A Safety and Efficacy Study of Mycophenolate Mofetil and Rilonacept in Patients With Alcoholic Hepatitis

Study Overview
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Brief Summary
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This clinical trial will test two new therapies for the treatment of alcoholic hepatitis. Patients who respond to the current standard of care therapy for alcoholic hepatitis(corticosteroid/prednisolone therapy) after 1 week of treatment will be randomly assigned to either continue on standard therapy, or, to begin treatment with rilonacept in combination with standard therapy. Patients who are non-responders to the current standard of care therapy after 1 week of treatment will be randomly assigned to standard of care or to begin treatment with mycophenolate mofetil in combination with standard therapy. Patients will be treated for a total of 4 weeks in this clinical trial. Patients will be followed for up to five months after completing therapy (6 months total).

Detailed Description
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This is a prospective, randomized trial of two experimental treatments, prednisolone + mycophenolate mofetil and prednisolone + rilonacept, in comparison with standard of care, in patients with alcoholic hepatitis. Patients will start therapy with prednisolone. At Day 8 response to prednisolone will be determined using the Lille score. Patients with a Lille score ≥ 0.45 will be randomized to standard of care (continue prednisolone, stop all therapy and/or offer palliative care) or to have prednisolone continued and mycophenolate added for the next three weeks. Patients with a Lille score <0.45 will be randomized to continue prednisolone alone (standard of care) or to have rilonacept added to their treatment regimen (experimental group) for the next three weeks. Patients will complete follow-up visits at Week 12 and Week 24.

Official Title
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A Phase II, Multicenter, Randomized, Open-label Study to Investigate the Safety and Efficacy of Mycophenolate Mofetil and Rilonacept (Anti-interleukin-1) in Patients With Alcoholic Hepatitis

Conditions
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Alcoholic Hepatitis

Intervention / Treatment
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* Drug: Mycophenolate mofetil
* Drug: Prednisolone
* Drug: Rilonacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of chronic alcohol consumption (defined as >60g ethanol/day for women and >80g ethanol/day for men) for at least the past 5 years Less than 8 weeks between last intake of alcohol and Screening Maddrey's Discriminant Function score (DF)>32 Willing to undergo liver biopsy for histological assessment of alcoholic hepatitis. Willing to provide liver tissue, whole blood, stool and ascitic fluid as part of a correlative study Onset of jaundice <3 months prior to Screening Age greater or equal to 18 years Exclusion Criteria (Brief): Liver disease significantly caused by etiologies other than alcohol. Upper GI bleeding requiring transfusion within 48 hours prior to start of prednisolone (Day 1) Infection that has been treated with appropriate antibiotics for less than 72 hours or which has not responded appropriately to 72 hours or more of antibiotic treatment prior to start of prednisolone (Day 1) Clinical evidence of select active infections in the past 3 months (fungal, mycobacterial, cytomegalovirus (CMV), herpes, coccidioidomycosis, tuberculosis (TB) and human immunodeficiency virus (HIV)) Renal insufficiency Laboratory exclusions Hemoglobin <7g/dL Total Bilirubin <7.5mg/dL Aspartate aminotransferase (AST) >500 IU/mL; or AST:Alanine aminotransferase (ALT) ratio < 1 Pregnant or breast-feeding or unwilling to use appropriate birth control Other clinically significant diseases (uncontrolled diabetes, severe cardiovascular or pulmonary disease, transplant recipient, recent cancer) Use of oral or systemic corticosteroids for more than 7 days during the 14 days prior to Day 1 or likely use of oral or systemic corticosteroids in the first 12 weeks of the clinical trial for underlying diseases Use of select contraindicated medications Previous randomization in the trial Based on the investigators judgment, subject is not capable of complying with the study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prednisolone (Lille <0.45)<br>At Day 8, after randomization, this participants will continue prednisolone 40 mg/day (current standard of care) for 21 days. | Drug: Prednisolone<br>* Corticosteroid<br>|
| Experimental: Prednisolone, rilonacept (Lille <0.45)<br>This group will continue Prednisolone (40mg/day). Additionally, they will receive rilonacept (Arcalyst®) once a week for 21 days. After randomization at Day 8, study participants will be given 320 mg subcutaneously (two injections of 2.0 ml, 160 mg each). On Day 15 and Day 22, study participants will be given 160 mg subcutaneously (one injection of 160 mg). | Drug: Prednisolone<br>* Corticosteroid<br>Drug: Rilonacept<br> <br> |
| Active Comparator: Prednisolone (Lille >0.45)<br>Prednisolone (40 mg/day) for the first 7 days, after randomization at Day 8, they will stop all therapy. | Drug: Prednisolone<br>* Corticosteroid<br>|
| Experimental: Prednisolone, mycophenolate(Lille <0.45)<br>This group will continue Prednisolone (40mg/day). Additionally, they will receive mycophenolate mofetil (CellCept®) for a total of 21 days. After randomization at Day 8, they will receive CellCept® at a dose of 1000 mg per day for the first four days followed by 2000 mg per day (two 500 mg tablets bid) for the remaining 17 days. | Drug: Mycophenolate mofetil<br>* Immunosuppressive agent<br>Drug: Prednisolone<br>* Corticosteroid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival at Day 29 of the Assigned Treatment | To determine whether treatment with prednisolone + mycophenolate mofetil is better than standard of care treatment among patients with alcoholic hepatitis who fail to respond to 1 week of prednisolone (i.e., Lille score of ≥0.45). Primary outcome is survival at Day 29. All study participants received the Standard of care (prednisolone) with or without experimental drug at Day 1 (based on randomization). Response to the treatment was determined at Day 8. Data was collected for both responders and non-responders. | Day 8 to Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Reported Ascites |  | Week 24 |