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Infectious Diseases clinical trial

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

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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