E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Inflammation of the liver due to excessive alcohol intake |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001624 |
E.1.2 | Term | Alcoholic hepatitis |
E.1.2 | System Organ Class | 100000004871 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is as follows: To evaluate the safety and tolerability of GS-4997 in combination with prednisolone versus prednisolone alone in subjects with severe AH. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are as follows: -To assess changes in hepatic synthetic function [liver biochemistry, Model for End-Stage Liver Disease [MELD] score, Child-Pugh score, the Lille model, Maddrey’s Discriminant Function (Maddrey’s DF), and the HepQuantTM test (optional sub-study, select sites only)]; To assess mortality at 28 days, 12 weeks and 24 weeks; -To determine the incidence of liver transplantation; -To determine the incidence of hepatorenal syndrome (HRS); -To determine the incidence of infection; -To assess length of hospital stay. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Intensive PK Substudy Subjects may choose to participate in an optional PK substudy. The PK substudy will be performed at one visit, at any time between Weeks 1 and 3 (inclusive). Blood samples will be drawn predose and at 0.5, 1, 2, 4, 6, 8, and 24 hours postdose.
HepQuantTM Sub-Study (for US sites only) The HepQuant™ test is an investigational test which assesses hepatic portal circulation and other measures of liver function using a combination of blood testing and non-radioactive isotopes. Results from the HepQuant™ testing will be correlated to clinical outcomes to advance the development of this non-invasive testing methodology. Participating US sites will be selected by Gilead Sciences. Subjects will have to sign a separate informed consent form prior to participation in this substudy. All subjects who enroll at the participating US sites will be eligible to enroll in this substudy, but participation will be optional. Each participant will undergo HepQuant™ testing at baseline/Day 1, Weeks 1, 4, 12, and 24. |
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E.3 | Principal 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 subjects with hepatic encephalopathy (HE), which may impair decision-making, consent will be obtained per hospital procedures (eg, by legal Authorized Representative); 3) Clinical diagnosis of severe AH 4) All female subjects 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 drug. If females utilize 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 utilize a barrier method as another form of contraception; 5) Male subjects must refrain from sperm donation from screening through at least 90 days following the last dose of study drug; 6) Male subjects must agree to use condoms during intercourse from screening through study completion and for 90 days following the last dose of study drug; 7) Female subjects must refrain from egg donation or harvest for 90 days after last dose of study drug; 8) Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions |
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E.4 | Principal exclusion criteria |
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) Subjects dependent on inotropic (eg, epinephrine or norepinephrine) or ventilatory support (ie, 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 (eg, 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). Subjects under evaluation for possible malignancy are not eligible. 19) Positive urine screen for amphetamines, cocaine or opiates (ie, heroin, morphine) at screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening may be included in the study. Subjects with positive cannabis drug screen may be included in the study. Subjects with a positive urine drug 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 drugs [eg, 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 subject or impair the assessment of study results; 24) Participation in another investigational study of a drug 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 drugs (GS-4997 and prednisolone), the metabolites, or formulation excipient; 27) Presence of any condition that could, in the opinion of the investigator, compromise the subject’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 subject’s compliance with the protocol procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the safety of GS-4997 in combination with prednisolone versus prednisolone alone in subjects with severe AH. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Study visits will occur at baseline/Day 1 and on Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. |
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E.5.2 | Secondary end point(s) |
Clinical outcomes: -Mortality at 28 days, 12 weeks, and 24 weeks -HRS -Infection -Length of hospital stay -Liver transplantation -Measures of hepatic synthetic function |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Study visits will occur at baseline/Day 1 and on Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
France |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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last subject’s last observation (or visit). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |