E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
severe alcoholic hepatitis |
hépatite alcoolique sévère |
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E.1.1.1 | Medical condition in easily understood language |
severe alcoholic hepatitis |
hépatite alcoolique sévère |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
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 |
To determine the impact of methylprednisolone on the reduction of mortality at 90 days in patients with severe alcoholic hepatitis and who have demonstrated an early spontaneous improvement |
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E.2.2 | Secondary objectives of the trial |
To evaluate the mortality rate at 28 days To estimate the number of infection (including bacterial, viral and fungal infections) at 90 days
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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 |
Genetic susceptibility to develop alcoholic hepatitis: It will be proposed to the already included patients to participate to a genetic study. The participation to the genetic substudy is not mandatory for participation to the main study. DNA will be sent and centralized at Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles
Central pathology review in order to correlate clinical data and pathology |
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E.3 | Principal inclusion criteria |
1.Male or female, 18 years of age or older at time of screening 2.Clinical syndrome of alcoholic hepatitis: recent jaudice or in recent aggravation (< 3 months) serum bilirubin > 5 mg/dL history of excess alcohol abuse (> 40g/day) 3. Alcoholic hepatitis proven by a liver biopsy (histological criteria of alcoholic hepatitis defined according to EASL clinical practice guidelines : steatosis, hepatocyte ballooning, and an inflammatory infiltrate with PMNs). The results are not mandatory for inclusion. However, the biopsy must be planned at the latest on Day 1. When the results become available and don’t confirm the alcoholic hepatitis, the patient must discontinue the study. 4. Spontaneous liver function improvement, defined by a decrease in serum bilirubin level > 10% between admission and day 5-10 after admission 5. less than 2 weeks since admission to hospital 6. Maddrey discriminant function* greater than or equal to 32 7. Subjects must voluntarily sign and date an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the initiation of any screening or study-specific procedures. 8. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements. Patients with significant hepatic encephalopathy are not excluded from participation to the trial. In this case, the patient should be accompanied by a legal representative that will decide participation in the clinical study and sign ICF.
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E.4 | Principal exclusion criteria |
1. Other causes of liver disease including viral hepatitis (positive HBs antigen, HCV RNA positive), auto-immune hepatitis, biliary obstruction 2. Other disease compromising 90-day survival 3. Positive HIV serology 4. Uncontrolled infection All patients will be screened for infection. This will involve chest radiography, urinalysis, PMNs count in ascites (if ascites present). All other sign or clinical suspicion of infection with or without antibiotherapy will be recorded as an infection. Positive culture and initiation of antibiotics with clinical or radiological signs of infection, as well as clinical suspicion, will be recorded as infection. Patients with evidence of sepsis will be treated for a minimum of 2 days with appropriate antibiotics. Once the local principal investigator considers that the sepsis is under control, the patient may be rescreened and randomised. 5. Uncontrolled gastrointestinal bleeding Bleeding must be judged as controlled for at least 5 days 6. Patient with serum creatinine > 2.5 mg/dL, under renal replacement therapy or under terlipressine (or other vasoactive drugs) 7. Pentoxyphilline therapy 8. Pregnant or lactating women
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Mortality at 28 days - Incidence of infections during the study period (90 days) - Incidence of Hepatorenal syndrome during the study period (90 days) - Assessment and comparison of biochemical response to therapy at Day 7 between both groups (fall in total bilirubin and Lille score).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 7 days: Assessment and comparison of biochemical response At 28 days: Mortality At 90 days : Incidence of infections and Hepatorenal syndrome |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | No |
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 | 21 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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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LSFD. After the LSFD (Last subject first dose), all the sites have 3 months to complete the trial. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |