies, fusion proteins, or murine
proteins or hypersensitivity to UTTR1147A (active drug substance) or any of the
excipients
• Has had or is currently undergoing, or is planning for, ulcer treatments with enzymes, growth factors, living skin,
dermal substitutes, or other advanced therapies, devices, or procedures
• Skin disorders that would in the opinion of the investigator, interfere with the
assessment or treatment of the index ulcer
• Skin lesion observed during examination that, in the investigator’s judgment, is
suspicious for malignancy unless fully evaluated by a dermatologist and deemed non-cancerous
• Planned procedure or surgery during the study
• Positive for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), or HIV antibody
• Illicit drug or alcohol abuse within 12 months prior to screening, in the opinion of
the investigator
• Any serious local or systemic infection requiring IV antibiotics within 3 months
prior to dosing, unless permitted by the Medical Monitor
•Current use of oral antibiotics for any reason other than mild infection of theindex ulcer at the time of screening
• Any serious medical condition or abnormality in clinical laboratory tests that, in
the investigator’s judgment, precludes the patient’s safe participation in and
completion of the study
• Donation or loss of whole blood (excluding the volume of blood that will be drawn during screening procedures) as
follows: 50−499 mL of whole blood within 30 days or >
499 mL of whole blood within 56 days prior to study drug administration
• History or presence of an abnormal electrocardiogram (ECG) that is clinically
significant in the investigator’s opinion, including complete left bundle branch
block, second- or third-degree heart block
• QT interval corrected using Fridericia’s formula (QTcF) > 440 ms demonstrated
by at least two ECGs > 30 minutes apart
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias
• Active coronary artery disease (CAD) or major adverse cardiac event (MACE)
within the past 18 months
• Congestive Heart Failure greater than Class II

Principal Investigator for this trial: Dr Kamal Chokkalingam

Research Ethics Committee Reference: 16/EE/0040

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SINGLE ARM STUDY OF ALXN1210 IN COMPLEMENT INHIBITOR TREATMENT-NAÏVE ADULT AND ADOLESCENT PATIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS)

Summary:
The purpose of this study is to determine the ability of a new drug, ALXN1210, to treat the disease atypical Hemolytic
Uremic Syndrome (aHUS) in adolescent and adult patients. aHUS is a rare, life-threatening, genetic disease that can
damage vital organs such as the kidneys, heart and brain. A drug similar to ALXN1210, called eculizumab (brand
name Soliris), is currently the standard of care for aHUS patients.
ALXN1210 is being developed for the treatment of disorders involving the complement system, a branch of the body’s
immune system that fights against infection. In aHUS, the complement system is not controlled properly and this can
result in damage to the blood vessels, known as thrombotic microangiopathy (TMA). In TMA, platelets (which are
required for normal blood clotting) become overactive and form clots in blood vessels throughout the body. These
clots can block blood flow, create inflammation, and travel to other organs, causing further damage.
ALXN1210 is classified as an immunosuppressant drug as it works by suppressing the activity of a specific portion of
the complement system. aHUS is an example of a complement disease that could be eventually treated with
ALXN1210. Patients with aHUS who have not had any previous treatment with a complement inhibitor are eligible.
The dose of ALXN1210 received by patients will be based on body weight. ALXN1210 will be administered
intravenously into a vein and blood samples will be collected throughout the study for various analyses.
There are 3 periods in this study: Screening Period (up to 7 days), a 26-week Initial Evaluation Period and an
Extension Period (up to 2 years). The duration of participation in the study is estimated to be approximately 2 and a half
years. It is expected that approximately 200 centres will be opened around the world in order to enrol 55 participants.

Inclusion criteria:
1. Male or female patients ≥ 12 years of age and weighing ≥ 40 kg at the time of consent.
2. Evidence of TMA, including thrombocytopenia, evidence of haemolysis, and kidney dysfunction, based on the
following Screening Visit laboratory findings:
a. Platelet count 3 days after the day of childbirth.
5. To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients must be vaccinated against
meningococcal infections within 3 years prior to, or at the time of, initiating study drug. Patients who receive a
meningococcal vaccine less than 2 weeks before initiating ALXN1210 treatment must receive treatment with
appropriate prophylactic antibiotics until 2 weeks after vaccination. Patients who have not been vaccinated prior to
initiating ALXN1210 treatment should receive prophylactic antibiotics prior to and for at least 2 weeks after
meningococcal vaccination.
6. Patients Exclusion criteria:
Patients will be excluded from study enrollment if they meet any of the following criteria:
1. Known ‘a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13’ (ADAMTS13)
deficiency (activity Principal Investigator for this trial: Dr Catherine Byrne

Research Ethics Committee Reference: 16/EM/0436

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A novel antimicrobial urinary catheter for long-term catheter users: a study of its safety

Summary:
Long-term urinary catheter users are at risk of catheter-associated urinary tract infections (CAUTI). This can mean
courses of antibiotics, early removal of the catheter, blockage of the catheter, and other serious complications for
patients. We have added to exisiting, licensed silicone urinary catheters three antimicrobial drugs which prevent
bacteria from attaching to the catheter to prevent infection. Laboratory studies show that this antimicrobial catheter can
prevent catheter colonisation by the main bacteria that cause CAUTI for 7-12 weeks. In order to bring this catheter to
long-term catheter users we need to understand if there are any side effects associated with the antimicrobial urinary
catheter.
Therefore, we plan to undertake an initial study of the safety of this antimicrobial urinary catheter in 60 adult, long-term
urinary catheters users (those patients who have had a catheter in place for at least 28 days and will require another
for at least 28 days) from Nottingham University Hospitals Trust. Consenting participants will receive the antimicrobial
urinary catheter at their next planned catheter insertion, and will be asked to answer questions regarding experience
with the antimicrobial catheter via 15 minute telephone interviews at 24 hours, 48 hours, 72 hours and every week after
the catheter is inserted. The participants’ involvement will range from 28 days to 84 days depending on their normal
catheterisation schedule (ie if they have their catheter changed every 6 weeks, the antimicrobial catheter will remain in
place for 6 weeks). The participants will also be asked to fill in a questionnaire about their interest and understanding
of a future randomised controlled trial which will inform the sample size calculation and feasibility for this future study.
Finally, at the end of the trial when the catheter is removed, it will be collected and analysed in the laboratory for
bacterial attachment.

Inclusion criteria:
The inclusion criteria for participation in this study are as follows:
– The participant must be aged 16 years or older
– The participant must have had a urethral urinary catheter in situ for 28 days or more and will require another urethral
urinary catheter for 28 days or more
– The participant must be able to understand spoken and written English as well as speak English fluently
– The participant must be able to verbally respond and speak on the phone about their treatment

Exclusion criteria:
The exclusion criteria for this study includes:
– Participants that are currently pregnant or likely to become pregnant
– Participants lacking the ability to consent for themselves
– Participants with allergy to any of the following:
– Rifampicin
– Sparfloxacin (or any other fluoroquinolone antibiotic)
– Triclosan
– Silicone
– Participants with a history of uncontrolled/unmanageable autonomic dysreflexia
– Participants with significantly impaired bladder and urethral sensation

Principal Investigator for this trial: Mr Richard J Parkinson

Research Ethics Committee Reference: 16/WM/0353

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Safety and efficacy of opicapone in clinical practice in Parkinson’s Disease patients with wearing-off motor fluctuations

Summary:
The study plans to collect more information about how well and how safe a new medication called opicapone (OPC) is at treating Parkinson’s disease with wearing-off motor fluctuations. Wearing-off motor fluctuation is a complication in Parkinson’s disease. During wearing-off, the symptoms of Parkinson’s disease re-appear or worsen before the next dose of medication is due, and improves after the next dose of medication is taken. Participants will be invited to take part in the study if they have Parkinson’s Disease with wearing-off motor fluctuations and are currently being treated with a medication containing Levodopa. Participants will be on the study for 6 months and will have to take opicapone, every day as capsule, at least one hour before bed or after their last daily dose of Levodopa. The study will be run at NHS hospitals.

Inclusion criteria:
1. Able to comprehend and willing to sign an informed consent form.
2. Male and female subjects aged 30 years or older.
3. Diagnosed with idiopathic PD according to the UK Parkinson’s Disease Society
Brain Bank Clinical Diagnostic Criteria.
4. Disease severity Stages I-IV (modified Hoehn &Yahr staging) at ON.
5. Treated with three to seven daily doses of L-dopa/DDCI or L-dopa/DDCI/entacapone,
which can include a slow-release formulation.
6. Signs of “wearing-off” phenomenon according to the 9-Symptom Wearing-off
Questionnaire (WOQ-9), despite optimal anti-PD therapy (based on the
investigator’s judgement). The wearing-off phenomenon has to be confirmed
clinically by the investigator.
7. For females: Postmenopausal for at least two years or surgically sterile for at
least six months before screening.

Exclusion criteria:
1. Non-idiopathic PD (atypical parkinsonism, secondary [acquired or symptomatic]
parkinsonism, Parkinson-plus syndrome).
2. Severe OFF periods. Patients with rare and/or short unpredictable OFF periods are
eligible.
3. Previous or current use of tolcapone and/or OPC.
4. Treatment with monoamine oxidase inhibitors (MAO-A and MAO-B; except selegiline
up to 10 mg/day in oral formulation or 1.25 mg/day in buccal absorption
formulation or rasagiline up to 1 mg/day or safinamide up to 100 mg/day) within
the month before screening.
5. Concomitant treatment with entacapone.
6. Previous or planned (during the entire trial duration) deep brain stimulation.
7. Previous or planned stereotactic surgery (e.g. pallidotomy, thalamotomy) or
previous or planned use of apomorphine or levodopa-carbidopa intestinal gel
(LCIG) pumps during the trial period.
8. Use of any other investigational medicinal product (IMP), currently or within the
three months (or within five half-lives of the IMP, whichever is longer) before
screening.
9. Any medical condition that might place the subject at increased risk or interfere
with assessments.
10. Past (within the past year) or present history of suicidal ideation or suicide
attempts.
11. Current or previous (within the past year) alcohol or substance abuse excluding
caffeine or nicotine.
12. Phaeochromocytoma, paraganglioma, or other catecholamine secreting neoplasms.
13. Known hypersensitivity to the ingredients of IMP (including lactose intolerance,
galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption).
14. History of neuroleptic malignant syndrome (NMS) or non-traumatic rhabdomyolysis.
15. Severe hepatic impairment (Child-Pugh Class C).
16. For females: Breastfeeding.
17. Employees of the investigator, trial centre, sponsor, clinical research
organisation and trial consultants, when employees are directly involved in the
trial or other studies under the direction of this investigator or trial centre,
and their family members.

Principal Investigator for this trial: Dr Jonathan Evans

Research Ethics Committee Reference: 16/EE/0357

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Randomised Efficacy & Safety Trial with Oral S 44819 after Recent ischemic cerebral Event (RESTORE) : international, multi-centre, randomised, double-blind, placebo-controlled phase II study

Summary:
This study is looking at the effectiveness and safety of 2 doses of S44819 in patients’ functional and cognitive recovery
after a recent disabling ischemic stroke. A total of 580 patients, male or female, aged between 18 and 80 years old will
take part in the study in 13 countries including the UK.
Preclinical/clinical studies show that post ischemic stroke there is an increased activity of GABAergic neurons to
defend the brain from nerve damage during this acute phase, due to reduced oxygen and energy supply. Increased
GABAergic activity however has a negative effect on neuroplasticity (how the brain adapts its activities, allowing
neurons to compensate for injury). Studies have shown that continued GABAergic activity is linked to poorer outcome.
It seems GABA-Aα5 receptors in particular have an important function in this activity.
S44819 is a competitive antagonist of the GABA-Aα5 receptor, currently in phase 1 development for functional recovery
(movement/cognition) after ischemic stroke. Patients require a Magnetic resonance imaging (MRI) to exclude a
lacunar stroke (blood flow to one of the small arterial vessels deep within the brain becomes blocked).
Patients will be given either 150mg or 300mg of S44819 or dummy drug twice daily over the course of 90 days and
have a 15 day follow (no drug).
Efficacy will be evaluated using several rating scales – to evaluate disability and dependency in daily activities after stroke, and 2 patient questionnaires to evaluate cognitive impairment.
Safety evaluation is done regarding adverse events, vital signs, blood analysis (blood cell counting, chemistry), heart
check up (electrocardiogram), assessment of suicide ideation/behaviour.
Patients will be asked to participate in an optional pharmacogenetic sub-study to do analysis of genetic variations aiming to allow better nderstanding of the efficacy and safety of the drug.

Inclusion criteria:
– Signed informed consent (by the patient or an authorised representative).
– Patients aged between 18 and 80 years (both inclusive).
The upper limit has been set as age is consistently reported as one of the most important factors predicting poor
functional outcome and most stroke studies (for example thrombolysis studies) have used an upper age limit of 80
years, data on patients aged >80 years are more sparse so that it would be difficult to get enough information about
prognostic factors and natural history of stroke in this age group necessary to adequately power the RESTORE-Brain
study. Once S 44819 has demonstrated improvement of post-stroke recovery in this population, it is foreseen to use
less restrictive inclusion criteria in Phase III studies, including age.
– Acute ischemic stroke that occurred at least 48 hours and less than 144 hours (both inclusive) before selection. If the
exact stroke onset time is unknown, patients can be included if the time interval between last seen well and stroke
discovery is less than 12 hours.
– No previous disability (neither physical nor cognitive pre-stroke impairment).
– NIHSS 7-20 (both inclusive).
– Patient clinically stable according to the investigator’s judgement.
– Brain MRI results available with at least DWI, T2*, FLAIR and showing an acute supratentorial cortical ischemic
stroke.
– Able to undertake rehabilitation after discharge from recruiting neurological department (e.g. in a specialised centre
and / or ambulatory and / or at home).
– Normal laboratory blood tests, ECG
– Negative pregnancy test (if applicable)
– patient or authorised representative willing to attend study visits
-Women of child-bearing potential must use a highly effective method of birth control e.g. intra uterine devices (IUDs),
intrauterine hormone-releasing system (IUS), true sexual abstinence (if in line with preferred and usual lifestyle),
sterilization or male partner sterilization (vasectomy). The barrier method of contraception i.e. condom or cap with
spermicide is slightly less effective but acceptable.

Exclusion criteria:
– Absence of signed informed consent (patient or an authorised representative),
– Unlikely to cooperate in the study
– Participation in another interventional study at the same time or within a time period of 3 months or already selected
in this study,
– Unable to undertake rehabilitation after the discharge from hospital.
– Carotid endarterectomy or endovascular therapy of brain or of neck vessels likely to be required during the next 3
months.
– Any previously clinically significant laboratory abnormalities likely to interfere with the ability to participate in the study
and/or with the study outcome, or from the local laboratory test (at least haemoglobin, platelets, leucocytes, creatinine,
creatinine clearance or eGFR (according to MDRD formula), AST, ALT and total bilirubin must be done) likely to
interfere with the ability to participate in the study and / or with the study outcome,
– Known severe renal impairment: creatinine clearance 3 x Upper Normal Limit
AST and/or ALT >2 x Upper Normal Limit + total bilirubin > Upper Normal Limit,
– Known positive HIV serology, unresolved hepatitis B and/or C infection,
-Any pathological findings not related to the stroke found during the physical examination and likely to interfere with the
conduct of the study
-Severe co-morbid medical conditions with a life expectancy 480ms (at least on 2 ECGs out of 3),
– Regular intake of benzodiazepine during the last month or longer that cannot be stopped without exposing the patient
to withdrawal side-effects,
– Pre-existing psychiatric disease likely to impact the clinical evaluations during the study,
– Class III or class IV Heart failure according to the New York Heart Association (NYHA) classification,
– Chronic alcohol abuse or drug abuse or addiction, as judged by the investigator (excluding nicotine). Refraining from
drinking alcohol is strongly recommended throughout the study.
– Epileptic seizure during the last 2 years or treatment for epilepsy during the last 12 months,
– Pregnancy, breastfeeding or possibility of becoming pregnant during the study or positive urinary or blood pregnancy
test
– Female patients with child bearing potential and procreative male patients not willing to use effective contraception
methods throughout the treatment period and at least 15 days after last treatment intake.
– Patient or authorised representative refusing to attend study visits or to take part in the study.

Principal Investigator for this trial: Dr Nikola Sprigg

Research Ethics Committee Reference: 16/WM/0317

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RCT of the efficacy and safety of an ICS/ LABA reliever therapy regimen in asthma (Novel START)

Summary:
We are investigating the safety and effectiveness in mild asthma of 3 treatment regimens:
1. A combination inhaled corticosteroid (ICS) and longacting beta agonist (LABA) inhaler on an as required (PRN)
basis in patients with mild asthma.
2. An as required short acting beta agonist (SABA).
3. Regular inhaled corticosteroid (ICS) with a SABA inhaler used as required.
Each participant will be randomised to one of the three treatment arms (as above) for a 52 week study period. There
are 7 scheduled visits in total (Visit 0 may be combined with Visit 1). The initial clinic visit involves obtaining informed
consent, reviewing eligibility for inclusion, collecting medical history and baseline respiratory function, asthma
questionnaires about asthma severity and medication compliance, and a blood test. All inhaler medication will be
provided to participants during clinic visits along with an asthma management plan specific to their arm of treatment.
Inhalers will be fitted with a usage monitoring device. Data can be downloaded at each clinic visit.
Education will be provided around inhaler technique and use. Each of the following 6 clinic visits will involve collecting
data from the inhaler monitors, repeating lung function testing and the asthma questionnaires, as well as
reviewing any asthma exacerbations or other reasons to withdraw a participant from the study.
The main outcome of the study is the rate of participants’ experiencing worsening of their asthma symptoms and how
frequently this happens in each of the three treatment groups. We can use these results to compare the different
inhaler regimens to see if one is more effective at controlling asthma symptoms. This information will help to guide
future management of patients with asthma.

Inclusion criteria:
1. Adults aged 18 to 75 years.
2. Self-report of a doctor’s diagnosis of asthma with:
a. Self-reported use of a SABA on ≥2 occasions in the previous 4 weeks but on average ≤2 occasions per day in the
previous 4 weeks, if there have been no severe exacerbations in the last 12 months, or
b. Self-reported use of a SABA on average ≤2 occasions per day in the previous 4 weeks, if there has been a history of
a severe exacerbation in the last 12 months.
3. Willing and able to give informed consent for participation in the trial.
4. In the Investigator’s opinion, able and willing to comply with all trial requirements.
5. Willing to allow their General Practitioner and/ or consultant, if appropriate, to be notified of participation in the trial.

Exclusion criteria:
1. Self-reported use of ICS, LABA, leukotriene receptor antagonist, theophylline, anticholinergic agent or cromone as
regular maintenance therapy in the 3 months before potential study entry. Note nasal corticosteroid therapy is
permitted.
2. Self-reported past admission to the Intensive Care Unit (ICU) with life-threatening asthma (patients at highest risk of
adverse asthma outcomes).
3. Self-reported hospital admission for asthma in the 12 months before potential study entry (patients at highest risk of
adverse asthma outcomes).
4. Self-reported treatment with oral prednisone in the six weeks before potential study entry, representing recent
unstable asthma.
5. A home supply of prednisone for use in worsening asthma.
6. Self-reported diagnosis of COPD, bronchiectasis or interstitial lung disease.
7. Self-reported greater than 20 pack year smoking history, or onset of respiratory symptoms after the age of 40 years
in current or ex-smokers with ≥10 pack year history.
8. Self-reported current pregnancy or breast feeding at the time of enrolment or planned pregnancy within the study
period.
9. Self-reported congestive heart failure, unstable coronary artery disease, atrial fibrillation or other clinically significant
cardiac disease.
10. Unwilling or unable to switch from current asthma treatment regimen.
11. Other illness(es) likely to compromise participant safety or impact on the feasibility of results, at the discretion of
the investigator.
12. Self-report of participation in another research trial involving an investigational product, in the past 12 weeks.
13. An on treatment FEV1 ≤50% of predicted at Visit 1 (predicted values must be calculated using the Global Lung
Function Initiative equations).

Principal Investigator for this trial: Dr Timothy W Harrison

Research Ethics Committee Reference: 16/SC/0453

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Long Term investigative Follow-up in TrialNet (LIFT)

Summary:
The aim of this study is to provide long term follow up information on people who have previously taken part in a
TrialNet study. Participants will be invited to join this study at the end of an intervention trial or when they are
diagnosed with diabetes in either the TrialNet Natural History study or another TrialNet intervention study.
The long term effects of receiving an intervention or of being diagnosed with diabetes at an early point in the disease
process will be studied. This will help fill the gaps in knowledge about what changes occur around the time of
diagnosis of type 1 diabetes and beyond, and the impact of prediabetes
values to postdiagnosis
clinical course.
Study visits will be either annual or semi annual and will involve a Mixed Meal tolerance test or an oral glucose
tolerance test depending on participant cpeptide
and diabetes status on entry to the study.
As the study is designed to give long term follow up information an end date has not been set and participants can stay
in follow up as long as LIFT continues.

Inclusion criteria:
Participants must meet all the following inclusion criteria:
1. Type 1 diabetes
2. Prior participation in TrialNet Study
3. Willing to give informed consent/assent

Exclusion criteria:
1. Be deemed unable or unlikely to comply with the protocol.

Principal Investigator for this trial: Dr Peter Mansell

Research Ethics Committee Reference: 14/SW/0073

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Long Term investigative Follow-up in TrialNet (LIFT)

Summary:
The aim of this study is to provide long term follow up information on people who have previously taken part in a
TrialNet study. Participants will be invited to join this study at the end of an intervention trial or when they are
diagnosed with diabetes in either the TrialNet Natural History study or another TrialNet intervention study.
The long term effects of receiving an intervention or of being diagnosed with diabetes at an early point in the disease
process will be studied. This will help fill the gaps in knowledge about what changes occur around the time of
diagnosis of type 1 diabetes and beyond, and the impact of prediabetes
values to postdiagnosis
clinical course.
Study visits will be either annual or semi annual and will involve a Mixed Meal tolerance test or an oral glucose
tolerance test depending on participant cpeptide
and diabetes status on entry to the study.
As the study is designed to give long term follow up information an end date has not been set and participants can stay
in follow up as long as LIFT continues.

Inclusion criteria:
Participants must meet all the following inclusion criteria:
1. Type 1 diabetes
2. Prior participation in TrialNet Study
3. Willing to give informed consent/assent

Exclusion criteria:
1. Be deemed unable or unlikely to comply with the protocol.

Principal Investigator for this trial: Dr Peter Mansell

Research Ethics Committee Reference: 14/SW/0073

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A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone.

Summary:
This trial involves patients with advanced prostate cancer. This trial will compare a group on hormone tablets alone with a group on combination of hormone tablets and a radioactive substance. This trial is supported by the European Organisation for Research and Treatment of Cancer (EORTC).

Doctors often treat advanced prostate cancer with a hormone therapy injection or on rare occasions by removal of both testicles. Both these treatments usually stop working after 13 to 22 months. This trial will
recruit these men whose prostate cancer is no longer responding to hormone injections or removal of testicles. Prostate cancer often spreads to bones and more than 90% of men with advanced prostate cancer have secondary cancer in their bones at this stage. Cancer that has spread to the bones can cause significant pain. The secondary cancer in bone significantly affects the men’s ability to enjoy life.

Radium 223 is a new type of radioactive injection. Radium 223 specifically targets cancer cells in the bones. Radium 223 spares lot of normal body tissues and lose its radioactivity very quickly. Radium 223 is safe to use and is already approved for use in advanced prostate cancer in UK and Europe. Enzalutamide is also a newly licensed hormone therapy tablet that is proven to work in patients after the first hormone injection has failed to work.

This trials aims to find out
>> if men having Enzalutamide tablets in combination with Radium 223 injection have longer duration of cancer control in bones compared to men having Enzalutamide tablets alone;
>> if men having the combination treatment live longer, have less bone complications, better pain control and have a better quality of life.
The trial also aims to collect the safety information in men having Radium 223 injections in combination with Enzalutamide tablets and in men having Enzalutamide tablets alone.

Inclusion criteria:
♦Histologically confirmed diagnosis of prostate adenocarcinoma
♦ Asymptomatic or mildly symptomatic (defined as no opioids and Brief Pain Inventory score, i.e. short form question #3 worst pain must be 25 g/L
♦ Normal cardiac function according to local standard by 12-lead ECG (complete, standardized 12-lead recording).
♦ Able to swallow the study drug and comply with study requirements
♦ Prior or concomitant therapy.
-Prior docetaxel is permitted under the following conditions: started within 2 months of ADT initiation, given for a maximum of 6 cycles and progression after 6 months of the last dose of docetaxel.
-Previous treatment with bicalutamide, flutamide, prednisone, or dexamethasone is allowed if it was stopped at least 4 weeks prior to randomization.
♦ Patients taking bisphosphonates or denosumab are eligible if they have received a stable dose for 4-weeks or more prior to randomization. (These treatments may then be continued on study).
♦ Drugs known to lower the seizure threshold or prolong QT interval are not permitted.
♦ Participants who have partners of childbearing potential must use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after last dose of enzalutamide and 6 months after the last dose of Ra223. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
♦ Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
♦ For participation in translational research, specific consent must be given.

Exclusion criteria:
♦ Known central nervous system metastases or leptomeningeal tumor spread.
♦ Significant cardiovascular disease including:
-Myocardial infarction within 6 months prior to screening.
-Uncontrolled angina within 3 months prior to screening.
-Congestive heart failure New York Heart Association (NYHA) class III or IV, or patients with history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram or multigated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%
-History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation,torsades de pointes).
-History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
-Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 millimeters of mercury (mm Hg) or diastolic blood pressure > 105 mm Hg at screening.
-Hypotension as indicated by systolic blood pressure Principal Investigator for this trial: Dr Santhanam Sundar

Research Ethics Committee Reference: 16/EM/0017

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A Phase I trial of pre-operative, margin intensive, stereotactic body radiation therapy for previously untreated borderline resectable pancreatic cancer

Summary:
In 2010, 8,463 people in the UK were diagnosed with pancreatic cancer and there were 7,901 deaths. In 20052009, 5yr overall survival is 4%. Only 20% of patients are amenable to surgery. Even in resected patients receiving optimum adjuvant chemotherapy, median survival is 24 months. Standard therapy for patients with borderline resectable pancreatic cancer in Europe is upfront surgery then adjuvant chemotherapy. The role of neoadjuvant radiotherapy in pancreatic cancer has been rarely addressed.

One of the significant challenges is to improve outcome post-surgery
by achieving clear resection margins. Positive margins have been reported in >35% of patients in the largest adjuvant trial in pancreatic cancer. Patients with positive margins have poor outcome.

The use of pre-operative RT/CRT is considered standard in some tumours where it has been shown to reduce risk of local recurrence and prolong survival. Its role in pancreas is less clear, possibly because pancreatic tumours are more radio-resistant.

Stereotactic body radiation therapy (SBRT) is a technique where an ablative dose of RT is delivered to a small volume targeting the surgical margin in a short time, achieving higher dose than conventionally fractionated RT. The short delivery and minimal acute toxicity makes this an attractive treatment option.

This study aims to test the safety and benefit of preoperative SBRT. We propose 5 fractions to decrease the risk of late normal tissue injury.

The non-interventional phase of followup at the end of study will also allow us to estimate the efficacy of pre-operative SBRT on overall survival and progression free survival.

We will recruit up to 24 patients from 3 UK centres. Eligible patients will receive 5 fractions of stereotactic radiotherapy over 5-8 days, and surgery will take place 5-6 weeks after radiotherapy. Patients will be on the study for 36 weeks.

Inclusion criteria:
1. Borderline resectable localised tumour of the pancreatic head/uncinate process/body (tumours of the tail of pancreas are not eligible for inclusion) as defined by CT +/MRI +/PET criteria within 28+/7 days prior to D1 SBRT.
2. Histologically proven pancreatic ductal adenocarcinoma or cytological proven pancreatic malignancy.
3. Able to undergo biliary drainage using a stent.
4. Deemed fit and suitable for surgical resection.
5. Male or female, Age ≥ 16 years.
6. Life expectancy of at least 6 months.
7. ECOG performance status 01
8. The patient is willing and able to comply with the protocol for the duration of the study, and scheduled follow-up visits and examinations.
9. Written (signed and dated) informed consent and be capable of cooperating with protocol.
10. Haematological and biochemical indices within given ranges.

Exclusion criteria:
1. Distant metastatic disease or local disease that cannot be encompassed in the SBRT field.
2. History of previous or concurrent malignancy diagnoses (except curatively-treated basal cell carcinoma of skin, carcinoma in situ of cervix; curatively treated cancer of other sites who are recurrence free for >3 years).
3. Serious medical or psychological condition precluding neo-adjuvant treatment and surgical resection.
4. Previous upper abdominal or chest wall radiotherapy.
5. Pregnancy. Pregnant or breastfeeding women or women of childbearing potential unless effective methods of contraception are used.
6. Any other psychological, social or medical condition, physical examination finding or laboratory abnormality that the Investigator considers makes the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of the trial results.

Principal Investigator for this trial: Dr Eleanor James

Research Ethics Committee Reference: 15/SC/0059

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A PHASE 3, LONG-TERM ACTIVE TREATMENT EXTENSION STUDY OF MONGERSEN (GED-0301) IN SUBJECTS WITH CROHN’S DISEASE

Summary:
The purpose of this clinical research study is to test the long-term effects of an investigational (being tested) study
medication, named mongersen or GED-0301. This study is designed to find out how well the body tolerates GED-
0301 over a long period of time, and if GED-0301 can or cannot improve the symptoms of Crohn’s disease over a
period of up to 4 years. The study medication, GED-0301, has not been approved for the treatment of Crohn’s
disease and its use in this study is investigational.
A computer program will determine which study treatment the subject had received in the original Phase 3 GED-0301
study and from this will decide which of the 5 study treatment groups, GED-0301 with or without placebo (a sugar pill
that contains no study medication but looks exactly like the study medication tablet) they will be assigned to in this
GED-0301 extension study. The computer makes this decision based on whether the subject had improvement or no
improvement in the original GED-0301 treatment study.
This study is double-blinded (neither the subject or study team will know which treatment the subject is receiving) for
the entire 208 weeks for the purpose of preserving the blind of the subject’s treatment allocation in the original Phase
3 GED-0301 study.
The maximum time a subject will be in the study is 216 weeks or 4 years and 2 months for a total of 55 visits.
The study will consist of 3 periods:
– Screening Period – up to 4 weeks (ie, 1 day to 28 days depending on when long-term
active treatment is available for the subject at the study centre)
– Long-term Active Treatment Period – 208 Weeks (Week 0 to Week 208)
– Follow-up Period – 4 weeks (ie, no investigational product [IP] taken)

Inclusion criteria:
Subjects must satisfy the following criteria to be screened and enrolled in the study:
1. Subject is a male or female ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Subject must have completed through Week 12 in the previous GED-0301 study AND
either:
Completed participation through the last study treatment visit
at Week 52 in Study GED-0301-CD-002 or at Week 12 in Study GED-0301-CD-003
OR
Met the “early escape criteria” (Appendix H) and were discontinued after Week 12 in Study GED-0301-CD-002.
5. Females of child bearing potential (FCBP)must have a negative pregnancy test at
screening and enrollment (Visits 1 and 2). While on IP and for at least 28 days after
taking the last dose of IP, FCBP who engage in activity in which conception is possible must use one of the approved
contraceptive options described below:
Option 1: Any one of the following highly effective methods: hormonal
contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or
partner’s vasectomy
OR
Option 2: Male or female condom PLUS 1 additional barrier method: (a) diaphragm
with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with
spermicide
6. Male subjects (including those who have had a vasectomy) when engaging in sexual
activity with females who are able to become pregnant must use barrier contraception
(male latex condom or nonlatex condom NOT made out of natural [animal] membrane
[for example, polyurethane]) while on IP and for at least 28 days after the last dose.

Exclusion criteria:
The presence of any of the following will exclude a subject from screening and enrolment:
1. Subject had experienced a serious adverse event (SAE) related to the IP while
participating in the previous Phase 3 GED-0301 study.
2. Subject has any continuing serious medical condition, laboratory abnormality, or
psychiatric illness that occurred while participating in the previous Phase 3 GED-0301 study.
3. Subject has or had a flare or worsening of CD that, in the opinion of the Investigator, would not be in the best interest
for the subject to participate in this long-term active treatment study.
4. Subject has initiated biologic agents, such as TNF-α blockers or integrin antagonists.
5. Subject has been diagnosed with colorectal cancer or colorectal dysplasia (with the exception of adenomatous
colonic polyps that have been completely resected) while
participating in the previous Phase 3 GED-0301 study.
6. Subject has a newly diagnosed malignancy while participating in the previous Phase 3 GED-0301 study. (However,
subject may be allowed to enter into this study on a case by case basis after discussion with the Sponsor.)
7. Subject is pregnant or breastfeeding.
8. Subject has been newly diagnosed with substance abuse.
9. Subject has developed a known hypersensitivity to oligonucleotides, GED-0301 or any ingredient in the IP.

Principal Investigator for this trial: Dr Gordon Moran

Research Ethics Committee Reference: 16/WS/0005

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Stratified Treatment OPtimisation for HCV-1 (STOPHCV-1)

Summary:
New treatments for Hepatitis C (HCV) can be taken for shorter periods of time, with less severe side-effects compared to previous treatments (6-12 months). Almost all people are cured with 12 weeks of treatment; it is unknown what the minimum duration of treatment could be in order to achieve cure, there have been limited investigations into shorter treatments.
The protocol has been designed as a platform protocol to look at varying (intervention) 4-6 weeks vs fixed (control) 8 weeks of first-line combined Direct Acting Antivirals (DAA) treatment with or without ribavirin for patients with mono-Hepatitis or co-infection (HIV/HCV) with genotype (GT) 1a/1b and mild disease:
A fixed dose triple combination of 3 novel direct acting antivirals (DAA); the Abbvie combination ombitasvir/paritaprevir/ritonavir (12.5mg/75mg/50mg) co-formulated film-coated tablets once daily (total daily dosage: 25/150/100mg) plus one dasabuvir 250 mg tablet twice daily (total daily dosage: 500mg) will be used plus or minus ribavirin (Ribavirin will be dosed twice daily, adjusted for weight).
The intervention duration will be stratified by baseline HCV RNA on a sliding scale, duration will be determined by estimated time for HCV RNA to decline to reduce levels to ~1 copy in the whole body at the end of treatment. If viral
failure is detected at any time from 4 weeks post-randomisation (first-line failure) patients will stop first line therapy and be treated with a fixed dose combination of sofosbuvir/ledispavir (400mg/90mg) once a day and ribavirin twice daily adjusted for by weight.
Visits will be on day 3, 7, 14 and 28 after randomisation, then every other week until 4 weeks post end of (first-line) treatment (EOT), then 4 weekly until 12 weeks post EOT, then 24 weeks after EOT a similar schedule will be followed for retreatment visits. Each visit will include a clinical assessment for adverse event outcomes and blood draw for standard safety tests and to check the level of virus.

Inclusion criteria:
1. Adults ≥18 years
2. Infected with HCV genotype 1a/1b with HCV RNA >LLOQ on more than one occasion at least six months previously with no intervening results showing undetectable viraemia
3. Plasma HCV RNA >LLOQ at screening
4. No evidence of significant liver fibrosis resulting from any aetiology (defined as Fibroscan* score ≤7.1kPa, equivalent to F0-F133, within 180 days prior to planned randomisation or biopsy consistent with mild fibrosis (Ishak score = 18 kg/m2
6.Laboratory tests: platelets >= 60 x109/l, haemoglobin >12 g/dl (male) or >11 g/dl (female), creatinine clearance (estimated glomerular filtration rate (eGFR) (Cockcroft-Gault)) >=60 mls/min, international normalised ratio (INR) 24 weeks

Exclusion criteria:
1. Previous DAA exposure (previous treatment with pegylated-interferon and/or ribavirin allowed)
2. FEMALES ONLY: Pregnant or planning to become pregnant for the duration of the study and within 4 months of the end of the study
3. MALES only: planning pregnancy in female partner during the study and within 7 months of the end of the study
4. Malignancy within 5 years of screening
5. Any condition in the judgement of the investigator which might limit the patient’s life expectancy.
6. Currently receiving medication known to interact with study medication (i.e. ombitasvir/paritparevir/dasabuvir/ritonavir, sofosbuvir, ledipasvir, ribavirin)
7. Disorder which may cause ongoing liver disease including, but not limited to active hepatitis B, ongoing alcohol misuse
8. Any disorder which in the opinion of the investigator may have a significant negative impact on the ability of the patient to adhere to the trial regimen
9. Use of other investigational products within 60 days of screening

Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 15/EE/0435

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A PHASE 3, LONG-TERM ACTIVE TREATMENT EXTENSION STUDY OF MONGERSEN (GED-0301) IN SUBJECTS WITH CROHN’S DISEASE

Summary:
The purpose of this clinical research study is to test the long-term effects of an investigational (being tested) study
medication, named mongersen or GED-0301. This study is designed to find out how well the body tolerates GED-
0301 over a long period of time, and if GED-0301 can or cannot improve the symptoms of Crohn’s disease over a
period of up to 4 years. The study medication, GED-0301, has not been approved for the treatment of Crohn’s
disease and its use in this study is investigational.
A computer program will determine which study treatment the subject had received in the original Phase 3 GED-0301
study and from this will decide which of the 5 study treatment groups, GED-0301 with or without placebo (a sugar pill
that contains no study medication but looks exactly like the study medication tablet) they will be assigned to in this
GED-0301 extension study. The computer makes this decision based on whether the subject had improvement or no
improvement in the original GED-0301 treatment study.
This study is double-blinded (neither the subject or study team will know which treatment the subject is receiving) for
the entire 208 weeks for the purpose of preserving the blind of the subject’s treatment allocation in the original Phase
3 GED-0301 study.
The maximum time a subject will be in the study is 216 weeks or 4 years and 2 months for a total of 55 visits.
The study will consist of 3 periods:
– Screening Period – up to 4 weeks (ie, 1 day to 28 days depending on when long-term
active treatment is available for the subject at the study centre)
– Long-term Active Treatment Period – 208 Weeks (Week 0 to Week 208)
– Follow-up Period – 4 weeks (ie, no investigational product [IP] taken)

Inclusion criteria:
Subjects must satisfy the following criteria to be screened and enrolled in the study:
1. Subject is a male or female ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Subject must have completed through Week 12 in the previous GED-0301 study AND
either:
Completed participation through the last study treatment visit
at Week 52 in Study GED-0301-CD-002 or at Week 12 in Study GED-0301-CD-003
OR
Met the “early escape criteria” (Appendix H) and were discontinued after Week 12 in Study GED-0301-CD-002.
5. Females of child bearing potential (FCBP)must have a negative pregnancy test at
screening and enrollment (Visits 1 and 2). While on IP and for at least 28 days after
taking the last dose of IP, FCBP who engage in activity in which conception is possible must use one of the approved
contraceptive options described below:
Option 1: Any one of the following highly effective methods: hormonal
contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or
partner’s vasectomy
OR
Option 2: Male or female condom PLUS 1 additional barrier method: (a) diaphragm
with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with
spermicide
6. Male subjects (including those who have had a vasectomy) when engaging in sexual
activity with females who are able to become pregnant must use barrier contraception
(male latex condom or nonlatex condom NOT made out of natural [animal] membrane
[for example, polyurethane]) while on IP and for at least 28 days after the last dose.

Exclusion criteria:
The presence of any of the following will exclude a subject from screening and enrolment:
1. Subject had experienced a serious adverse event (SAE) related to the IP while
participating in the previous Phase 3 GED-0301 study.
2. Subject has any continuing serious medical condition, laboratory abnormality, or
psychiatric illness that occurred while participating in the previous Phase 3 GED-0301 study.
3. Subject has or had a flare or worsening of CD that, in the opinion of the Investigator, would not be in the best interest
for the subject to participate in this long-term active treatment study.
4. Subject has initiated biologic agents, such as TNF-α blockers or integrin antagonists.
5. Subject has been diagnosed with colorectal cancer or colorectal dysplasia (with the exception of adenomatous
colonic polyps that have been completely resected) while
participating in the previous Phase 3 GED-0301 study.
6. Subject has a newly diagnosed malignancy while participating in the previous Phase 3 GED-0301 study. (However,
subject may be allowed to enter into this study on a case by case basis after discussion with the Sponsor.)
7. Subject is pregnant or breastfeeding.
8. Subject has been newly diagnosed with substance abuse.
9. Subject has developed a known hypersensitivity to oligonucleotides, GED-0301 or any ingredient in the IP.

Principal Investigator for this trial: Dr Gordon Moran

Research Ethics Committee Reference: 16/WS/0005

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Assessment and Treatment of patients with Amblyopia using interactive binocular computer games

Summary:
This study will treat amblyopia (lazy eye) using 3-D computer technology and active shutter glasses. Computer games and DVD’s are viewed through the active shutter glasses and are specially prepared to preferentially stimulate the lazy eye; the child can only play the games accurately if they are using their lazy eye. The study is funded by the NIHR and will be undertaken as a randomised control trial to compare this against normal computer games and DVD viewing combined with continuing refractive adaptation i.e. wearing glasses if necessary (a process that is known to occur for up to 30 weeks). Patients will receive 6 weeks of treatment (recommended 30 mins minimum of play time on 6 days per week for 6 weeks in the treatment arm) and level of vision will be assessed after 6 weeks. The visual improvement (they will be wearing glasses if necessary and also undergoing refractive adaptation) will be compared with the control group. Patients will return to standard care after the trial period which, at 6 weeks, should not affect the final visual outcome in a negative way. The participants will be recruited from patients currently attending one of the 4 trial sites (Nottingham University Hospitals NHS Trust, Cambridge University Hospitals NHS Foundation Trust, Moorfields Eye Hospital and Royal Stoke University Hospital) and will have a diagnosis of amblyopia, and be aged between 3 years 6 months and 9 years 11 months. Current treatments for amblyopia include wearing an eye patch over the good eye for up to 6 hours per day, or using eye drops to blur the image in the good eye for periods of 4 weeks at a time. The aim is both to avoid the need for patching or eye drops (which are unpopular treatments) and to get an improved visual outcome.

Inclusion criteria:
Assessment study – The inclusion criteria are children aged between 3.5 -9 years and with an amblyopic eye with vision of 0.3 logMAR or worse in the amblyopic eye.

– Clinical trial – The child must be aged between 3 years 6 months and 9 years 11 months (upper limit is one day before their 10th birthday on day of consent.)
– Visual acuity difference of at least 0.2 log units, with the amblyopic eye being 0.3 logMAR or worse. Must have undergone a minimum of 12 weeks refractive adaptation.
– Those in group one must not have had patching or penalisation at all previously but the other two groups’ participants may have had previous patching/penalisation.
– Must not have had previous strabismus surgery (for groups one and two, and for group three, they must start the treatment within 4 weeks of having surgery, but no other previous surgery).
– Must be able to use the I-BiT plus system.

Exclusion criteria:
Assessment study – Exclusion criteria are inability to perform the tests on I-BiT (a screening log will be maintained) , stimulus deprivation amblyopia, presence of manifest nystagmus or presence of any other ophthalmological or neurological disease affecting the visual pathway.

– Clinical trial – Stimulus deprivation amblyopia.
– Other ocular or neurological disease affecting the visual system (including Down’s syndrome, developmental delay, Craniofacial syndrome,Foetal Alcohol Syndrome, and cerebral palsy among other conditions).
– Presence of manifest nystagmus.
– Parent, guardian or child not prepared to give consent.

Principal Investigator for this trial: Mr Alex J Foss

Research Ethics Committee Reference: 16/EM/0224

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CORE – A randomised trial of COnventional care versus Radioablation (stereotactic body radiotherapy) for Extracranial oligometastases

Summary:
Metastatic spread of cancer from its primary site to distant organs is the commonest cause of death from cancer. The term oligometastases describes an intermediate metastatic state, in which cancer exists as a limited number of metastases at first, before cells acquire the ability to metastasise more widely. For the large majority of solid cancers, once metastatic disease has been diagnosed the chances of cure are small. There are several situations where this is not the case, but it is not known if stereotactic body radiotherapy (SBRT) for oligometastatic disease will alter outcomes or whether the toxicity burden of this treatment is justified. SBRT is targeted radiotherapy which destroys cancer cells in the area of the body it is aimed at however low dose radiation may be received by surrounding tissue. It is difficult to quantify incidence of patients with multiple primary cancers developing at intervals that are representative of oligometastatic stage IV disease, (defined for the purposes of this trial as ≤ 3 metastatic sites). However an increase in the use of surveillance imaging, together with improved diagnostic sensitivity has led to the diagnosis of patients with asymptomatic oligometastatic relapse becoming a more common clinical occurrence. The CORE study is a randomized controlled trial that will be conducted in patients with cancer in one of three primary sites where oligometastatic disease relapse is a common clinical scenario: breast, prostate and non-small cell lung cancer (NSCLC). The study will evaluate the use of SBRT in this patient population. Eligible patients who consent to participate in this clinical trial will be randomized to receive standard care or standard care plus SBRT we hope to recruit approximately 206 patients to the study and the primary outcome measure is progression free survival.

Inclusion criteria:
INCLUSION CRITERIA:
1. Age ≥ 18 years.

2. WHO performance status 0-2.

3. Histological confirmation of primary malignancy (histological confirmation of metastasis is not mandatory but should be performed in any situation where there is diagnostic uncertainty). Patients with breast, NSCLC or prostate primary malignancies are eligible.

4. Predicted life expectancy > 6 months.

5. ≤ 3 metastatic lesions (total). A maximum of 2 different organ systems (e.g. liver, lung, bone, nodal) may contain metastases but the total number of lesions must not exceed 3. For example, a patient with 3 liver metastases or 1 liver metastasis and 2 lung metastases would be eligible. A patient with 1 lung metastasis, 1 liver metastasis and an adrenal metastasis is ineligible.

6. All metastases must be visible, imaging defined targets and be suitable for treatment with SBRT in accordance with the dose fractionation options specified in the protocol. (See the associated CORE trial radiotherapy delivery guidelines for detailed SBRT guidance by metastatic site.

7. Patients who have received prior ablative therapy (e.g. surgery, RFA or SBRT) for metastatic disease are eligible, as long as this site is controlled on imaging at the point of trial entry and the total number of metastases over time since diagnosis of metastatic disease does not exceed 3. Patients with 2 or 3 metastases in which ablative therapy (e.g. surgery/RFA) to 1 site is deemed appropriate as part of standard therapy may be entered into the trial after ablative treatment, following successful delivery of clinical treatment.

8. Metachronous metastatic disease presentation only. Primary site must be controlled. Disease-free interval from completion of radical treatment (including any adjuvant therapy) to diagnosis of metastases:
– Breast: ≥ 6 months. Patients who have relapsed whilst on adjuvant endocrine therapy are eligible.
– NSCLC: ≥ 4 months
– Prostate: ≥ 6 months. Patients who have relapsed whilst on adjuvant endocrine therapy are eligible.

9. Systemic therapy naïve in the metastatic setting. Prior systemic therapy is permitted in the adjuvant setting is permitted. Concurrent endocrine therapy with SBRT is allowed.

10. Adequate baseline organ function to allow SBRT to all relevant targets dependent on location of metastatic subsite for necessary baseline investigations).

11. Negative pregnancy test (for women of childbearing potential.

12. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

13. Written informed consent.

Exclusion criteria:
EXCLUSION CRITERIA:
1. Intra-cranial metastases.

2. Malignant pleural effusion.

3. Malignant peritoneal disease.

4. Any single metastasis >6cm,( >5cm for lung metastases).

5. Prior radiotherapy to a site that precludes safe delivery of SBRT.

6. Co-morbidities precluding staging or follow up imaging, or precluding procedures required to facilitate SBRT.

7. Loco-regional nodal relapse where surgery or regional field radiotherapy is standard of care. Patients with supraclavicular, axillary and internalmammary nodal relapse from breast cancer are excluded.

8. Spinal cord compression.

9. Any condition or significant clinical co-morbidities that precludes the safe delivery of SBRT (eg history of clinically significant diffuse interstitial lung disease if SBRT to lung metastases or lesions adjacent to lungs are considered or clinically significant colitis ie ulcerative colitis /Crohn’s disease if SBRT to the pelvis or abdomen is considered).

10. Prostate cancer patients previously relapsing on Androgen Deprivation Therapy (ADT) or CAB and receiving abiraterone, enzalutamide or docetaxel are ineligible.

11. Patients whose entry to the trial will cause unacceptable clinical delays to their planned management.

Principal Investigator for this trial: Dr Claire Esler

Research Ethics Committee Reference: 16/LO/0529

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Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction – UK multicentre collaboration “MINERVA”

Summary:
Sudden cardiac death (SCD) is responsible for over 3 million deaths worldwide annually. These deaths could be prevented with implantable cardioverter defibrillators (ICDs). Choosing appropriate patients for ICDs can be extremely difficult, leading to patients who we think are “high-risk” receiving ICDs without ever using them, while the majority of SCD occurs in a large population regarded as “low-risk”.

At Leicester we have developed the Regional Restitution Instability Index (R2I2) and Peak ECG Restitution Slope (PERS). These are numerical values of cardiac risk, based on the electrocardiogram (ECG) which is a simple everyday test performed to record the rhythm and electrical activity of the heart. R2I2 and PERS take into account subtle differences in the electrical properties around different regions of the heart. We have already shown these tools to be effective in a series of small studies performed at Leicester that were recently published.

The study will recruit patients from the some of the UK’s leading specialist cardiac centres. Suitable patients will include those enlisted for ICD implants who also have ischaemic heart disease (caused by narrowing of arteries). Entering the study will involve an extra test performed during ECG recording at the time of ICD implant via the ICD device itself. The test is not painful, will not involve extra visits to the hospital and will take around 20 minutes to perform. The stored data is analysed to calculate R2I2 and PERS and values are later correlated with patient outcomes.

R2I2 and PERS are simple and inexpensive to perform. If the findings from our previous studies are replicated, we will move closer to being able to incorporate them into clinical practice. Implementing these tests in patients being considered for ICDs has the potential to save lives and reduce the burden of harm and cost by improving the allocation of ICDs.

Inclusion criteria:
● Participant is willing and able to give informed consent for participation in the study
● Male or Female, aged 18 years or above
● Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the study and for 3 months thereafter
● Diagnosed with a history of ischaemic cardiomyopathy
● Stable dose of current regular medication (specify type if needed) for at least 4 weeks prior to study entry.
● Able (in the Investigators opinion) and willing to comply with all study requirements.
● Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study
● Patients must be able to attend follow up at the study site until the study closure
● Attending for first time primary prevention ICD (including CRT-D) implantation under NICE criteria [18] (see Table 3):
● Patients must be able to read and understand English

Exclusion criteria:
QRS level:
1) QRS interval Principal Investigator for this trial: Dr Andrew Staniforth

Research Ethics Committee Reference: 16/NI/0069

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A 52-week, multicenter, randomized, double-blind, placebo controlled study to assess the efficacy and safety of QAW039 when added to existing asthma therapy in patients with uncontrolled severe asthma

Summary:
Asthma presents a major global health burden. Despite existing therapies, there is still significant unmet medical need in asthma, with an estimated 300 million people affected worldwide. Uncontrolled asthma has a prevalence of greater than 6 million patients worldwide.

Currently, there is a need for well tolerated, easily-administered, anti-inflammatory therapies. QAW039 is an experimental medicine being tested for the treatment of people with asthma. The purpose of this study is to see if QAW039 works better than placebo (dummy drug) when taken with usual asthma medicines (Standard-of-Care treatment). The aim of treatment is to determine if QAW039 can reduce the number of asthma attacks, make asthma symptoms better and improve quality of life.

If a participant gives consent to take part, they will be randomly assigned to one of three treatment groups on an equal basis:

(1) QAW039 150 mg once daily
(2) QAW039 450 mg once daily
(3) Placebo to QAW039 once daily

100 UK participants will be recruited at approx 20 sites and remain in the study for about 14 months. 846 participants with severe asthma aged 12 years and older will be recruited globally in to the study. Participants will be separated in to two groups based on their eosinophil (a type of blood cell) count. Participants will attend 12 study visits.

Inclusion criteria:
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained within 14 days prior to or at Visit 1 before any assessment is performed including any adjustment to asthma medication.
2. Male and female patients aged ≥12 years.
3. Patients must have a diagnosis of asthma (according to GINA 2015) for a period of at least 24 months prior to Visit 1.
4. Patients have been treated with high-dose inhaled corticosteroids plus a LABA (or alternate therapy: montelukast or theophylline or tiotropium) with or without maintenance oral corticosteroids for at least 3 months prior to Visit 1(See GINA 2015 for the definition of high dose ICS and controller options). The doses must have been stable for at least 4 weeks prior to Visit 1.
5. FEV1 of ≥40% and ≤80% of the predicted normal value for the patient, after withholding bronchodilators at Visit 1 and Visit 101.
6. Demonstration of inadequate control of asthma based on an ACQ score ≥1.5 at Visit 1.
7. A history of 2 or more asthma exacerbations within the 12 months prior to Visit 1 that
required either:
– Treatment with systemic corticosteroids (tablets, suspension or injection) .
OR
– Hospitalization (defined as an inpatient stay or >24-hour stay in an observation area in the emergency room of other equivalent facility.
8. A clinical diagnosis of asthma supported by at least one of the following:
An increase of ≥12% and ≥200 ml in FEV1 within 30 minutes after administration of 400 mcg of salbutamol/albuterol (or equivalent dose) prior to randomization. All patients must perform a reversibility test at Visit 1. If reversibility is not demonstrated at Visit 1*, the following historical information may be used:
– Documented evidence of reversibility that was performed according to ATS/ERS guidelines (ATS/ERS 2005) with the 2 years prior to Visit 1. Where a patient is assessed as eligible based on historical evidence of reversibility, a copy of the original printed spirometry report with relevant spirometry tracings must be available as source documentation.

– Documented evidence of a positive airways hyper-reactivity (AHR) test result within the 2 years prior to or at Visit 101, defined as a provoked fall in FEV1 of 20% by methacholine at ≤8 mg/ml (or histamine ≤10 mg/ml or acetylcholine Exclusion criteria:
1. Use of other investigational drugs within 5 halflives of enrollment, or within 30 days until the expected pharmacodynamic effect has returned to baseline, whichever is longer
2. Patients who have participated in another trial of QAW039
3. History of hypersensitivity to any ingredients of the study drugs/drugs related to QAW039
4. Patients who have a clinically significant ECG abnormality such as (but not limited to) sustained ventricular tachycardia, or clinically significant second/third degree AV block without a pacemaker
5. Patients with a history of familial long QT syndrome or known family history of Torsades de Pointes
6. Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at Visit 1/Visit 101
7. Patients receiving any medications or other agents known to prolong QT interval
8. Patients with a history of malignancy of any organ, treated or untreated, whether or not there is evidence of local recurrence of metastases, with the exception of local basal cell carcinoma of the skin
9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
10. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless using effective methods of contraception during study treatment
11. Patients who have smoked or inhaled tobacco products within the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack years
12. Patients who have had an asthma attack/exacerbation requiring systemic corticosteroids hospitalization or emergency room visit within 6 weeks prior to Visit 1 13. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks of Visit 1
14. Patients with any chronic condition of the respiratory tract which may interfere with study evaluation or optimal participation in the study
15. Patients with a history of chronic lung disease other than asthma, including (but not limited to) chronic obstructive pulmonary disease, bronchiectasis, (non-clinically significant bronchiectasis may be allowed provided recent [within 3 months prior to Visit 101] CT scan proof is available), sarcoidosis, interstitial lung disease, cystic fibrosis, and tuberculosis
16. Patients with uncontrolled diabetes having an HbA1c test result ≥8% at Visit 101
17. Patients who have a clinically significant laboratory abnormality at Visit 1/Visit 101
18. Patients who have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease,
neurodegenerative diseases, or other neurological disease, uncontrolled hypoand hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical
condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study
19. Patients with a history of myocardial infarction within 12 months of Visit 1
20. Patients with serious comorbidities including, but not limited to, neurodegenerative diseases, rheumatoid arthritis and other autoimmune diseases
21. Patients with a history of alcohol or drug abuse within 12 months prior to Visit 1
22. Patients with a weight 2 X ULN at Visit 1
36. Patients on rifampin, probenecid, ritonavir and valproic acid

Principal Investigator for this trial: Dr Dominick Shaw

Research Ethics Committee Reference: 15/EM/0500

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A randomized phase III trial of Palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for hormone receptor positive (HR+) / human epidermal growth factor receptor 2 (HER2)-negative early breast cancer

Summary:
Although many patients with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) early breast cancer may be cured of their disease with optimal local and systemic therapy, a significant number of patients with stage II and III disease will experience disease recurrence. Adjuvant endocrine therapy for breast cancer can be extremely effective, particularly with extension beyond 5 years. However disease recurrence can occur, with risk distributed over the decades following initial diagnosis. Methods to improve the effectiveness of endocrine therapy, and delay the onset of resistance, are therefore needed.

HR+ breast cancer biologically may demonstrate features suggestive of sensitivity to CDK4/6 inhibition with drugs such as palbociclib. Given the demonstrated activity and safety of palbociclib in the first-line treatment of metastatic HR+/ HER2- breast cancer, supporting FDA approval, there is interest in whether the benefits of CDK4/6 inhibition may translate into the adjuvant setting. The PALLAS study has been designed to investigate this question, as to whether palbociclib given in addition to endocrine therapy can reduce the risks of recurrence in women with early stage (II and III) breast cancer. Whilst palbociclib has FDA approval for use in the metastatic setting, and is used in this population in clinical trials and a compassionate use programme in the UK, this drug is experimental in this setting of early stage (II and III) breast cancer.

PALLAS is a randomised, controlled, two-arm study, where participants will be treated with oral palbociclib and/or standard adjuvant endocrine therapy. About 4600 participants aged 18 years and over will be in the study across
multiple countries. The purpose of the PALLAS study is to determine the effect of palbociclib + standard adjuvant endocrine therapy vs standard adjuvant endocrine therapy on invasive disease-free survival in patients with
HR+/HER2- early breast cancer.

Inclusion criteria:
(1) Signed informed consent obtained prior to any study specific assessments and procedures.
(2) Age ≥18 years (or per national guidelines).
(3) Premenopausal and postmenopausal women or men with Stage II (Stage IIA limited to a max. of 1000 participants) or Stage III early invasive breast cancer per AJCC Breast Cancer Staging version 7 /UICC . Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
(4) participants with multicentric and/or multifocal and/or bilateral early invasive breast cancer whose histopathologically examined tumors all meet pathologic criteria for ER+ and/or PR+ and HER2-.
(5) participants must have histologically confirmed hormone receptor positive (ER+ and/or PR+), HER2-, early invasive breast cancer. ER, PR and HER2 measurements should be performed acc. to institutional guidelines, in a CLIAapproved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP guidelines. participants with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 treatment. Testing may occur on diagnostic core or surgical tumor tissue.
(6) participants must have undergone breast surgery for the current malignancy.
(7) A formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be transmitted to a central sample repository and confirmation of receipt must be available prior to randomization.
(8) ECOG performance status 0-1.
(9) participants must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
(10) Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in participants who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male participants randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 6 months after the last treatment with
palbociclib if they are in arm A.
Prior Treatment Specifics
(11) participants may or may not have received neo/adjuvant therapy, but must be after last dose of chemotherapy and/or biologic therapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
(12) participants may or may not have received breast/axilla/post-mastectomy chest wall radiotherapy, but must be after last dose of radiotherapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
(13) participants must have sufficient resolution of any surgical side effects from the last surgery per physician assessment with no active wound healing complications at the time of randomization
(14) participants must either be initiating or have already started adjuvant hormonal treatment. participants may already have initiated endocrine therapy at the time of randomization, but randomization must take place within 12 months of date of histological diagnosis and within 6 months of initiating standard adjuvant endocrine therapy. participants who received neoadjuvant endocrine therapy are eligible as long as they are enrolled within 12 months of initial histological diagnosis and after completing no more than 6 months of adjuvant endocrine therapy. participants
may be receiving either tamoxifen or aromatase inhibitor (AI: letrozole, anastrozole, or exemestane). For premenopausal participants and men, concurrent LHRH agonist use is allowable and may also be ongoing at the
time of randomization.

Baseline Body Function Specifics
(15) Absolute neutrophil count ≥ 1,500/mm3
(16) Platelets ≥ 100,000/ mm3
(17) Hemoglobin ≥ 10g/dL
(18) Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in participants with documented Gilbert’s Syndrome.
(19) Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT or SGPT) ≤ 1.5 × institutional ULN.
(20) Serum creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with serum creatinine levels above institutional ULN.

Exclusion criteria:
(1) Concurrent therapy with other Investigational Products.
(2) Prior therapy with any CDK inhibitor.
(3) participants with Stage I or IV breast cancer are not eligible. Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
(4) History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
(5) participants receiving any medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization.
(6) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
(7) Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
(8) participants with a history of any malignancy are ineligible except for the following circumstances:
• participants with a malignancy history other than invasive breast cancer are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy.
• participants with the following cancers are eligible, even if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and non-metastatic non-melanomatous skin cancer.
(9) participants are not eligible if they have previously received endocrine therapy within 5 years prior to diagnosis of the current malignancy. This includes use for prophylactic reasons, including treatment of osteoporosis or cancer prevention with tamoxifen, raloxifene or AI. participants may concurrently receive bisphosphonates or rank ligand inhibitors while on this study if necessary for treatment or prevention of osteopenia or osteoporosis.
(10) participants on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
(11) participants with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis, etc.
(12) participants receiving concurrent exogenous hormone therapy (hormone replacement therapy, oral or any other hormonal contraceptives such as hormonal contraceptive coil, etc.) are not eligible but topical vaginal estrogen therapy is allowable.

Principal Investigator for this trial: Dr Anjana Anand

Research Ethics Committee Reference: 16/LO/1069

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A global, prospective, non-interventional, observational study of presentation, treatment patterns, and outcomes in multiple myeloma patients

Summary:
Myeloma, also known as multiple myeloma (MM), is a cancer arising from plasma cells, a type of white blood cell which is made in the bone marrow. Bone marrow is the ‘spongy’ material found in the centre of the larger bones in the body. The bone marrow is where all blood cells are made. In Europe, the estimated annual incidence in 2012 was 38,900 new cases and 24,300 deaths. The incidence of MM is increasing slowly; this may be related to an ageing population, as well as to increasing obesity rates. However, deaths from MM are decreasing. Although advances in chemotherapy and novel agents have improved the prognosis and increased disease-free survival for patients with MM, currently available data on presentation, treatment patterns, and outcomes for MM at the global level are limited.

The main goals of this study include conducting non-interventional, observational research to gain a better understanding of the disease and and clinical outcomes associated with MM and the impact of treatment on safety, effectiveness, and quality of life. No modification of standard care will be assigned, the assignment of an eligible patient to a particular therapy shall be decided by the treating healthcare provider. Patients will be asked to complete a patient survey and validated questionnaires during the course of the study, using a secure electronic data collection system.

Information regarding patient characteristics, diagnosis, and previous treatments will be recorded. MM management data and safety data will be obtained as part of routine office visits.

Patients will be enrolled over a period of 3 years, and each included patient will be evaluated and followed-up for a period of at least 5 years, until death, or the end of the study, whichever comes first. The study will attempt to enroll a minimum of 5000 patients globally.

Inclusion criteria:
Each patient must meet all of the following criteria to be included in this study:
•Is 18 years of age or older.
•Is experiencing one of the following:

o Newly diagnosed and not yet relapsed MM with documented month and year of diagnosis, criteria met for diagnosis, stage, and MM-directed treatment history, including duration.
o Relapsed/refractory MM with documented data in the medical record regarding diagnosis (month and year), prior exposure to classes of medications (e.g., proteosome inhibitors, immunomodulatory drugs), and number of previous lines of therapies.

•Is willing and able to sign informed consent to participate.
•Is willing and able to complete patient assessment questionnaires.

Exclusion criteria:
Patients meeting any of the following criteria will be excluded from the study:
•Patients reporting to a site in this study for a second opinion (consultation only) or patients whose frequency of consult and follow-up are not adequate for quarterly electronic case report form (eCRF) completion.
• Participation in another study (observational or interventional) that prohibits participation in this study.
• Unable or unwilling to complete HRQoL and PROs.

Principal Investigator for this trial: Dr Cathy Williams

Research Ethics Committee Reference: 16/WM/0289

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Stratified Treatment OPtimisation for HCV-1 (STOPHCV-1)

Summary:
New treatments for Hepatitis C (HCV) can be taken for shorter periods of time, with less severe side-effects compared to previous treatments (6-12 months). Almost all people are cured with 12 weeks of treatment; it is unknown what the minimum duration of treatment could be in order to achieve cure, there have been limited investigations into shorter treatments.
The protocol has been designed as a platform protocol to look at varying (intervention) 4-6 weeks vs fixed (control) 8 weeks of first-line combined Direct Acting Antivirals (DAA) treatment with or without ribavirin for patients with mono-Hepatitis or co-infection (HIV/HCV) with genotype (GT) 1a/1b and mild disease:
A fixed dose triple combination of 3 novel direct acting antivirals (DAA); the Abbvie combination ombitasvir/paritaprevir/ritonavir (12.5mg/75mg/50mg) co-formulated film-coated tablets once daily (total daily dosage: 25/150/100mg) plus one dasabuvir 250 mg tablet twice daily (total daily dosage: 500mg) will be used plus or minus ribavirin (Ribavirin will be dosed twice daily, adjusted for weight).
The intervention duration will be stratified by baseline HCV RNA on a sliding scale, duration will be determined by estimated time for HCV RNA to decline to reduce levels to ~1 copy in the whole body at the end of treatment. If viral
failure is detected at any time from 4 weeks post-randomisation (first-line failure) patients will stop first line therapy and be treated with a fixed dose combination of sofosbuvir/ledispavir (400mg/90mg) once a day and ribavirin twice daily adjusted for by weight.
Visits will be on day 3, 7, 14 and 28 after randomisation, then every other week until 4 weeks post end of (first-line) treatment (EOT), then 4 weekly until 12 weeks post EOT, then 24 weeks after EOT a similar schedule will be followed for retreatment visits. Each visit will include a clinical assessment for adverse event outcomes and blood draw for standard safety tests and to check the level of virus.

Inclusion criteria:
1. Adults ≥18 years
2. Infected with HCV genotype 1a/1b with HCV RNA >LLOQ on more than one occasion at least six months previously with no intervening results showing undetectable viraemia
3. Plasma HCV RNA >LLOQ at screening
4. No evidence of significant liver fibrosis resulting from any aetiology (defined as Fibroscan* score ≤7.1kPa, equivalent to F0-F133, within 180 days prior to planned randomisation or biopsy consistent with mild fibrosis (Ishak score = 18 kg/m2
6.Laboratory tests: platelets >= 60 x109/l, haemoglobin >12 g/dl (male) or >11 g/dl (female), creatinine clearance (estimated glomerular filtration rate (eGFR) (Cockcroft-Gault)) >=60 mls/min, international normalised ratio (INR) 24 weeks

Exclusion criteria:
1. Previous DAA exposure (previous treatment with pegylated-interferon and/or ribavirin allowed)
2. FEMALES ONLY: Pregnant or planning to become pregnant for the duration of the study and within 4 months of the end of the study
3. MALES only: planning pregnancy in female partner during the study and within 7 months of the end of the study
4. Malignancy within 5 years of screening
5. Any condition in the judgement of the investigator which might limit the patient’s life expectancy.
6. Currently receiving medication known to interact with study medication (i.e. ombitasvir/paritparevir/dasabuvir/ritonavir, sofosbuvir, ledipasvir, ribavirin)
7. Disorder which may cause ongoing liver disease including, but not limited to active hepatitis B, ongoing alcohol misuse
8. Any disorder which in the opinion of the investigator may have a significant negative impact on the ability of the patient to adhere to the trial regimen
9. Use of other investigational products within 60 days of screening

Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 15/EE/0435

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A 52-week, multicenter, randomized, double-blind, placebo controlled study to assess the efficacy and safety of QAW039 when added to existing asthma therapy in patients with uncontrolled severe asthma

Summary:
Asthma presents a major global health burden. Despite existing therapies, there is still significant unmet medical need in asthma, with an estimated 300 million people affected worldwide. Uncontrolled asthma has a prevalence of greater than 6 million patients worldwide.

Currently, there is a need for well tolerated, easily-administered, anti-inflammatory therapies. QAW039 is an experimental medicine being tested for the treatment of people with asthma. The purpose of this study is to see if QAW039 works better than placebo (dummy drug) when taken with usual asthma medicines (Standard-of-Care treatment). The aim of treatment is to determine if QAW039 can reduce the number of asthma attacks, make asthma symptoms better and improve quality of life.

If a participant gives consent to take part, they will be randomly assigned to one of three treatment groups on an equal basis:

(1) QAW039 150 mg once daily
(2) QAW039 450 mg once daily
(3) Placebo to QAW039 once daily

100 UK participants will be recruited at approx 20 sites and remain in the study for about 14 months. 846 participants with severe asthma aged 12 years and older will be recruited globally in to the study. Participants will be separated in to two groups based on their eosinophil (a type of blood cell) count. Participants will attend 12 study visits.

Inclusion criteria:
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained within 14 days prior to or at Visit 1 before any assessment is performed including any adjustment to asthma medication.
2. Male and female patients aged ≥12 years.
3. Patients must have a diagnosis of asthma (according to GINA 2015) for a period of at least 24 months prior to Visit 1.
4. Patients have been treated with high-dose inhaled corticosteroids plus a LABA (or alternate therapy: montelukast or theophylline or tiotropium) with or without maintenance oral corticosteroids for at least 3 months prior to Visit 1(See GINA 2015 for the definition of high dose ICS and controller options). The doses must have been stable for at least 4 weeks prior to Visit 1.
5. FEV1 of ≥40% and ≤80% of the predicted normal value for the patient, after withholding bronchodilators at Visit 1 and Visit 101.
6. Demonstration of inadequate control of asthma based on an ACQ score ≥1.5 at Visit 1.
7. A history of 2 or more asthma exacerbations within the 12 months prior to Visit 1 that
required either:
– Treatment with systemic corticosteroids (tablets, suspension or injection) .
OR
– Hospitalization (defined as an inpatient stay or >24-hour stay in an observation area in the emergency room of other equivalent facility.
8. A clinical diagnosis of asthma supported by at least one of the following:
An increase of ≥12% and ≥200 ml in FEV1 within 30 minutes after administration of 400 mcg of salbutamol/albuterol (or equivalent dose) prior to randomization. All patients must perform a reversibility test at Visit 1. If reversibility is not demonstrated at Visit 1*, the following historical information may be used:
– Documented evidence of reversibility that was performed according to ATS/ERS guidelines (ATS/ERS 2005) with the 2 years prior to Visit 1. Where a patient is assessed as eligible based on historical evidence of reversibility, a copy of the original printed spirometry report with relevant spirometry tracings must be available as source documentation.

– Documented evidence of a positive airways hyper-reactivity (AHR) test result within the 2 years prior to or at Visit 101, defined as a provoked fall in FEV1 of 20% by methacholine at ≤8 mg/ml (or histamine ≤10 mg/ml or acetylcholine Exclusion criteria:
1. Use of other investigational drugs within 5 halflives of enrollment, or within 30 days until the expected pharmacodynamic effect has returned to baseline, whichever is longer
2. Patients who have participated in another trial of QAW039
3. History of hypersensitivity to any ingredients of the study drugs/drugs related to QAW039
4. Patients who have a clinically significant ECG abnormality such as (but not limited to) sustained ventricular tachycardia, or clinically significant second/third degree AV block without a pacemaker
5. Patients with a history of familial long QT syndrome or known family history of Torsades de Pointes
6. Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at Visit 1/Visit 101
7. Patients receiving any medications or other agents known to prolong QT interval
8. Patients with a history of malignancy of any organ, treated or untreated, whether or not there is evidence of local recurrence of metastases, with the exception of local basal cell carcinoma of the skin
9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
10. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless using effective methods of contraception during study treatment
11. Patients who have smoked or inhaled tobacco products within the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack years
12. Patients who have had an asthma attack/exacerbation requiring systemic corticosteroids hospitalization or emergency room visit within 6 weeks prior to Visit 1 13. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks of Visit 1
14. Patients with any chronic condition of the respiratory tract which may interfere with study evaluation or optimal participation in the study
15. Patients with a history of chronic lung disease other than asthma, including (but not limited to) chronic obstructive pulmonary disease, bronchiectasis, (non-clinically significant bronchiectasis may be allowed provided recent [within 3 months prior to Visit 101] CT scan proof is available), sarcoidosis, interstitial lung disease, cystic fibrosis, and tuberculosis
16. Patients with uncontrolled diabetes having an HbA1c test result ≥8% at Visit 101
17. Patients who have a clinically significant laboratory abnormality at Visit 1/Visit 101
18. Patients who have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease,
neurodegenerative diseases, or other neurological disease, uncontrolled hypoand hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical
condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study
19. Patients with a history of myocardial infarction within 12 months of Visit 1
20. Patients with serious comorbidities including, but not limited to, neurodegenerative diseases, rheumatoid arthritis and other autoimmune diseases
21. Patients with a history of alcohol or drug abuse within 12 months prior to Visit 1
22. Patients with a weight 2 X ULN at Visit 1
36. Patients on rifampin, probenecid, ritonavir and valproic acid

Principal Investigator for this trial: Dr Dominick Shaw

Research Ethics Committee Reference: 15/EM/0500

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A prospective Randomized multicenter study comparing horse Antithymocyte globuline (hATG) + Cyclosporine A (CsA) with or without Eltrombopag as front-line therapy for severe aplastic anemia patients

Summary:
Title: Will eltrombopag added to standard immunosuppressive treatment increase the rate of early (3 months) complete response (defined as Hb >10 g/dL, ANC > 1,000/μL and Plt >100,000 μL) in untreated SAA patients?

Background:
Severe aplastic anemia (SAA)is an hematological disease of the bone marrow resulting in an impairment of the production of blood cells and a lack of all blood cells.

Standard treatment, Immunesuppression therapy, for SAA is based on the association of antithymocyte globulin (ATG) and cyclosporine A (CsA). Despite the demonstration that this treatment may result in clinical response in about two thirds of patients, about one third of patient may relapse.

Very recently a new drug, eltrombopag, has been investigated for the treatment of SAA. Eltrombopag has to be considered a compound which stimulates the functioning of the bone marrow independently from immunesuppression therapy. In a recent study eltrombopag resulted in excellent response rate in SAA patients who were refractory to immunosuppression therapy.

Design of the study:
This study will be conducted by the Severe Aplastic Anaemia Working Party of the European Group for Blood and Marrow Transplantation in seven countries throughout Europe and a total of 31 participating hospitals. The research is funded by GlaxoSmithKline. SAA patients who are not eligible for bone marrow transplantation (no available HLA-indentical donor) are approached to take part in this study. After signing consent they will be randomized in either treatment arm A (hATG + CsA) or treatment arm B (hATG + CsA + eltrombopag). For both treatment arms, patients are administered in the hospital for 4 days (hATG treatment). After these 4 days, patients can continue their treatment with CsA and for arm B eltrombopag, at home (orally). Patients are closely monitored during 22 visits divided over a total duration of 2 years (treatment + follow up).

Inclusion criteria:
1.Diagnosis of severe or very severe aplastic anemia, defined by
• At least two of the following:
– Absolute neutrophil counts Exclusion criteria:
1.Prior immunosuppressive therapy with ATG (horse of rabbit) or any other lymphocyte depleting agent (i.e., alemtuzumab)

2.Eligibility to a sibling allogeneic stem cell transplantation

3.Evidence of a myelodysplastic syndrome, defined by the presence of myelodysplastic features, excess of blasts or karyotypic abnormalities typical of MDS (according to revised WHO 2008 criteria), as well as other primitive marrow disease. Patients with diagnosis of AA with cytogenetic abnormalities which are recurrent in MDS (according to revised WHO 2008 criteria) should be included in this category, and are not eligible for the study; patients with del(20q), +8 and –Y are not included in this category, and thus are eligible for this study. The list of karyotypic abnormalities which qualifies for the diagnosis of MDS are listed in Appendix 1 of the protocol

4.History or clinical suspect of constitutional aplastic anemia (i.e. Fanconi Anemia with positive DEB/MMC test or Dyskeratosis Congenita)

5.History of malignant tumors with active disease within 5 years from enrollment and/or previous chemo-rediotherapy

6.Previous history of stem cell transplantation

7.Treatment with cyclosporin A Principal Investigator for this trial: Professor Nigel Russell

Research Ethics Committee Reference: 15/LO/1149

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A phase III multicentre randomised, double blind, placebo controlled trial to assess the role of intravenous immunoglobulin in the management of children with encephalitis (The IgNiTE study)

Summary:
Encephalitis means inflammation of the brain and there are lots of different causes. Encephalitis could be caused by an infection (infectious encephalitis) or by the body’s immune system turning against itself by producing proteins that attack the brain called auto-antibodies (immune mediated encephalitis). For up to two-thirds of cases, the cause is unknown. Encephalitis is an important health problem. Despite the current standard of care, up to 20% of affected children die while up to 50% end up with significant problems. This highlights the need for newer treatment options. There is some evidence that pooled antibody from blood donors (intravenous immunoglobulin) also known as IVIG
may improve outcomes for children with encephalitis. However, the evidence is only based on a small number of children or those with specific types of encephalitis. There are no research studies that have looked at the effect of IVIG when used to treat a large number of children, regardless of the type of encephalitis that they have. Also, although some doctors may use IVIG to treat children with encephalitis, this is often given late in the illness so we do not know the effect of IVIG when used early after diagnosis. In this study, we would like to find out whether early (within five days of hospitalisation) treatment with IVIG benefits children with encephalitis. We will be comparing the children who are treated with IVIG to those who are not. We will enrol 308 children between 6 weeks and 16 years. They will be randomly
allocated to two groups to receive either IVIG or placebo (a ‘treatment’ that looks like IVIG but has no medical effect in encephalitis) in addition to standard treatment. Every child will have an equal chance of being allocated to each group. Children will be recruited from NHS hospitals in England, Wales, Scotland, and Northern Ireland. All children will be followed up for 12 months after treatment and we will be collecting information on their health and wellbeing through the use of questionnaires, brain scan and neuropsychologist (an expert who studies how the brain works). The study
is funded by the National Institute for Health Research and is coordinated by the Department of Paediatrics, University of Oxford.

Inclusion criteria:
1) 6 weeks to 16 years of age (day before 17th birthday)
AND
2) Acute (within 24 hours) or sub-acute (between 24 hours and 4 weeks) onset of altered mental state (reduced or altered conscious level, irritability, altered personality or behaviour, lethargy) not attributable to a metabolic cause
AND
3) At least two of:

(a) fever >38oC within 72 hours before or after presentation to hospital
(b) brain imaging evidence consistent with encephalitis or immune-mediated encephalopathy that is either new from prior studies or appears acute in onset
(c) CSF pleocytosis >4 white blood cells (WBCs)/microlitre
(d) generalised or partial seizures not fully attributable to a preexisting seizure disorder
(e) new onset focal neurological signs (including movement disorders) for >6 hours
(f) abnormality on EEG that is consistent with encephalitis and not clearly attributable to another cause.
AND
4) Parent/guardian/ legal representative/child (if 16 years at the time of enrolment and has capacity to give consent) able to give informed consent and assent (if Exclusion criteria:
•high clinical suspicion of bacterial meningitis or TB meningitis (for example: presence of frankly
purulent CSF; CSF WBCs >1000/microlitre; bacteria on Gram stain and/or culture)
•Traumatic brain injury
•Known metabolic encephalopathy
•Toxic encephalopathy (i.e. encephalopathy secondary to exposure to intoxicants, including alcohol,prescription or
recreational drugs)
•hypertensive encephalopathy/posterior reversible encephalopathy syndrome
•preexisting
demyelinating disorder; preexisting antibody mediated CNS disorder; preexisting CSF diversion
•ischaemic or haemorrhagic stroke
•children with a contraindication to IVIG or albumin (i.e. history of anaphylactic reaction to either products, known IgA deficiency and history of hypersensitisation)
•Known hypercoagulable state
•significant renal impairment defined as GFR of 29mls/min/1.73m2 and below (Chronic Kidney
Disease Stage 4)
•Known hyperprolinaemia
•Known to be pregnant
•Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial
•participants who are actively being followed up in another research trial involving an investigational product thought to have an immunomodulatory or neuroprotective effect
•Administration of study drug not feasible within 120 hours of hospital admission as determined by the study team
• Any other condition which, in the opinion of the investigator, may interfere with the ability to fulfil study requirements, especially relating to the primary objective of the study (this include plans to be outside the UK for more than 12 months after enrolment)

Principal Investigator for this trial: Dr William Whitehouse

Research Ethics Committee Reference: 14/SC/1416

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The SCOTTY Study – whole genome sequencing study of young colon cancer patients and their parents.

Summary:
Cancer of the large bowel (colorectal cancer) is common in the general population and the lifetime risk for someone living in the UK is 1 in 17. Whilst modern surgery, radiotherapy and chemotherapy treatments have impacted beneficially on survival outcome, many patients still die from their disease. Hence, there is a pressing need to understand the causes of colorectal cancer and to intervene early. Colorectal cancer under the age of 40 years of age is particularly rare, with less than 1.2% of all cases aged Inclusion criteria:
PATIENT INCLUSION CRITERIA

•Patients who have developed colorectal cancer at aged 40 years of age or younger at the time of diagnosis.
(Individuals OVER the age of 40 years ARE eligible if they were previously diagnosed with colorectal cancer when aged 40 years or younger).

•Patients will not have a known molecular genetic predisposition to the development of colorectal cancer or a strong family history of cancer consistent with known dominant disorders.

•Patients are able to provide written informed consent for whole genome sequencing and blood/saliva biomarkers.

•Documentary evidence of a pathologically confirmed adenocarcinoma of colon or rectum along with consent to access archived tumour material from the time of operation.

•Demographic and drug history are available or can be ascertained from patient.

•If the patient is under the age of 16 years, both parents are available to sign/countersign a consent form. Whilst
cases under the age of 16 years are extremely rare, these cases greatly enhance the value of their contribution to the study.

•Inclusion can be from any part of mainland GB and Northern Ireland and of any ancestry.

•Patients will be asked if they agree to being re-contacted if further confirmatory samples are required and/or results are of clinically significant relevance.

PARENTS INLCUSION CRITERIA

•Neither parent will have had a past or present diagnosis of colorectal cancer or other cancer relevant to CRC
predisposition such as endometrial cancer.

•Both parents will be alive and are contactable within the United Kingdom and Northern Ireland.

•Both parents will not have a known genetic predisposition to the development of colon cancer.

•Both parents will be able to provide written informed consent for sampling.

•Both parents will provide a simple blood sample for whole genome sequencing & blood or saliva biomarkers.

•Demographic and drug history are available or can be ascertained from parents.

•Both parents will be asked to agree to being re-contacted if further confirmatory samples are required and/or results have clinical implications.

Exclusion criteria:
– BOTH parents unable to provide samples.
– The inability to provide informed consent.
– Patients who have developed CRC aged over 40 years at diagnosis.
– Tumour that has shown loss of DNA mismatch repair gene protein expression or tumour that has exhibited MSI (micro satellite instability).
– Familial CRC (a strong family history)

Exclusion criteria – PARENTS

– Both parents are unable to provide samples.
– The inability to provide informed consent.

– Known mutations in colorectal susceptibility genes within the family (eg APC,MLH1, MSH2, MSH6, PMS2, MUTYH, POLE1, POLD1, SMAD4/BRCA/STK11).

Principal Investigator for this trial: Dr Abhijit Dixit

Research Ethics Committee Reference: 16/SS/0082

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A PROSPECTIVE MULTI-CENTRE STUDY OF EFFECTIVENESS OF RIPPLE MAPPING FOR ATRIAL TACHYCARDIA ABLATION

Summary:
Tachycardia’s (fast heart rhythms) can lead to troublesome palpitations, dizziness, blackouts and breathlessness. They are caused either by a cluster of abnormal cells within the heart, or an electrical short circuit which rotates rapidly around the heart. Sometimes these can be controlled with tablets, though owing to side effects many patients want something else. Many tachycardia’s can be cured by a procedure known as an “ablation”. In essence, either the focus of abnormal cells or the narrowest point of the short circuit causing the abnormal heart rhythm (the source) is electrically destroyed (burnt) resulting in restoration of the normal heart beat.

One form of tachycardia is known is Atrial Tachycardia (AT). These arise from the top two chambers of the heart (the atrium). Interestingly, this problem is frequently seen in patients who have previously undergone an ablation or
surgical procedure for a condition called Atrial Fibrillation. In others the reason for its occurrence is unknown.

Current strategies to find the “source” during an ablation procedure are technically challenging resulting in long
procedure times. Sometimes the wrong source is found resulting in ablation at the incorrect site.

Ripple Mapping (RM) is a novel system that we are looking to study. RM displays electrical information within the heart as a series of bars coming out of the chamber, with each bar representing signals travelling down the heart. By seeing the pattern of electrical information, we believe it will show the pattern of the tachycardia better than conventional techniques. In a previous study that we conducted, RM found the source of the tachycardia in 80% of the maps, compared to only 50% with the current system. We know why we did not get 100% and we believe that, in future, RM will find the source of the tachycardia first time, and every time

Inclusion criteria:
1. Patients undergoing clinically indicated ablation of sustained atrial tachycardia using 3D mapping.
2. Signed informed consent
3. Between the age of 18 – 85

Exclusion criteria:
1. Patients with typical flutter.
2. Patient with non-sustained atrial tachycardia
3. Contraindication to catheter ablation
4. Unable to give informed consent

Principal Investigator for this trial: Dr Shahnaz Jamil-Copley

Research Ethics Committee Reference: 14/LO/2060

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A PROSPECTIVE MULTI-CENTRE STUDY OF EFFECTIVENESS OF RIPPLE MAPPING FOR ATRIAL TACHYCARDIA ABLATION

Summary:
Tachycardia’s (fast heart rhythms) can lead to troublesome palpitations, dizziness, blackouts and breathlessness. They are caused either by a cluster of abnormal cells within the heart, or an electrical short circuit which rotates rapidly around the heart. Sometimes these can be controlled with tablets, though owing to side effects many patients want something else. Many tachycardia’s can be cured by a procedure known as an “ablation”. In essence, either the focus of abnormal cells or the narrowest point of the short circuit causing the abnormal heart rhythm (the source) is electrically destroyed (burnt) resulting in restoration of the normal heart beat.

One form of tachycardia is known is Atrial Tachycardia (AT). These arise from the top two chambers of the heart (the atrium). Interestingly, this problem is frequently seen in patients who have previously undergone an ablation or
surgical procedure for a condition called Atrial Fibrillation. In others the reason for its occurrence is unknown.

Current strategies to find the “source” during an ablation procedure are technically challenging resulting in long
procedure times. Sometimes the wrong source is found resulting in ablation at the incorrect site.

Ripple Mapping (RM) is a novel system that we are looking to study. RM displays electrical information within the heart as a series of bars coming out of the chamber, with each bar representing signals travelling down the heart. By seeing the pattern of electrical information, we believe it will show the pattern of the tachycardia better than conventional techniques. In a previous study that we conducted, RM found the source of the tachycardia in 80% of the maps, compared to only 50% with the current system. We know why we did not get 100% and we believe that, in future, RM will find the source of the tachycardia first time, and every time

Inclusion criteria:
1. Patients undergoing clinically indicated ablation of sustained atrial tachycardia using 3D mapping.
2. Signed informed consent
3. Between the age of 18 – 85

Exclusion criteria:
1. Patients with typical flutter.
2. Patient with non-sustained atrial tachycardia
3. Contraindication to catheter ablation
4. Unable to give informed consent

Principal Investigator for this trial: Dr Shahnaz Jamil-Copley

Research Ethics Committee Reference: 14/LO/2060

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CONCEPT – A randomised phase II pilot study of 3 weekly Cabazitaxel versus weekly Paclitaxel chemotherapy in the first line treatment of HER2 negative metastatic breast cancer

Summary:
Metastatic breast cancer has several treatment options based on the parameters of the disease. Chemotherapy is one of the standard options in this situation. Recent advances have increased the use of docetaxel chemotherapy in the adjuvant (early) setting of breast cancer. In prostate cancer chemotherapy with Cabazitaxel has shown to be effective in patients with progressive disease after docetaxel chemotherapy.
Paclitaxel chemotherapy is a standard first line chemotherapy treatment in metastatic breast cancer. This study will evaluate the efficacy of cabazitaxel chemotherapy in comparison to paclitaxel chemotherapy as first line chemotherapy treatment in metastatic breast cancer.

Inclusion criteria:
– Written informed consent
– Metastatic breast cancer, fit to receive cytotoxic chemotherapy as palliative treatment.
– Measurable disease as per RECIST 1.1 by CT or MRI within 4 weeks of registration.
– ECOG performance status 0 or 1
– No prior cytotoxic chemotherapy for metastatic disease. Neoadjuvant or adjuvant chemotherapy permitted if given more than 3 months prior to registration.
– Patients may be taxane naive or have received docetaxel chemotherapy in the adjuvant setting.
– Prior histology to confirm HER 2 negative defined as IHC 0+, 1+ or IHC 2+ with FISH/SISH/CISH (Ratio 6 months.
– Adequate liver, renal and bone marrow function defined as:
– Haemoglobin >9.0g/dL
– Absolute neutrophil count > 1.5 x 10^9/L
– Platelet count >100 x 10^9/L
– ALTExclusion criteria:
– HER 2 + breast cancer (IHC 3+ or FISH/SISH/CISH ratio 2.0 )
– Previous paclitaxel chemotherapy in the adjuvant setting.
– Prior cytotoxic chemotherapy for metastatic disease.
– Palliative radio therapy for metastatic disease within 4 weeks of randomisation.
– Symptomatic brain metastases.
– History or other malignancy (excluding non-melanomatous skin cancer).
– Grade ≥ 2 peripheral motor +/or sensory neuropathy.
– Grade ≥ 2 oral mucositis.
– History of severe hypersensitivity reaction (≥ grade 3) to taxanes.
– History of severe hypersensitivity reaction (≥ grade 3) to polysorbate 80- containing drugs.
– Clinically significant (active) cardiovascular disease, including cerebrovascular accident (within 6 months before enrolment), myocardial infarction, arterial thrombotic events within 6 months before enrolment, unstable angina pectoris, New York heart association grade 2 congestive heart failure, serious cardiac arrythmia requiring medication during the study and that might intefere with regularity of the study treatment, or not controlled by medication.

– comply with the study procedures or interfere with interpretation of study results.( such as significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures.)
– Active infection requiring systemic antibiotics or antifungal medication.
– Prior endocrine therapy treatment must be stopped before study entry.
– Concurrent treatment on another clinical trial.
– Requirement for radiation therapy concurrent withthe study.
– Inability and unwillingness to comply with study visits, treatment, testing and to comply with the protocol.
– Other concurrent serious illness or medical conditions which make it undesirable for the patient to enter the trial
– including uncontrolled diabetes mellitus.
– Inadequate organ and bone marrow function as evidenced by :
– Haemoglobin 2.5 x ULN
– Total bilirubin > 1.5 x ULN
– Serum creatinine > 1.5 x ULN. If creatinine is 1.01.5
x ULN, creatinine clearnace will be calculated according to CKDEPI formula and patients with creatinine clearance Principal Investigator for this trial: Dr Stephen Y Chan

Research Ethics Committee Reference: 14/SC/0221

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A randomized phase II trial of Hippocampal Sparing versus Conventional Whole Brain Radiotherapy after surgical resection or radiosurgery in favourable prognosis patients with 1-4 brain metastases

Summary:
Participants will be patients diagnosed with 1 – 4 brain metastases (brain tumours which have grown from cancer cells which have spread to the brain from a cancer elsewhere in the body) and who have had surgery or focused radiotherapy (“stereotactic radiosurgery” or SRS) to the brain to try to control the metastases and are now to receive whole brain radiotherapy. Whole brain radiotherapy is radiotherapy to the whole of the brain including the sites of already treated tumours. This is given as extra treatment to the already operated or SRS treated metastases and to try to prevent other tumours growing elsewhere in the brain, from cancer cells which may have spread there but are still too small to be detected on a scan.
However, whole brain radiotherapy can reduce cognitive function, which is the brain’s ability to process information. This means functions such as memory, learning, problem solving and decision making can be affected. It is thought this is because whole brain radiotherapy may slightly damage the left and right hippocampi which are areas of the brain important for such functions.
In this study we aim to test whether avoiding irradiating the hippocampi during whole brain radiotherapy (hippocampal sparing whole brain radiotherapy) will help to preserve cognitive function.
HIPPO will be carried out across approximately 13 hospitals in the UK. Participants will be randomly allocated (that is, by chance) to receive either standard whole brain radiotherapy or ‘hippocampal sparing’ whole brain radiotherapy.
There is an equal chance of receiving one or other of these treatments. Whole brain radiotherapy or ‘hippocampal sparing’ whole brain radiotherapy will be administered as 10 separate doses or ‘fractions’. Patients will then be seen at 2, 4, 6, 9, 12, 18 and 24 months after completion of the radiotherapy to assess health status and cognitive function.

Inclusion criteria:
• Age ≥ 16 years.
• Karnofsky Performance Status (KPS) ≥ 70.
• Brain metastases from systemic malignancy which has been histologically confirmed (from the primary or any
metastatic site).
• In total, at most 4 distinct brain metastases based on MRI imaging with contrast at any prior timepoints.
• Each of the brain metastases to have been treated by neurosurgery or by SRS in line with UK SRS commissioning guidelines, which in addition for SRS treated patients means:
o Patient selection for SRS by the appropriate MDT(s),
o No pressure symptoms which would be best relieved by surgery,
o Life expectancy from extracranial disease greater than 6 months,
o Gross tumour volume at time of SRS ≤ 20 cc.
• Ability to comply with the following timelines:
o Randomisation 2 – 4 weeks after neurosurgery or last SRS fraction,
o Start of WBRT or HSWBRT 4 – 6 weeks after neurosurgery or last SRS fraction.
• Ability to complete the NCF test battery (including ability to speak English).
• Willing and able to give consent and to comply with treatment and follow up schedule.

Exclusion criteria:
• Metastases from small cell carcinoma from any site, haematological malignancy, or central nervous system
malignancy,
• Leptomeningeal metastases,
• Contraindication to MRI imaging with contrast,
• Prior radiotherapy to the brain (apart from a single course of SRS for brain metastases completed within 24
weeks of randomisation and within 46 weeks of start of the HIPPO trial treatment),
• Prior neurosurgery for brain metastases (apart from a single operation within 2-4 weeks of randomisation and within 4-6 weeks of start of HIPPO trial treatment), except that prior neurosurgery will be allowed if :
o there is no evidence of residual tumour at the resection site on contrast MRI imaging, or
o residual tumour at the resection site has been treated by SRS immediately prior to entering HIPPO,
• One or more metastases currently or previously within 5 mm of either hippocampus,
• One or more metastases within the brainstem,
• One or more SRS treated metastases in close proximity to critical normal organs, unless the local investigator is satisfied that the dose already received by the critical organ allows for subsequent delivery of the HIPPO protocol radiotherapy doses,
• Disease specific graded prognostic assessment (DSGPA) score ≤ 1.0 for any of the histologies for which DSGPA has been defined (see Appendix 2),
• Past medical history of dementia which is thought to be unrelated to the brain metastases,
• Women of childbearing potential who are known to be pregnant, or are unwilling to use an acceptable method of contraception from the time of informed consent until completion of the course of radiotherapy.

Principal Investigator for this trial: Dr Matthew Griffin

Research Ethics Committee Reference: 14/NW/1500

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Evaluation of a growth guiding construct vs standard dual growing rods and VEPTR for the treatment of early onset scoliosis patients: A prospective multi-centre cohort study with a matched historical control

Summary:
The foremost challenge when managing early onset scoliosis (when a person’s spine is curved from side to side) is to prevent curve progression while maintaining longitudinal growth of the spine. Current treatment options (Risser casting; growing rods; VEPTR) require repetitive interventions as the spine and the child grow. The TROLLEY device will help the spine to grow straight. It also allow the rods to “grow” at the same time as the child grows. The surgeon will put screws in the bones of the child’s spine. Metal rods are attached to the screws. The rod will be attached to the screw with something that looks like a cable tie.This allows the rods to slide past each other while the child grows. This new operation may reduce the number of future operations because the screw and rods “grow” with the spine.

Aim of this study: compare two techniques of growth modulation: Standard dual growing rods and VEPTR (historical comparison group) versus the TROLLEY growth guiding construction with regards to:
• Growth
• Curve / deformity type characteristics
• Pulmonary function
• Predicted thoracic dimension
• Complication rates
• Quality of life

Patient will be followed-up: postoperativly, 6 weeks, 6 months, 1 year, 1.5 years, 2 years, 2.5 years and 3 years after surgery
Thereafter, the patients will be followed-up yearly up to and including 10 years or until the patient is skeletally mature (whichever occurs first).

Inclusion criteria:
• Male or female patients (any ethnicities) aged 5 – 10 years
• Diagnosis of Early Onset Scoliosis with any of the following etiologies:
o Idiopathic
o Congenital
o Neuromuscular
o Syndromic
o Mesenchymal
• Significant growth potential defined by any of the following:
o pre peak growth velocity
o bone age Exclusion criteria:
Curve magnitude and rigidity: Cobb greater than 100 degrees or bends less than 50 degrees
Prior spinal surgery
Skeletal maturity
Any not medically managed severe systemic disease (except for the disease under investigation)
Participation in any other medical device or medicinal product study within the previous month that could influence the results of the present study

Intraoperative exclusion criteria
Contraindication for the use of the TROLLEY system

Principal Investigator for this trial: Mr Michael P Grevitt

Research Ethics Committee Reference: 15/EM/0419

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Evaluation of a growth guiding construct vs standard dual growing rods and VEPTR for the treatment of early onset scoliosis patients: A prospective multi-centre cohort study with a matched historical control

Summary:
The foremost challenge when managing early onset scoliosis (when a person’s spine is curved from side to side) is to prevent curve progression while maintaining longitudinal growth of the spine. Current treatment options (Risser casting; growing rods; VEPTR) require repetitive interventions as the spine and the child grow. The TROLLEY device will help the spine to grow straight. It also allow the rods to “grow” at the same time as the child grows. The surgeon will put screws in the bones of the child’s spine. Metal rods are attached to the screws. The rod will be attached to the screw with something that looks like a cable tie.This allows the rods to slide past each other while the child grows. This new operation may reduce the number of future operations because the screw and rods “grow” with the spine.

Aim of this study: compare two techniques of growth modulation: Standard dual growing rods and VEPTR (historical comparison group) versus the TROLLEY growth guiding construction with regards to:
• Growth
• Curve / deformity type characteristics
• Pulmonary function
• Predicted thoracic dimension
• Complication rates
• Quality of life

Patient will be followed-up: postoperativly, 6 weeks, 6 months, 1 year, 1.5 years, 2 years, 2.5 years and 3 years after surgery
Thereafter, the patients will be followed-up yearly up to and including 10 years or until the patient is skeletally mature (whichever occurs first).

Inclusion criteria:
• Male or female patients (any ethnicities) aged 5 – 10 years
• Diagnosis of Early Onset Scoliosis with any of the following etiologies:
o Idiopathic
o Congenital
o Neuromuscular
o Syndromic
o Mesenchymal
• Significant growth potential defined by any of the following:
o pre peak growth velocity
o bone age Exclusion criteria:
Curve magnitude and rigidity: Cobb greater than 100 degrees or bends less than 50 degrees
Prior spinal surgery
Skeletal maturity
Any not medically managed severe systemic disease (except for the disease under investigation)
Participation in any other medical device or medicinal product study within the previous month that could influence the results of the present study

Intraoperative exclusion criteria
Contraindication for the use of the TROLLEY system

Principal Investigator for this trial: Mr Michael P Grevitt

Research Ethics Committee Reference: 15/EM/0419

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Multi-centre randomised controlled trial of clinical and cost-effectiveness of drug coated balloons, drug eluting stents and plain balloon angioplasty with bail-out bare metal stent revascularisation strategies for severe limb ischaemia due to atherosclerotic femoro-popliteal, with or without infra-popliteal involvement, peripheral arterial disease

Summary:
One in every 1000-2000 people in the UK will be diagnosed with advanced cases of Severe Limb Ischemia (SLI) yearly. As a result of a combination of smoking, diabetes mellitus, high blood pressure, high cholesterol levels, kidney failure and the ageing process, some people develop atherosclerosis (aka ‘hardening’ of the arteries) in their legs. In SLI even minor injuries to the foot can fail to heal, resulting in the development of ulceration, even gangrene.
Unless the blood supply to the leg and foot is improved, many people affected by SLI will lose their limb and/or die within 12 months. As well as causing great suffering, SLI places a large economic burden upon health (NHS) and social care services.
Most SLI patients with disease in the femoro-popliteal arteries are treated by endovascular means, which involves opening up the diseased arteries with balloons and sometimes the use of metal tubes called stents. In recent years, a number of “advanced” endovascular technologies – drug eluting stent (DES) and drug coated balloons (DCB) – have become available but the evidence base for using these new technologies is weak and they are much more expensive than the traditional methods.

The purpose of BASIL-3 is to determine which treatment is best at preventing amputation and death, getting the ulcers and gangrene to heal, and relieving pain in people with SLI. The costs of the 3 revascularisation strategies will be studied to see which offers the best value for money for the NHS.

Inclusion criteria:
In order to be considered for randomisation in BASIL-3, patients must:
•Have severe limb ischaemia due to femoro-popliteal, with or without infra-popliteal, peripheral artery disease
•Be judged by the responsible clinicians (consultant vascular surgeon, interventional radiologist, diabetologist) working as part of a multidisciplinary team to require early endovascular femoro-popliteal, with or without infrapopliteal revascularisation in addition to best medical treatment, foot and wound care
•Have adequate ‘inflow’ to support all possible trial revascularisation strategies
•Be judged suitable for all possible trial revascularisation strategies following diagnostic imaging and a formal
(documented) discussion by a multi-disciplinary team meeting.

Exclusion criteria:
Patient will be excluded from BASIL-3 if they
•Have an anticipated life expectancy Principal Investigator for this trial: Dr Said Habib

Research Ethics Committee Reference: 15/NS/0070

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LuCID: Lung Cancer Indicator Detection

Summary:
Rationale
Early detection of lung cancer is of paramount importance to improve patient outcome. Unfortunately most early stage tumors are asymptomatic. At this stage cancer cells do already have considerable changes in their metabolism. Part of these metabolites are exhaled through the breath and their detection is a potential tool for early diagnosis of lung cancer. The Lung Cancer Indicator Detection (LuCID) study aims to validate the use of a high-throughput breath analysis technique in a population of patients whom are clinically suspected of having lung cancer.

Methods
LuCID is a multinational, multi-center cross-sectional case-control study. Patients referred by their GP or treating specialist for a diagnostic lung cancer workup will be invited to participate in the study. Depending on interim sample size analysis two- to six-hundred patients whom consent to partake in this study will be asked to provide a breath sample. This is a noninvasive procedure during which subjects breath normally into a face-mask to collect 2.5l of breath (±10 minutes). The resulting samples will be analyzed for VOCs by Gas Chromatography coupled to Mass
Spectrometry (GC-MS) and Gas Chromotography coupled to Field Assymetrical Ion Mobility Spectrometry (GC-FAIMS). The resulting VOC profiles will be used to generate a diagnostic algorithm differentiating between patients with and without lung cancer in the intention to diagnose population. This study will in no way intervene with the standard care
offered at the clinical sites.

Expected outcome
The results of this study will provide detailed insights into the accuracy of breath analysis for the detection of lung cancer in the intention to diagnose population. If sufficiently accurate for early stage disease, analysis of breath VOCs could help implement large-scale screening for lung cancer, significantly decreasing the morbidity and mortality of the disease.

Inclusion criteria:
o 18 years or older at time of consent
o Referred for investigation due to suspicion of lung cancer
o Capable of understanding written and/or spoken English
o Able to provide informed consent

Exclusion criteria:
o (Anticipated) inability to complete breath sampling procedure due to e.g. hyperor hypoventilation, respiratory failure
or claustrophobia when wearing the sampling mask
o Participating in an interventional drug trial
o CT-scan with contrast in the past 48 hours
o Received diagnostic bronchoscopy in past 48 hours
o Current active malignancy or nonlung cancer tumor in the past 3 years

Principal Investigator for this trial: Dr David R Baldwin

Research Ethics Committee Reference: 15/EE/0298

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TAMARIN – Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms

Summary:
Myeloproliferative neoplasms (MPNs) are blood cancers which affect the normal production of blood cells from the bone marrow. They are caused by changes (mutations) in blood stem cells, frequently in the genes that produce proteins called JAK2, CALR or MPL. MPNs have a risk of developing to an acute leukaemia (a more advanced stage of disease) and currently has no effective cure, apart from bone marrow transplantation which is not possible for many patients.
Recent work in mouse studies has suggested that tamoxifen, a drug widely used to treatment breast cancer, may reduce the number of mutated cells by mimicking oestrogen (a female sex hormone) which has a role in the survival and production of new stem cells that give rise to blood cancers. In these studies, tamoxifen prevented the excessive production of blood cells by restoring normal levels of cell death in the mutated cells.
This is a single arm, multicentre phase II trial designed to assess if adding tamoxifen to patients receiving therapy for their MPN reduces the number of mutated cells found in the blood by ≥ 50% after 24 weeks of treatment compared to the start of the study. Collection of blood and bone marrow samples will also allow laboratory researchers to study the biological effects of tamoxifen and how this correlates with the patient’s disease and response to therapy.
Patients will receive treatment with 20mg once daily (oral tablet) of tamoxifen with their normal therapy for their MPN. 42 patients will be recruited from 13-15 UK centres over 12 months.

Inclusion criteria:
• Age ≥ 60 years (men aged between 50-59 may also be considered following discussion with the Chief Investigator)
• Women must be post-menopausal (defined as amenorrhoeic for at least 12 consecutive months following cessation of all exogenous hormonal treatments)
• Confirmed diagnosis of JAK2-V617F or CALR positive Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) (primary or secondary) for ≥ 6 months
• JAK2-V617F or CALR mutant allele burden ≥ 20% in peripheral blood granulocyte DNA at study entry (assessed via central review)
• WHO performance status 0-2
• For patients with PV or ET, maintenance of at least a partial haematological response according to 2009 ELN criteria must have been achieved for the previous 6 months (prior to registration), without introduction of any new therapeutic agents for their MPN
• For patients with MF, there must not have been any evidence of disease progression* for the previous 6 months (prior to registration) and no new therapeutic agents for their MPN introduced during this period.
• Patients receiving cytoreductive therapy for their MPN (not solely aspirin or venesection)
• Adequate hepatic function, defined as:
o bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with elevated bilirubin due to Gilbert’s syndrome are eligible)
o AST/ALT/ALP ≤ 2.5 x ULN
• Adequate renal function (creatinine clearance >30 mL/min)
• Male patients must agree to use effective contraception during participation in the trial and for 2 months after the last dose of trial treatment
• Patient must be able to give written informed consent
*Defined by IWG-MRT ELN criteria (Appendix 6). Please note no baseline bone marrow is required to confirm absence of “Leukemic transformation confirmed by a bone marrow blast count of ≥20%”.

Exclusion criteria:
• Leukaemic transformation (>20% blasts in blood, marrow or extramedullary site).
• Accelerated phase of disease as indicated by >5% blasts in the peripheral blood
• Treatment of ET, PV or MF with Interferon alpha or JAK inhibitors, such as ruxolitinib, or other investigational agents for their MPN within 6 months prior to trial entry
• Any of the following previous thrombotic events at any time:
o Portal or other splanchnic venous thrombosis
o Vascular access complication
o Ischemia cerebrovascular
o Stroke
o Transient Ischaemic attack
o Superficial thrombophlebitis
o Venous Thromboembolic events including pulmonary embolism (PE) and deep vein thrombosis (DVT)
o Peripheral vascular ischemia
o Visceral arterial ischemia
o Acute coronary syndrome
o Myocardial infarction
• Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
• Previous endometrial cancer, hyperplasia or polyps
• Prior treatment with hematopoietic stem cell transplantation
• Patients who do not carry any mutations in JAK2V617F or CALR or allele burden grade 1
• Any serious underlying medical condition (at the judgment of the Investigator), which could impair the ability of the patient to participate in the trial (e.g. liver disease, active autoimmune disease, uncontrolled diabetes, uncontrolled infection (HIV, Hepatitis B and C), known genetic defect (apart from MPN) relating to venous thromboembolic events, or psychiatric disorder precluding understanding of trial information)
• Known hypersensitivity to tamoxifen or hypersensitivity to any other component of tamoxifen
• Concomitant drugs contraindicated for use with the trial drug according to the Summary of Product Characteristics
• Known planned scheduled elective surgery during study with the exception of dental and low risk eye surgery (e.g. cataracts)

Principal Investigator for this trial: Professor Nigel Russell

Research Ethics Committee Reference: 16/EM/0181

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A Phase III, open label, multicentre randomised clinical study comparing Acelarin (NUC1031) with Gemcitabine in patient with metastatic pancreatic carcinoma (ACELARATE)

Summary:
Pancreatic cancer remains the most lethal of solid tumours with little progress being made to improve patient outcomes over the past 30 years of research. The incidence in the UK is approximately 9,000 new cases per year and, with a 5 year survival remaining at just 3%, mortality approximates incidence. These dismal outcomes reflect:
1. Advanced stage at presentation such that only a minority of patients are suitable for surgery with curative intent;
2. High rates of recurrence even in those undergoing radical surgery;
3. Limited efficacy of systemic therapies.

Gemcitabine has been a standard chemotherapy for these patients for more than 15 years, but drug resistance is common.

Acelarin has been developed to overcome the resistances, which are known to limit the effect of gemcitabine and works by preventing cancer cells from dividing by attacking their DNA (deoxyribonucleic acid) resulting in tumour cell death. Non-clinical and clinical studies have shown that Acelarin is more effective than gemcitabine because it is able to reach cancer cells by passive diffusion, is less easily degraded by the cancer cell, and delivers the monophosphate form of the active agent.

The primary purpose of this study is to investigate if Acelarin is more effective than gemcitabine in treating patients with metastatic pancreatic cancer.

The study will investigate if Acelarin treatment compared with gemcitabine therapy prolongs the life of patients. We will also evaluate how Acelarin compared with gemcitabine therapy reduce the effects of pancreatic cancer and investigate the safety of Acelarin. A further objective is to discover if blood and tumour tissue from pancreatic cancer patients contains possible proteins, which predict if treatment with Acelarin is better than using gemcitabine.

Inclusion criteria:
a) Age ≥ 18 years.
b) Histologically or cytologically proven pancreatic ductal adenocarcinoma or undifferentiated carcinoma of the
pancreas.*
c) Metastatic disease precluding curative surgical resection or definitive locally directed therapies such as chemo radiation. Patients who have relapsed following previously resected pancreatic cancer can be included.
d) Contrast enhanced computerised tomography (CT) scan of the thorax, abdomen and pelvis within 28 days prior to commencing treatment
e) Unidimensionally measurable disease.
f) ECOG performance status 0, 1 or 2 where treatment with combination chemotherapy is not deemed appropriate or is declined by the patient.
g) Platelets ≥100 x 109/l; neutrophils ≥ 1.5 x 109/l at entry.
h) Documented life expectancy > 3 months.
i) Informed written consent.

*Patients will be approached for consenting to provide either an additional core of tissue material for biomarker
discovery at the same time as a diagnostic biopsy or in those patients that have already had a diagnostic biopsy to undergo a second biopsy after randomisation into the trial. Neither of these biopsies is compulsory. Patients who don’t wish to have extra tissue taken for Biomarker discovery will be approached for consent to released surplus tissue from the original diagnostic specimen if this exists.

Exclusion criteria:
a) Laboratory results:
• Serum bilirubin ≥ 1.5x the upper limit of reference range (ULRR).
• Haemoglobin 2.5 x ULN or > 5x ULN if judged by the investigator to be related to liver metastases.
b) Medical or psychiatric conditions compromising informed consent.
c) Intracerebral metastases or meningeal carcinomatosis.
d) Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.
e) Pregnancy or breast feeding.
f) Previous chemotherapy for locally advanced and metastatic disease. Adjuvant chemotherapy for resected pancreatic cancer will be permitted provided that chemotherapy was completed > 12 months previously.
g) Radiotherapy within the last 4 weeks prior to start of study treatment.
h) Concurrent malignancies or invasive cancers diagnosed within past 5 years except for adequately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix or resected pancreatic cancer.
i) Hypersensitivity to gemcitabine or any of the excipients of gemcitabine or Acelarin (NUC1031).
j) All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be from the list below, the other must be a condom1 or abstaining from sexual intercourse, until six months after treatment has ended:
o Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: either oral, intravaginal or transdermal.
o Progesterone-only hormonal contraception associated with inhibition of ovulation: either oral, injectable or implantable.
o Intrauterine device (IUD)
o Intrauterine hormonereleasing system (IUS)
o Bilateral tubal occlusion
o Vasectomised partner2
o Sexual abstinence3

1 Male or female condom with or without spermicide is not an acceptable method of contraception alone.
2 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomised partner has received medical assessment of the surgical success.
3 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

Principal Investigator for this trial: Dr Arvind Arora

Research Ethics Committee Reference: 15/EM/0095

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Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA1 trial). A randomized, multidisciplinary, multinational AIO/DGAV/DGVS phase III trial.

Summary:
Biliary tract tumours are relatively rare, accounting for 0.7% of malignant tumours in adults, with approximately 1200 new cases registered each year in England and Wales. The 1-year and 5-year survival is poor at 22% and 9% respectively (Cancer Survival Trends in England and Wales 1971 – 1995). Approximately 1520%
of cases are suitable for surgical resection but the outlook remains poor with survival at 5 years approximately 15% (Cancer Survival Trends in England and Wales 1971 – 1995. Most tumours are advanced at presentation and are unsuitable for surgical resection.

The ACTICCA-1 trial will investigate the role of adjuvant chemotherapy with Cisplatin and Gemcitabine compared to surveillance. This study will determine whether the Cisplatin and Gemcitabine regimen which is effective in advanced disease will show a benefit in the adjuvant setting.

This is an international, multicentre, prospective, randomised controlled trial comparing adjuvant treatment with Cisplatin and Gemcitabine with no adjuvant treatment in patients who have undergone a complete macroscopic

resection of biliary tract cancer. Patients will be followed up for a period of 5 years, primarily assessing disease free survival and overall survival at 2 and 5 years respectively. Quality of Life sub studies are planned to be investigated within the trial also.

The results of this study will be used to further define the optimum management for patients who undergo a complete resection of their biliary tract cancer. This result could have the potential to change the current practice for treating these patients.

Inclusion criteria:
Eligibility criteria for enrolment phase
1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or
extrahepatic biliary tract cancer, or muscle invasive gallbladder cancer) scheduled for radical surgical therapy
2. Written informed consent
3. No prior chemotherapy for biliary tract cancer
4. No previous malignancy within 3 years or concomitant malignancy, except: non-melanomatous skin cancer or adequately treated in situ cervical cancer
5. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia)
6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent
7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial
8. Fertile women (18 years
5. Adequate haematologic function: ANC ≥1.5 x 109/L, platelets ≥100 x109/L, haemoglobin ≥9 g/dl or ≥5.59 mmol/L
6. Adequate liver function as measured by serum transaminases (AST and ALT) ≤5 x ULN and bilirubin ≤3 x ULN
7. Adequate renal function, i.e. serum creatinine ≤1.5 x ULN, glomerular filtration rate ≥ 60 mL/min (MDRD
8. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy
9. No concurrent treatment with other experimental drugs or other anticancer therapy, treatment in a clinical trial within 30 days prior to randomisation
10. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women Exclusion criteria:
Mixed hepatocellular tumours are excluded.

Principal Investigator for this trial: Dr Arvind Arora

Research Ethics Committee Reference: 15/LO/1044

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA1 trial). A randomized, multidisciplinary, multinational AIO/DGAV/DGVS phase III trial.

Summary:
Biliary tract tumours are relatively rare, accounting for 0.7% of malignant tumours in adults, with approximately 1200 new cases registered each year in England and Wales. The 1-year and 5-year survival is poor at 22% and 9% respectively (Cancer Survival Trends in England and Wales 1971 – 1995). Approximately 1520%
of cases are suitable for surgical resection but the outlook remains poor with survival at 5 years approximately 15% (Cancer Survival Trends in England and Wales 1971 – 1995. Most tumours are advanced at presentation and are unsuitable for surgical resection.

The ACTICCA-1 trial will investigate the role of adjuvant chemotherapy with Cisplatin and Gemcitabine compared to surveillance. This study will determine whether the Cisplatin and Gemcitabine regimen which is effective in advanced disease will show a benefit in the adjuvant setting.

This is an international, multicentre, prospective, randomised controlled trial comparing adjuvant treatment with Cisplatin and Gemcitabine with no adjuvant treatment in patients who have undergone a complete macroscopic

resection of biliary tract cancer. Patients will be followed up for a period of 5 years, primarily assessing disease free survival and overall survival at 2 and 5 years respectively. Quality of Life sub studies are planned to be investigated within the trial also.

The results of this study will be used to further define the optimum management for patients who undergo a complete resection of their biliary tract cancer. This result could have the potential to change the current practice for treating these patients.

Inclusion criteria:
Eligibility criteria for enrolment phase
1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or
extrahepatic biliary tract cancer, or muscle invasive gallbladder cancer) scheduled for radical surgical therapy
2. Written informed consent
3. No prior chemotherapy for biliary tract cancer
4. No previous malignancy within 3 years or concomitant malignancy, except: non-melanomatous skin cancer or adequately treated in situ cervical cancer
5. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia)
6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent
7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial
8. Fertile women (18 years
5. Adequate haematologic function: ANC ≥1.5 x 109/L, platelets ≥100 x109/L, haemoglobin ≥9 g/dl or ≥5.59 mmol/L
6. Adequate liver function as measured by serum transaminases (AST and ALT) ≤5 x ULN and bilirubin ≤3 x ULN
7. Adequate renal function, i.e. serum creatinine ≤1.5 x ULN, glomerular filtration rate ≥ 60 mL/min (MDRD
8. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy
9. No concurrent treatment with other experimental drugs or other anticancer therapy, treatment in a clinical trial within 30 days prior to randomisation
10. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women Exclusion criteria:
Mixed hepatocellular tumours are excluded.

Principal Investigator for this trial: Dr Arvind Arora

Research Ethics Committee Reference: 15/LO/1044

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Hughes Abdominal Repair Trial – Abdominal wall closure techniques to reduce the incidence of incisional hernias: A multi-centre pragmatic randomised trial

Summary:
The study is a multi centre parallel-group pragmatic randomised trial using two techniques for wound closure; the traditional mass closure of all layers of the abdominal wall and the Hughes repair (a near and far repair designed to distribute tension across the wound). The trial is designed to assess if the incidence of incisional hernias is altered postoperatively using the Hughes technique. Assessors will be blind to the technique of closure performed (except for the surgeon performing the procedure). Our aim is to evaluate whether the Hughes Repair changes: the prevalence of incisional hernias one year after surgery in patients with colorectal cancer, as measured by clinical evaluation (primary outcome); their quality of life; and the resulting cost. They will also be assessed by imaging. We shall treat wound dehiscence within 30 days of surgery as an outcome to be included in the analysis of the study.

Inclusion criteria:
Patients aged 18 years and over who are undergoing colorectal cancer resections with a midline laparotomy wound (open or laparoscopic assisted).

Exclusion criteria:
Patients who are not able to provide consent. Patients under the age of 18 years.

Principal Investigator for this trial: Mr Austin Acheson

Research Ethics Committee Reference: 12/WA/0374

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Immune control of EBV­positive diffuse large B-cell lymphoma (DLBCL): prospective and retrospective studies (ICEPOP Study)

Summary:
Diffuse large B cell lymphoma (DLBCL) is common and highly aggressive. Many patients fail existing treatments and 30% will die from their disease. The tumours frequently appear to have avoided immune responses directed against them, although how they avoid these responses and the identity of the immune targets in the cancer cells are poorly understood.
The most aggressive form of DLBCL carries the Epstein Barr virus (EBV) and the cancer cells contain viral proteins that, being totally foreign to the immune system, should be easy targets for the immune system to recognise. How these tumours develop and avoid the strong antiviral immunity present in most people is unknown. Understanding this will help develop novel approaches to treat both the viral and nonviral forms of DLBCL.
We will collect blood and tumour samples from patients with EBV DLBCL to identify potential immune defects that allow the disease to develop. We will also study the role the virus plays in the disease. We will also study patients whose tumour doesn’t carry the virus. This comparison will help identify distinct aspects of EBV-DLBCL and allow us to learn more about the disease in general. We aim to study blood and tumour from all cases of EBV-DLBCL that we identify (an estimated 10-20 cases in our patient population) and some two to three times that number of EBV-negative cases for comparison. Because of the rarity of EBVDLBCL
we will also need to make as much use as possible of
archived DLBCL biopsy specimens, from patients enrolled on the study (using their original diagnostic biopsy) and collections of DLBCL biopsies held elsewhere. We will screen these biopsy samples for EBV positivity and study the virus positive cases (and some negative cases for comparison) in depth. It is expected the study will take about 3.5 years to complete.

Inclusion criteria:
1. Patients must have DLBCL
2. Patients and healthy donors must be 16 years or over
3. Patients and healthy donors must be willing and able to give consent

Exclusion criteria:
Patients and healthy donors unable to provide informed consent.

Principal Investigator for this trial: Dr Christopher P Fox

Research Ethics Committee Reference: 15/WM/0419

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Immune control of EBV­positive diffuse large B-cell lymphoma (DLBCL): prospective and retrospective studies (ICEPOP Study)

Summary:
Diffuse large B cell lymphoma (DLBCL) is common and highly aggressive. Many patients fail existing treatments and 30% will die from their disease. The tumours frequently appear to have avoided immune responses directed against them, although how they avoid these responses and the identity of the immune targets in the cancer cells are poorly understood.
The most aggressive form of DLBCL carries the Epstein Barr virus (EBV) and the cancer cells contain viral proteins that, being totally foreign to the immune system, should be easy targets for the immune system to recognise. How these tumours develop and avoid the strong antiviral immunity present in most people is unknown. Understanding this will help develop novel approaches to treat both the viral and nonviral forms of DLBCL.
We will collect blood and tumour samples from patients with EBV DLBCL to identify potential immune defects that allow the disease to develop. We will also study the role the virus plays in the disease. We will also study patients whose tumour doesn’t carry the virus. This comparison will help identify distinct aspects of EBV-DLBCL and allow us to learn more about the disease in general. We aim to study blood and tumour from all cases of EBV-DLBCL that we identify (an estimated 10-20 cases in our patient population) and some two to three times that number of EBV-negative cases for comparison. Because of the rarity of EBVDLBCL
we will also need to make as much use as possible of
archived DLBCL biopsy specimens, from patients enrolled on the study (using their original diagnostic biopsy) and collections of DLBCL biopsies held elsewhere. We will screen these biopsy samples for EBV positivity and study the virus positive cases (and some negative cases for comparison) in depth. It is expected the study will take about 3.5 years to complete.

Inclusion criteria:
1. Patients must have DLBCL
2. Patients and healthy donors must be 16 years or over
3. Patients and healthy donors must be willing and able to give consent

Exclusion criteria:
Patients and healthy donors unable to provide informed consent.

Principal Investigator for this trial: Dr Christopher P Fox

Research Ethics Committee Reference: 15/WM/0419

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Defining the evidence base for health care delivery in congenital adrenal hyperplasia – a multi-centre CAH-UK (Children & Adolescents with CAH in the UK) initiative)

Summary:
Congenital Adrenal Hyperplasia (CAH) is associated with significant morbidity and mortality and occurs in about 1 in 10,000 life-births (about 6,300 individuals in the UK). Recent clinical data suggest impaired heath in young adults with CAH. The onset of such problems during childhood remains unclear. However, it is of paramount importance to define an evidence base to develop strategies for secondary prevention of future health problems. To define novel predictive markers of long-term health problems, we have formed a clinical consortium (CAH-UK) involving 16 tertiary UK centres to explore the current health status in 8 to 18 year olds with CAH. We have designed a cross-sectional study to define the current health in children and young people with CAH in the UK. These patients undergo there to six monthly blood tests as part of the routine clinical care. We have planned to add on additional blood, urine and saliva collections to devise novel test and explore the metabolic status. In addition, we will for the first time define if quality of life is already altered at this young age as it is in young adults. We will establish the presence and onset of potential health problems in children and young persons with CAH in the UK. Study participants will have an immediate benefit from this study as their therapy can be individualised. After validation novel markers of disease control will be implemented into clinical practice within the next 2-3 years improving personalisation of treatment in all patients with CAH. The identification of altered health related quality of life would aid developing care strategies. This combination of investigations represents a major step towards a personalised therapeutic approach in CAH.

Inclusion criteria:
Patients with CAH
1) Patients with known CAH due to 21-hydroxylase deficiency confirmed by hormonal and/ or genetic testing
2) Aged 8 – 18 years
3) Participants must have capacity to assent/consent and provide a signed and dated informed consent.

Controls
a) Aged 8 – 18 years
b) Participants must have capacity to assent/consent and provide a signed and dated informed consent.

Exclusion criteria:
Patients with CAH
1) Pregnancy

Controls
1) Past or present history of an endocrinopathy (all stages)
2) Type 1, diabetes, Type 2 diabetes, Insulin resistance
3) Known conditions of lipid/ cholesterol metabolism
4) Presence of any psychiatric disorder
5) Current or past use of psychiatric medication
6) Glucocorticoid use within the last 6 months
7) Diagnosed learning difficulties and/or full-scale IQ Principal Investigator for this trial: Dr Tabitha Randell

Research Ethics Committee Reference: 15/YH/0537

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Palliative radiotherapy in addition to self expanding metal stent for improving outcomes of dysphagia and survival in advanced oesophageal cancer (ROCS)

Summary:
The single most distressing symptom for more than 70% of patients with oesophageal cancer is difficulty in swallowing (dysphagia) caused by blockage of the gullet by a tumour. This causes severe restrictions on food intake, physical activity, social functioning and overall quality of life. Amongst the more effective treatments for improving swallowing, is the insertion of a metal stent (Self Expanding Metal Stent or SEMS) across the blocked part, which then self-expands to open up the gullet. The addition of radiotherapy may help to improve the problems caused by dysphagia and provide an additional survival benefit.
The purpose of this study is to test the impact of adding radiotherapy to SEMS on:
i) the length of time swallow remains improved for
ii) quality of life
iii) survival

Patients will be eligible to take part in the trial if they have oesophageal cancer, are in need of SEMS because of dysphagia, are aged 16 years or older, have been clinically assessed to be able to receive radiotherapy, have an expected survival of at least 12 weeks and are able to give written informed consent.
Four hundred and ninety-six patients will be randomised to receive either SEMS alone or SEMS with radiotherapy. The radiotherapy will be given as an outpatient either as five treatments (one per day) over one week, or ten treatments over two weeks. Questionnaires will be completed before treatment, within one week of stent insertion and then four
weeks after stent insertion until death to assess quality of life and cost. Interviews will be held with a sub-set of trial participants at three time points to explore their experiences whilst on the trial. Interviews will also be held with patients who do not consent to take part in the trial to explore their reasons for non-consent.

Inclusion criteria:
1. Histological confirmation of oesophageal carcinoma excluding small cell histology
2. Not suitable for radical treatment (oesophagectomy or radical chemoradiotherapy) either because of patient choice or medical reasons
3. Dysphagia clinically assessed as needing stent as primary treatment of the dysphagia
4. Age 16 or over
5. Discussion and treatment decision for SEMS placement made by an Upper GI multi-disciplinary team
6. Clinician assessment of ability to attend for radiotherapy
7. Expected survival of at least 12 weeks
8. Written informed consent

Exclusion criteria:
1. Histology of small cell carcinoma type
2. Tumour length of greater than 12 cm
3. Tumour growth within 2 cm of the upper oesophageal sphincter
4. Endoscopic treatment of the tumour, other than dilatation, planned in the peri-stent period
5. Presence of a tracheo-oesophageal fistula
6. Presence of a pacemaker
7. Previous radiotherapy to the area of the proposed radiotherapy field
8. Endoscopic treatment of the tumour (e.g. laser) in the immediate peri-stenting period
9. Pregnancy

Principal Investigator for this trial: Mr Ravinder Vohra

Research Ethics Committee Reference: 12/WA/0230

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Palliative radiotherapy in addition to self expanding metal stent for improving outcomes of dysphagia and survival in advanced oesophageal cancer (ROCS)

Summary:
The single most distressing symptom for more than 70% of patients with oesophageal cancer is difficulty in swallowing (dysphagia) caused by blockage of the gullet by a tumour. This causes severe restrictions on food intake, physical activity, social functioning and overall quality of life. Amongst the more effective treatments for improving swallowing, is the insertion of a metal stent (Self Expanding Metal Stent or SEMS) across the blocked part, which then self-expands to open up the gullet. The addition of radiotherapy may help to improve the problems caused by dysphagia and provide an additional survival benefit.
The purpose of this study is to test the impact of adding radiotherapy to SEMS on:
i) the length of time swallow remains improved for
ii) quality of life
iii) survival

Patients will be eligible to take part in the trial if they have oesophageal cancer, are in need of SEMS because of dysphagia, are aged 16 years or older, have been clinically assessed to be able to receive radiotherapy, have an expected survival of at least 12 weeks and are able to give written informed consent.
Four hundred and ninety-six patients will be randomised to receive either SEMS alone or SEMS with radiotherapy. The radiotherapy will be given as an outpatient either as five treatments (one per day) over one week, or ten treatments over two weeks. Questionnaires will be completed before treatment, within one week of stent insertion and then four
weeks after stent insertion until death to assess quality of life and cost. Interviews will be held with a sub-set of trial participants at three time points to explore their experiences whilst on the trial. Interviews will also be held with patients who do not consent to take part in the trial to explore their reasons for non-consent.

Inclusion criteria:
1. Histological confirmation of oesophageal carcinoma excluding small cell histology
2. Not suitable for radical treatment (oesophagectomy or radical chemoradiotherapy) either because of patient choice or medical reasons
3. Dysphagia clinically assessed as needing stent as primary treatment of the dysphagia
4. Age 16 or over
5. Discussion and treatment decision for SEMS placement made by an Upper GI multi-disciplinary team
6. Clinician assessment of ability to attend for radiotherapy
7. Expected survival of at least 12 weeks
8. Written informed consent

Exclusion criteria:
1. Histology of small cell carcinoma type
2. Tumour length of greater than 12 cm
3. Tumour growth within 2 cm of the upper oesophageal sphincter
4. Endoscopic treatment of the tumour, other than dilatation, planned in the peri-stent period
5. Presence of a tracheo-oesophageal fistula
6. Presence of a pacemaker
7. Previous radiotherapy to the area of the proposed radiotherapy field
8. Endoscopic treatment of the tumour (e.g. laser) in the immediate peri-stenting period
9. Pregnancy

Principal Investigator for this trial: Mr Ravinder Vohra

Research Ethics Committee Reference: 12/WA/0230

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

Randomised Clinical Trial of neoadjuvant and adjuvant chemotherapy (MAGIC regimen) vs. neoadjuvant chemoradiation (CROSS protocol) in adenocarcinoma of the oesophagus and oesophago-gastric junction.

Summary:
Cancer of the oesophagus (gullet/food pipe) and oesophagogastric junction (junction between the oesophagus and stomach) have increased in incidence in the West over the last 25 years. Oesophageal cancer is now the 9th most common cancer in the UK, accounting for 3% of all new cases. The aim of this research study is to compare and evaluate two established treatments for oesophageal cancer in order to establish if one treatment is superior to the other. The research group believe it is not currently clear which regimen is of greatest benefit to patients. These 2
regimens have been tested in previous randomised trials (MAGIC & CROSS). The 2 treatments are either
chemotherapy before and after surgery, or chemotherapy with radiotherapy before surgery. Both treatments are
standard and have been in use as treatments for oesophageal cancer for several years. 594 patients with
oesophageal and oesophagogastric junction cancer will be randomly allocated to these 2 treatments. During the trial patients will have a variety of clinical assessments and will complete health-related questionnaires. Following treatment they will be followed up for 3 years. The main objective of this trial is to look at overall survival. Secondary objectives are patient quality of life, complications and relief of swallowing problems.

Inclusion criteria:
1. Histologically-verified adenocarcinoma of the oesophagus or oesophagogastric junction based on OGD.
2. CT-18FDG-PET in all patients and EUS, if feasible
3. Staging laparoscopy will be performed for tumours of the abdominal oesophagus, junction and proximal stomach i.e. AEG II and AEG III (at the investigator’s discretion)
4. Pre-treatment stage cT23, N03, M0
5. No prior abdominal or thoracic radiotherapy
6. Male/female patients aged >18 years
7. ECOG Performance Status 0, 1 or 2
8. ASA Grading I-II
9. Adequate cardiac function. For all patients an ejection fraction of ≥ 50% is required. If patients have a known
significant cardiac history(e.g. known ischaemic disease, cardiomyopathy) an ejection fraction >50% and cardiac clearance by a consultant cardiologist for major surgery and cancer therapies is required. Where necessary, the Chief Investigator should be consulted to discuss the patient’s eligibility.
10. Adequate respiratory function. Patients should have pulmonary function tests completed with FEV1 >1.5L
11.Adequate bone marrow function: absolute neutrophil count (ANC) >1.5×109/l; white blood cell count >3×109/l;
platelets >100×109/l; haemoglobin (Hb) >9g/dl (can be posttransfusion).
12.Adequate renal function: glomerular filtration rate >60ml/minute calculated using the Cockcroft-Gault
Formula
13.Adequate liver function: serum bilirubin Exclusion criteria:
1. Tumours of squamous histology.
2. Patients with advanced inoperable or metastatic oesophageal, junctional or gastric adenocarcinoma.
3. Any prior chemotherapy for gastrointestinal cancer.
4. Prior abdominal or thoracic radiation.
5. Patients who are unfit for surgery or cancer treatments based on cardiac disease.
6. Patients with acute systemic infections.
7. Patients who are receiving treatment with Sorivudine or it’s chemical related analogues, such as Brivudine, which is contraindicated with capecitabine and 5-Fluorouracil administration.
8. Clinical COPD with significant obstructive airways disease classified by FEV1 Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible).
10. Known positive tests for human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B infection.
11. Any other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
12. Women who are pregnant or who are breastfeeding.

Principal Investigator for this trial: Mr Simon Leslie Parsons

Research Ethics Committee Reference: 14/EM/1284

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

An open randomised trial of the Arabin pessary to prevent preterm birth in twin pregnancy, with health economics and acceptability – STOPPIT 2.

Summary:
This study aims to confirm whether the Arabin cervical pessary prevents preterm birth in women with a twin pregnancy and a short cervix. Preterm birth is associated with increased risk of death and ill-health for the baby, so if preterm birth could be prevented in twins this would be a very good thing.

The Arabin cervical pessary is used to reduce preterm birth in women with a singleton pregnancy (one baby). A Dutch study which finished late last year has suggested that the cervical pessary might also prevent preterm birth in twins. Although the pessary did not work in all twins, it appeared to reduce preterm birth in those women with a twin pregnancy who had a short cervix (neck of the womb).

The study we propose here will resolve uncertainty around whether the Arabin pessary reduces spontaneous preterm birth in twins and improves outcomes for babies, define any adverse effects for mother and baby, ascertain whether women find the treatment acceptable and will calculate the costs for the NHS.

In a large number of NHS centres, we will ask around 1850 women with a twin pregnancy if they will have an
ultrasound scan to measure their cervix around the same time as they have a fetal anomaly scan. Women who are in the lowest 30% of cervical length measurements (around 500) will be asked if they want to join the treatment phase of the study.

Those agree will be treated with either the Arabin pessary, or standard treatment. The pessary will be inserted between the beginning of the 18th to the end of the 20th week of pregnancy, and then removed at 36 weeks. We will look at the proportion of babies who are born before 34 weeks, and the complications that happen to babies and we will compare these between the two groups. We will also perform an economic analysis to determine the cost-effectiveness of the Arabin pessary, and ask women about their experience of using the pessary.

Inclusion criteria:
INCLUSION CRITERIA (all must apply)
• Women presenting with twin pregnancy (monochorionic or dichorionic).
• Women with gestation established by scan at ≤16 weeks according to NICE guidelines.
• Women aged 16 years or older
• Women wishing to participate in both the SCREENING and TREATMENT phase of the study

Exclusion criteria:
EXCLUSION CRITERIA – SCREENING PHASE (none must apply)
• Women unable to give written informed consent
• Women with known significant congenital structural or chromosomal fetal anomaly at the time of inclusion
• Women with existing or planned cervical cerclage in the current pregnancy
• Women who with existing or planned (prior to 20+6 weeks gestation) treatment for twin to twin transfusion syndrome in the current pregnancy
• Women with suspected or proven rupture of the fetal membranes at the time of recruitment
• Women with singleton pregnancy or higher order multiple pregnancies
• Women with known sensitivity, contraindication or intolerance to silicone
• Women involved in a clinical trial of an investigational medicinal product (CTIMP)

EXCLUSION CRITERIA – TREATMENT PHASE (none must apply)
• Women with a cervical length > 30mm at 18+0 – 20+6 weeks gestation.

Principal Investigator for this trial: Ms Nia Jones

Research Ethics Committee Reference: 14/SS/1031

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

The Prognosis in Palliative care Study II (PiPS2): A multicentre prospective, observational, validation cohort study.

Summary:
Doctors’ estimates about how long patients with advanced cancer have left to live are not very accurate. The Prognosis in Palliative care Scales (PiPS) were developed in order to provide an objective aid to clinicians’ intuition. Two different PiPS scores can be calculated depending upon whether or not the patient has capacity to agree to providing a blood test. Before recommending PiPS for routine use it is important to check that the scores are accurate and reliable. Four
other scores may also be useful and need to be tested: the Palliative Prognostic Index (PPI), the Palliative
Performance Scale (PPS), the Palliative Prognostic (PaP) score and the Feliu Prognostic Nomogram (FPN).

The aim of our study is to check that PiPS is accurate when used in a different group of cancer patients and to
compare its accuracy against clinicians’ survival estimates. We will also look at the performance of PaP, FPN, PPI and PPS. We will ask patients with advanced incurable cancer, who have recently been referred to palliative (“hospice”) care services, to take part in our study. If patients have capacity then, with their approval, we will collect information from their medical notes and we will take a blood test. If patients lack capacity then we will ask their relatives for permission to record information from their medical notes. We will not take blood tests from patients who lack capacity. With this information we will be able to calculate PiPS, PaP, FPN, PPI & PPS scores. When patients die we will be able to work out the accuracy of the various predictions.

Inclusion criteria:
1. Patient has been recently referred (or re-referred) to palliative care service. For inpatient palliative care patients, “recent” referral means that the patient should have been first seen by a member of the palliative care team no more than 7-days previously. For a community, day-hospice or palliative care outpatient, “recent” means that the patient should have had fewer than three previous contacts with the palliative care service before they are recruited to the study.
2. Patients with locally advanced or metastatic, incurable cancer.
3. Aged 18 years or over.
4. Sufficient English language skills for competent patients to understand study literature and undertake study assessments. Whenever possible translation services will be used to maximise the potential for patients or carers to give consent / agreement to participate.

Exclusion criteria:
1.Currently receiving (or planned to receive) potentially curative treatment for cancer.

Principal Investigator for this trial: Dr Andrew Wilcock

Research Ethics Committee Reference: 16/YH/0132

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

The United Kingdom Autoimmune Hepatitis Cohort: a multi-centre platform for research and translational medicine (UK-AIH)

Summary:
Our immune system normally protects us by attacking the bugs that cause infections. Very occasionally a person’s
immune system can develop a fault and start to attack parts of the body instead. In autoimmune hepatitis a faulty
immune system attacks the liver. This can damage the liver leading to liver failure and cirrhosis. Autoimmune hepatitis
is a rare disease which affects around 10 thousand people in the UK. People who develop autoimmune hepatitis need
treatment with medicines to reduce the activity of the immune system, and many need lifelong treatment. Not everybody
responds well to the current treatments and some people suffer from side effects of treatment. Some people still die of
the condition and some others need to have a liver transplant. We want to collect more information about the condition
to help to improve treatments.
UKAIH
is a study for anyone with autoimmune hepatitis in the UK. It will collect information from any patient who wishes to participate. Some people will be asked to donate blood samples, answer questionnaires, and let
researchers use any liver tissue samples that are taken as part of their normal medical care. All this information will be
studied to identify new tests and treatments. We will store safely the information and samples, and samples of
participants’ DNA, so that they can be used to answer new questions about autoimmune hepatitis that may come up in
the future. We will also ask people for permission to contact them or their doctors in the future if there are new studies
or trials of new treatments for which they might be suitable.
This study is being paid for by the National Institute for Health Research and is being coordinated by Newcastle
University and Newcastle upon Tyne Hospitals NHS Foundation Trust which is the sponsoring organisation.

Inclusion criteria:
Whole UKAIH
cohort inclusion criteria
1. Under medical care (primary or secondary care) in the UK for a diagnosis of autoimmune hepatitis. This is the whole
patient population likely to benefit from any study outputs.
2. Able to give informed consent. The small minority who cannot give informed consent are not otherwise different from
the rest of the study population, so have the potential to benefit from study outputs without the need to participate.
New diagnosis cohort inclusion criteria (200 participants)
1. All criteria above
2. ALT above the upper reference limit for the analysing laboratory. Permits detection of biochemical response to
treatment
3. Hepatitis B S antigen negative, hepatitis C antibody negative (or, if HCV antibody positive, HCV RNA undetectable by
PCR). Chronic viral hepatitis can confound immune phenotype and ALT
4. No clinical suspicion of other viral hepatitis (including exclusion of acute hepatitis A and E, EBV and CMV by serology
if clinically appropriate). Acute viral hepatitis can confound diagnosis as well as immune phenotype and ALT
5. AMA titre Exclusion criteria:
Whole UKAIH
cohort exclusion criteria
1. Age under 16 years. The systems and safeguards of the study will be established in consenting adult patients. If the
findings of this study are encouraging, we intend to move towards recruiting a paediatric cohort with a new request for
ethical review.
New diagnosis cohort exclusion criteria (200 participants)
1. All criteria above
2. Any immunosuppressive medications in the 12 weeks before recruitment. This includes: any systemic corticosteroid
(includes oral budesonide, but nasal, inhaled and topical steroids are acceptable), azathioprine, mycophenolate
mofetil, mycophenolic acid, tacrolimus, ciclosporin, cyclophosphamide, rituximab, methotrexate. Immunosupressants
have the potential to alter disease phenotype and confound the results
3. Diagnosis of another liver disease, including PBC, PSC and their overlap syndromes with AIH, also chronic viral
hepatitis B or C, haemochromatosis, Wilson disease, alcoholrelated
liver disease, alpha1antitrypsin
deficiency,
granulomatous hepatitis, hepatic sarcoidosis, BuddChiari
syndrome, nonalcoholic
steatohepatitis.
The presence of simple steatosis on imaging / biopsy is acceptable only if steatohepatitis is confidently excluded on
clinical / histological evaluation. These conditions can elevate ALT and confound the results
4. Diagnosis of lymphoma, IgG4 disease, myeloma or monoclonal gammopathy of uncertain significance (MGUS).
These conditions can elevate immunoglobulins and confound the results
5. Metastatic cancer. These conditions have a relatively high probability of influencing clinical variables or outcome
during the period of study
6. Primary hepatocellular cancer, cholangiocarcinoma or pancreatic cancer. These conditions have a relatively high
probability of elevating ALT or influencing clinical variables during the period of the study
7. Alcohol intake greater than 14 units a week for females, 21 units a week for males, on average over the previous 12
weeks. Higher alcohol intakes can elevate ALT and confound the results
8. HIV positive HIV, even on antiretroviral therapy, may alter the immune phenotype and confound the results
9. Previous liver transplant. The alloimmune
response of immune hepatitis after liver transplantation may differ from
AIH and confound the results
10. Registered on liver transplant waiting list. Reasonable probability that transplant will alter immune phenotype and
ALT within 12 months
Complete response group exclusion criteria (100 participants)
1. All criteria above
2. Biopsy evidence of cirrhosis, or evidence of portal hypertension (ascites or varices on imaging, varices on
gastroscopy, hepatic encephalopathy), or liver synthetic dysfunction (elevated prothrombin time unless on Warfarin,
elevated bilirubin unless diagnosed Gilbert syndrome). Patients with advanced disease remain at high risk of clinical
events and changes in ALT and IgG may not purely reflect AIH activity
Incomplete response group exclusion criteria (200 participants)
1. All criteria above
2. Clinical suspicion that something other than AIH is responsible for a persistently elevated ALT (eg frequent nonsteroidal
antiinflammatory
drug use, new or worsening fatty liver disease). Particularly when IgG is normal but ALT
remains elevated, these factors could lead to a patient being considered to have an incomplete response incorrectly
and confound the results
3. Patients whose corticosteroid dose is dictated by the requirements of another disease (eg polymyalgia rheumatica).
If the ALT and IgG are normal, the high steroid dose could lead to a patient being considered to have an incomplete
response incorrectly and confound the results. Patients should only be included on the basis of ongoing
highdose
steroid requirements when there is record that lower doses are associated with elevation of the ALT.

Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 14/LO/0303

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

The United Kingdom Autoimmune Hepatitis Cohort: a multi-centre platform for research and translational medicine (UK-AIH)

Summary:
Our immune system normally protects us by attacking the bugs that cause infections. Very occasionally a person’s
immune system can develop a fault and start to attack parts of the body instead. In autoimmune hepatitis a faulty
immune system attacks the liver. This can damage the liver leading to liver failure and cirrhosis. Autoimmune hepatitis
is a rare disease which affects around 10 thousand people in the UK. People who develop autoimmune hepatitis need
treatment with medicines to reduce the activity of the immune system, and many need lifelong treatment. Not everybody
responds well to the current treatments and some people suffer from side effects of treatment. Some people still die of
the condition and some others need to have a liver transplant. We want to collect more information about the condition
to help to improve treatments.
UKAIH
is a study for anyone with autoimmune hepatitis in the UK. It will collect information from any patient who wishes to participate. Some people will be asked to donate blood samples, answer questionnaires, and let
researchers use any liver tissue samples that are taken as part of their normal medical care. All this information will be
studied to identify new tests and treatments. We will store safely the information and samples, and samples of
participants’ DNA, so that they can be used to answer new questions about autoimmune hepatitis that may come up in
the future. We will also ask people for permission to contact them or their doctors in the future if there are new studies
or trials of new treatments for which they might be suitable.
This study is being paid for by the National Institute for Health Research and is being coordinated by Newcastle
University and Newcastle upon Tyne Hospitals NHS Foundation Trust which is the sponsoring organisation.

Inclusion criteria:
Whole UKAIH
cohort inclusion criteria
1. Under medical care (primary or secondary care) in the UK for a diagnosis of autoimmune hepatitis. This is the whole
patient population likely to benefit from any study outputs.
2. Able to give informed consent. The small minority who cannot give informed consent are not otherwise different from
the rest of the study population, so have the potential to benefit from study outputs without the need to participate.
New diagnosis cohort inclusion criteria (200 participants)
1. All criteria above
2. ALT above the upper reference limit for the analysing laboratory. Permits detection of biochemical response to
treatment
3. Hepatitis B S antigen negative, hepatitis C antibody negative (or, if HCV antibody positive, HCV RNA undetectable by
PCR). Chronic viral hepatitis can confound immune phenotype and ALT
4. No clinical suspicion of other viral hepatitis (including exclusion of acute hepatitis A and E, EBV and CMV by serology
if clinically appropriate). Acute viral hepatitis can confound diagnosis as well as immune phenotype and ALT
5. AMA titre Exclusion criteria:
Whole UKAIH
cohort exclusion criteria
1. Age under 16 years. The systems and safeguards of the study will be established in consenting adult patients. If the
findings of this study are encouraging, we intend to move towards recruiting a paediatric cohort with a new request for
ethical review.
New diagnosis cohort exclusion criteria (200 participants)
1. All criteria above
2. Any immunosuppressive medications in the 12 weeks before recruitment. This includes: any systemic corticosteroid
(includes oral budesonide, but nasal, inhaled and topical steroids are acceptable), azathioprine, mycophenolate
mofetil, mycophenolic acid, tacrolimus, ciclosporin, cyclophosphamide, rituximab, methotrexate. Immunosupressants
have the potential to alter disease phenotype and confound the results
3. Diagnosis of another liver disease, including PBC, PSC and their overlap syndromes with AIH, also chronic viral
hepatitis B or C, haemochromatosis, Wilson disease, alcoholrelated
liver disease, alpha1antitrypsin
deficiency,
granulomatous hepatitis, hepatic sarcoidosis, BuddChiari
syndrome, nonalcoholic
steatohepatitis.
The presence of simple steatosis on imaging / biopsy is acceptable only if steatohepatitis is confidently excluded on
clinical / histological evaluation. These conditions can elevate ALT and confound the results
4. Diagnosis of lymphoma, IgG4 disease, myeloma or monoclonal gammopathy of uncertain significance (MGUS).
These conditions can elevate immunoglobulins and confound the results
5. Metastatic cancer. These conditions have a relatively high probability of influencing clinical variables or outcome
during the period of study
6. Primary hepatocellular cancer, cholangiocarcinoma or pancreatic cancer. These conditions have a relatively high
probability of elevating ALT or influencing clinical variables during the period of the study
7. Alcohol intake greater than 14 units a week for females, 21 units a week for males, on average over the previous 12
weeks. Higher alcohol intakes can elevate ALT and confound the results
8. HIV positive HIV, even on antiretroviral therapy, may alter the immune phenotype and confound the results
9. Previous liver transplant. The alloimmune
response of immune hepatitis after liver transplantation may differ from
AIH and confound the results
10. Registered on liver transplant waiting list. Reasonable probability that transplant will alter immune phenotype and
ALT within 12 months
Complete response group exclusion criteria (100 participants)
1. All criteria above
2. Biopsy evidence of cirrhosis, or evidence of portal hypertension (ascites or varices on imaging, varices on
gastroscopy, hepatic encephalopathy), or liver synthetic dysfunction (elevated prothrombin time unless on Warfarin,
elevated bilirubin unless diagnosed Gilbert syndrome). Patients with advanced disease remain at high risk of clinical
events and changes in ALT and IgG may not purely reflect AIH activity
Incomplete response group exclusion criteria (200 participants)
1. All criteria above
2. Clinical suspicion that something other than AIH is responsible for a persistently elevated ALT (eg frequent nonsteroidal
antiinflammatory
drug use, new or worsening fatty liver disease). Particularly when IgG is normal but ALT
remains elevated, these factors could lead to a patient being considered to have an incomplete response incorrectly
and confound the results
3. Patients whose corticosteroid dose is dictated by the requirements of another disease (eg polymyalgia rheumatica).
If the ALT and IgG are normal, the high steroid dose could lead to a patient being considered to have an incomplete
response incorrectly and confound the results. Patients should only be included on the basis of ongoing
highdose
steroid requirements when there is record that lower doses are associated with elevation of the ALT.

Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 14/LO/0303

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A two year, multicenter, randomized, doubleblind, placebocontrolled, parallel group trial to evaluate efficacy, safety, tolerability, and pharmacokinetics of Teriflunomide administered orally once daily in Pediatric patients with Relapsing forms of Multiple Sclerosis followed by an Open-Label extension.

Summary:
Multiple Sclerosis (MS) is a neurological disease which commonly affects patients between 20 to 40 years of age. However, pediatric MS, defined as onset of MS before the age of 16, is increasingly recognised and is thought to account for approximately 5 percent of cases.

Multiple Sclerosis in children and differences from the common adult form of MS to a large extent are understudied. There are no approved disease modifying drugs for pediatric MS and the effects of drugs in children have not been formally evaluated in clinical trials.

Teriflunomide has demonstrated advantages in adult relapsing forms of MS patients in reducing frequency of relapse rate, disease progression, and MRI activity.

The objectives of the proposed clinical pediatric development program are to assess the efficacy, safety/tolerability, and pharmacokinetics (PK) of teriflunomide in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis (RMS).

Inclusion criteria:
– Patients with relapsing multiple sclerosis are eligible. Patients should meet the criteria of MS based on McDonald criteria 2010 and International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for pediatric MS, version of 2012 (Krupp et al 2013 Mult Scler. 19(10):12617) and have:
– at least one relapse (or attack) in the 12 months preceding randomization, or
– at least 2 relapses (or attack) in the 24 months preceding randomization.
– ≤17 years of age and ≥10 years of age at randomization.
– Signed informed consent/assent obtained from patient and patient’s legal representative (parents or guardians) according to local legislation.

Exclusion criteria:
• EDSS score greater than 5.5 at screening or randomization visit
• Relapse within 30 days prior to randomization
• Treated with
– glatiramer acetate, interferons, or dimethyl fumarate within 1 month prior to randomization
– fingolimod, or intravenous immunoglobulins within 3 months prior to randomization
– natalizumab, other immunosuppressant or immunomodulatory agents such as cyclophosphamide, azathioprine, cyclosporine, methotrexate, mycophenolate, within 6 months prior to randomization
– cladribine or mitoxantrone within 2 years preceding randomization
• Treated with alemtuzumab at any time
• History of HIV infection
• Contraindication for MRI
• Pregnant or breastfeeding females or those who plan to become pregnant during the study.
• Female patients of childbearing
potential not using highly effective contraceptive method (contraception in both female and male is required)

Principal Investigator for this trial: Dr William Whitehouse

Research Ethics Committee Reference:

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

A two year, multicenter, randomized, doubleblind, placebocontrolled, parallel group trial to evaluate efficacy, safety, tolerability, and pharmacokinetics of Teriflunomide administered orally once daily in Pediatric patients with Relapsing forms of Multiple Sclerosis followed by an Open-Label extension.

Summary:
Multiple Sclerosis (MS) is a neurological disease which commonly affects patients between 20 to 40 years of age. However, pediatric MS, defined as onset of MS before the age of 16, is increasingly recognised and is thought to account for approximately 5 percent of cases.

Multiple Sclerosis in children and differences from the common adult form of MS to a large extent are understudied. There are no approved disease modifying drugs for pediatric MS and the effects of drugs in children have not been formally evaluated in clinical trials.

Teriflunomide has demonstrated advantages in adult relapsing forms of MS patients in reducing frequency of relapse rate, disease progression, and MRI activity.

The objectives of the proposed clinical pediatric development program are to assess the efficacy, safety/tolerability, and pharmacokinetics (PK) of teriflunomide in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis (RMS).

Inclusion criteria:
– Patients with relapsing multiple sclerosis are eligible. Patients should meet the criteria of MS based on McDonald criteria 2010 and International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for pediatric MS, version of 2012 (Krupp et al 2013 Mult Scler. 19(10):12617) and have:
– at least one relapse (or attack) in the 12 months preceding randomization, or
– at least 2 relapses (or attack) in the 24 months preceding randomization.
– ≤17 years of age and ≥10 years of age at randomization.
– Signed informed consent/assent obtained from patient and patient’s legal representative (parents or guardians) according to local legislation.

Exclusion criteria:
• EDSS score greater than 5.5 at screening or randomization visit
• Relapse within 30 days prior to randomization
• Treated with
– glatiramer acetate, interferons, or dimethyl fumarate within 1 month prior to randomization
– fingolimod, or intravenous immunoglobulins within 3 months prior to randomization
– natalizumab, other immunosuppressant or immunomodulatory agents such as cyclophosphamide, azathioprine, cyclosporine, methotrexate, mycophenolate, within 6 months prior to randomization
– cladribine or mitoxantrone within 2 years preceding randomization
• Treated with alemtuzumab at any time
• History of HIV infection
• Contraindication for MRI
• Pregnant or breastfeeding females or those who plan to become pregnant during the study.
• Female patients of childbearing
potential not using highly effective contraceptive method (contraception in both female and male is required)

Principal Investigator for this trial: Dr William Whitehouse

Research Ethics Committee Reference:

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

International Randomised Phase III Clinical Trial in Children with Acute Myeloid Leukaemia Incorporating an Embedded Dose Finding Study for Gemtuzumab Ozogamicin in Combination with Induction Chemotherapy

Summary:
MyeChild 01 is an international phase III clinical trial in children with acute myeloid leukaemia (AML); a disease with a significant mortality. It will compare two induction chemotherapy regimens: mitoxantrone and cytarabine (current standard treatment) with liposomal daunorubicin and cytarabine. This will test liposomal daunorubicin, which is believed to be less cardiotoxic than similar conventional drugs, although this is unproven. Patients responding well to induction chemotherapy are eligible for a randomisation of two consolidation regimens: high dose cytarabine (current standard treatment) or fludarabine and cytarabine (FLA); a regimen commonly used in patients with relapsed disease, testing whether FLA is more effective in front line therapy than standard consolidation treatment. Patients with cytogenetic features associated with a higher risk of relapse and those responding suboptimally to induction treatment are candidates for haemopoeitic stem cell transplant (HSCT) and are eligible for a randomisation comparing two HSCT conditioning regimens: myeloablative conditioning (MAC) (current UK standard) or reduced intensity conditioning (RIC). HSCT has not consistently shown benefit in high-risk patients because the mortality associated with the procedure has outweighed the advantage from a reduction in relapse risk. This will test whether reducing the intensity of conditioning improves survival by reducing transplant related deaths without increasing the relapse rate.
The trial incorporates a dose finding study for gemtuzumab ozogamicin, the most promising new drug in AML. The aim is to identify the optimum tolerated number of doses of gemtuzumab ozogamicin (up to a total of 3 doses), which can be safely combined with either of the induction chemotherapy regimens and then to compare this number of doses with one dose of gemtuzumab ozogamicin.
The intensity of treatment will be directed by cytogenetics/molecular genetics and response assessed by minimal residual disease (MRD) levels measured by flow cytometry and molecular methodology.

Inclusion criteria:
Inclusion criteria for trial entry and Randomisation 1 (induction chemotherapy randomisation):
– A diagnosis of AML/high risk myelodysplastic syndrome (MDS)/isolated myeloid sarcoma (either de novo or secondary)
– Age 3 logs after course 2 for those with an informative molecular marker but without an informative marker of sufficient sensitivity for flow MRD monitoring
or
2) Patients with intermediate risk cytogenetics/molecular genetics with a MRD level 3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring
– Written informed consent from the patient and/or parent/legal guardian

Inclusion criteria for participation in R4:
– Patient meets the eligibility criteria for trial entry
– Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial
– Patient is in CR or CRi defined as 0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of >0.1% may be used
3) Good risk cytogenetics with flow MRD >0.1% confirmed by a decrease in molecular MRD of Exclusion criteria:
Exclusion criteria for all randomisations
– Acute promyelocytic leukaemia (APL)
– Myeloid leukaemia of Down Syndrome (ML DS)
– Blast crisis of chronic myeloid leukaemia
– Relapsed or refractory AML
– Bone marrow failure syndromes
– Prior anthracycline exposure which would inhibit the delivery of study anthracyclines
– Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML
– Pregnant or lactating females

Principal Investigator for this trial: Dr Emma Astwood

Research Ethics Committee Reference: 15/WA/0316

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

International Randomised Phase III Clinical Trial in Children with Acute Myeloid Leukaemia Incorporating an Embedded Dose Finding Study for Gemtuzumab Ozogamicin in Combination with Induction Chemotherapy

Summary:
MyeChild 01 is an international phase III clinical trial in children with acute myeloid leukaemia (AML); a disease with a significant mortality. It will compare two induction chemotherapy regimens: mitoxantrone and cytarabine (current standard treatment) with liposomal daunorubicin and cytarabine. This will test liposomal daunorubicin, which is believed to be less cardiotoxic than similar conventional drugs, although this is unproven. Patients responding well to induction chemotherapy are eligible for a randomisation of two consolidation regimens: high dose cytarabine (current standard treatment) or fludarabine and cytarabine (FLA); a regimen commonly used in patients with relapsed disease, testing whether FLA is more effective in front line therapy than standard consolidation treatment. Patients with cytogenetic features associated with a higher risk of relapse and those responding suboptimally to induction treatment are candidates for haemopoeitic stem cell transplant (HSCT) and are eligible for a randomisation comparing two HSCT conditioning regimens: myeloablative conditioning (MAC) (current UK standard) or reduced intensity conditioning (RIC). HSCT has not consistently shown benefit in high-risk patients because the mortality associated with the procedure has outweighed the advantage from a reduction in relapse risk. This will test whether reducing the intensity of conditioning improves survival by reducing transplant related deaths without increasing the relapse rate.
The trial incorporates a dose finding study for gemtuzumab ozogamicin, the most promising new drug in AML. The aim is to identify the optimum tolerated number of doses of gemtuzumab ozogamicin (up to a total of 3 doses), which can be safely combined with either of the induction chemotherapy regimens and then to compare this number of doses with one dose of gemtuzumab ozogamicin.
The intensity of treatment will be directed by cytogenetics/molecular genetics and response assessed by minimal residual disease (MRD) levels measured by flow cytometry and molecular methodology.

Inclusion criteria:
Inclusion criteria for trial entry and Randomisation 1 (induction chemotherapy randomisation):
– A diagnosis of AML/high risk myelodysplastic syndrome (MDS)/isolated myeloid sarcoma (either de novo or secondary)
– Age 3 logs after course 2 for those with an informative molecular marker but without an informative marker of sufficient sensitivity for flow MRD monitoring
or
2) Patients with intermediate risk cytogenetics/molecular genetics with a MRD level 3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring
– Written informed consent from the patient and/or parent/legal guardian

Inclusion criteria for participation in R4:
– Patient meets the eligibility criteria for trial entry
– Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial
– Patient is in CR or CRi defined as 0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of >0.1% may be used
3) Good risk cytogenetics with flow MRD >0.1% confirmed by a decrease in molecular MRD of Exclusion criteria:
Exclusion criteria for all randomisations
– Acute promyelocytic leukaemia (APL)
– Myeloid leukaemia of Down Syndrome (ML DS)
– Blast crisis of chronic myeloid leukaemia
– Relapsed or refractory AML
– Bone marrow failure syndromes
– Prior anthracycline exposure which would inhibit the delivery of study anthracyclines
– Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML
– Pregnant or lactating females

Principal Investigator for this trial: Dr Emma Astwood

Research Ethics Committee Reference: 15/WA/0316

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

OCTOPUS:  Ovarian Cancer Trials of Weekly Paclitaxel – Umbrella Study: A Randomised, Phase II Umbrella Trial of a Weekly Paclitaxel +/­ Novel Agents in Platinum-Resistant Ovarian Cancer

Summary:
More than 4,200 women with ovarian cancer die from the disease every year in the UK. Most patients with relapsed
ovarian cancer initially respond to chemotherapy but then the disease becomes resistant to treatment. Eventually, all patients develop relapse within 6 months from the end of last platinum containing chemotherapy-a
term called platinum-resistance. The response rate to chemotherapy for women with platinum-resistant
ovarian cancer is low (1055%). The average time before the cancer worsens (‘median progression-free survival’) is approximately 4 months and overall survival is only 12 months. There is an urgent need to improve patient outcomes.

Chemotherapy using paclitaxel delivered weekly is a useful strategy. OCTOPUS is a phase II clinical trial framework for testing whether novel targeted agents (either as single agents or in combination with weekly paclitaxel‘ experimental’ arm) provide any promising activity signals in platinum-resistant ovarian cancer compared to weekly paclitaxel alone (standard care). This trial design allows for new targeted agents to be screened in the context of a rolling, randomised, placebo-controlled phase II setting. New agents will be introduced/removed from OCTOPUS by amendment thus reducing the study time and costs. In each randomised placebo controlled study, a total of 140 patients will be
recruited and randomised in a 1:1 ratio to receive paclitaxel plus novel agent or paclitaxel plus placebo.

The aim of the trial is to investigate whether the experimental arm is superior to standard chemotherapy (paclitaxel), to determine the safety, quality of life and to explore whether markers predicting which patients are likely to benefit most can be found.

The first drug to be tested in combination with weekly paclitaxel is AZD2014. This oral drug blocks molecules called mTORC1 and 2 which are known to be involved in cancer growth. Early clinical trials have shown very promising results in ovarian cancer.

Inclusion criteria:
1. Age ≥ 18 years
2. Histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer (please note that patients who have an original diagnosis based on cytology only will not be eligible for entry into the study unless a biopsy confirming high grade serous histology is performed). Please note that Grade 3 serous on pathology reports are accepted as high grade serous. Any patient originally diagnosed with a ‘grade 2 serous’ pathology must undergo pathology review to confirm high grade pathology.
3. Platinum-resistant disease defined as progression within 6 months of completing prior platinum therapy. This includes platinum-refractory disease. Progression is defined by RECIST criteria v1.1 (radiologically with measurable disease), but patients with CA125 progression (GCIG CA125 Criteria) plus symptoms indicative of progression will also be allowed to enter.
4. Measurable or evaluable disease (if not measurable by RECIST criteria v1.1, must be evaluable by GCIG CA125 criteria). Patients with CA125 progression in the absence of symptoms will NOT be eligible.
5. Histological tissue specimen available (tissue block or 8-10 unstained slides) must be available (specimen can be the sample at diagnosis or taken at relapse). Otherwise, a biopsy must be carried out to obtain sufficient tissue for histological assessment.
6. Willingness to undergo mandatory biopsy pre cycle 1 day 1. Target lesions (RECIST criteria v1.1) should be avoided if possible.
7. Prior taxane use: Patients whom have received prior 3 weekly paclitaxel (or other 3 weekly taxane) are permitted. Patients whom received weekly paclitaxel as part of first line treatment in combination with platinum are eligible if the interval since the last dose of weekly paclitaxel is > 6 months at the time of randomisation. Patients whom received prior weekly paclitaxel (alone or in combination) for platinum-resistant disease are excluded. If patients have received prior taxane, the interval since the last taxane treatment must be known. The treatment immediately prior to study entry
need not be platinum-based. Entry into the trial is not limited to first line treatment for platinum-resistant ovarian cancer ie. patients can have prior lines of therapy for platinum-resistant disease.
8. Ability to provide written informed consent prior to participating in the trial and any trial related procedures being performed
9. Adequate haematological and biochemical function as indicated below. These measurements must be performed within 7 days prior to randomisation:
• Absolute neutrophil count ≥1.5 x 109/L
• Platelet count ≥100 x 109/L
• Haemoglobin ≥90 g/L
• Serum creatinine Exclusion criteria:
1. Non high grade serous histologies including carcinosarcoma.
2. Prior chemotherapy, biological therapy, radiation therapy, hormonal anti-cancer therapy, immunotherapy, other anti-cancer agents within 14 days of starting study treatment (not including palliative radiotherapy at focal sites). Treatment with any investigational agent within the preceding 4 weeks or within 5 halflives
of the investigational agent, whichever is longer.
3. Pregnant or lactating women
4. Women of childbearing age and potential who are not willing to use two highly effective forms of contraception as detailed Pregnancy section. In addition, patients will be excluded if they are not willing to use contraception for the duration as documented in Pregnancy Sections.
5. With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.03) Grade 1 at the time of starting study treatment.
6. Major surgery within 4 weeks prior to entry to the study or minor surgery within 2 weeks of entry into the study (excluding placement of vascular access)
7. Spinal cord compression, known leptomeningeal involvement or brain metastases, unless treated and stable off steroids for at least 4 weeks prior to randomisation
8. Oral anticoagulants such as warfarin are not permitted, with the exception of 1mg daily warfarin dose for the prevention of hickman line clotting. Anticoagulation with low molecular weight heparin is allowed.
9. Any haemopoietic growth factors (e.g., GCSF,
GMCSF) and blood transfusions within 2 weeks prior to
randomisation
10. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease], uncontrolled chronic renal diseases (glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis), current unstable or uncompensated respiratory or cardiac conditions, uncontrolled hypertension, active bleeding diatheses or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required.
11. Torsades de Pointes within 12 months of study entry
12. Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements
13. Patients with a history of grade 3 or 4 allergic reaction (CTCAEv4.03) to paclitaxel are not permitted. Patients who have had prior grade 1 or 2 hypersensitivity reactions are permitted providing the weekly paclitaxel is administered using the desensitisation schedule (section 5.7.2).
14. Patients who have a new diagnosis of deep vein thrombosis or pulmonary embolism within 2 weeks of
randomisation are permitted if clinically stable on a therapeutic dose of LMWH.

Principal Investigator for this trial: Dr Anjana Anand

Research Ethics Committee Reference: 15/LO/1302

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076 Continue reading

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