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Respiratory Medicine clinical trial

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 <20 mg/mL) when not on ICS or ≤16 mg/ml or histamine ≤20 mg/ml or acetylcholine <40 mg/mL) on ICS therapy performed according to ATS/ERS guidelines. 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 <30 kg 23. Patients receiving any medications in the classes listed in the protocol should be excluded unless they meet the criteria 24. Patients receiving medications in the classes listed in the protocol should be excluded unless the medication has been stabilized for the specified period and the stated conditions have been met 25. Patients who started immunotherapy or desensitization for allergies, within 3 months prior to Visit 1, or where the maintenance dose is expected to change during the study 26. Patients with a known history of noncompliance to medication or who are unable or unwilling to complete an electronic patient diary or who are unable or unwilling to use Electronic Peak Flow device 27. Inability to comply with all study requirements and demonstrate good medication compliance during the treatment runin epoch 28. Patients with any medical or psychological condition that renders the patient unable to understand the nature, scope, and possible consequences of the study 29. Patients with a history of being unable to swallow tablets 30. Patients who have received methotrexate, oral gold, troleandomycin, cyclosporine azathioprine or any experimental anti-inflammatory therapies within 6 months of Visit 1 33. Patients with a history of immunodeficiency disease or hepatitis B/hepatitis C 34. Patients on greater than 20mg of simvastatin 35. Patients on any statin therapy with a CK level >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

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