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

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ClinicalTrials.gov Identifier: NCT01903798
Recruitment Status : Completed
First Posted : July 19, 2013
Last Update Posted : May 10, 2018
Sponsor:
Collaborators:
University of Southern California
Los Angeles Biomedical Research Institute
VA Long Beach Healthcare System
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Information provided by (Responsible Party):
Timothy Morgan, MD, VA Long Beach Healthcare System

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Alcoholic Hepatitis Drug: Rilonacept Drug: Mycophenolate mofetil Drug: Prednisolone Phase 2

Detailed Description:
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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : December 2014
Actual Primary Completion Date : April 2016
Actual Study Completion Date : April 2016


Arm Intervention/treatment
Active Comparator: Continue Prednisolone (Lille <0.45)
Continue prednisolone 40 mg/day (current standard of care) for 21 days.
Drug: Prednisolone
Corticosteroid

Experimental: Rilonacept + Prednisolone (Lille <0.45)
Prednisolone (40mg/day) and rilonacept (Arcalyst®) subcutaneously once a week for 21 days (320 mg on study Day 8 and 160 mg on study Day 15 and study Day 22).
Drug: Rilonacept
Interleukin-1 blocker
Other Name: ARCALYST®

Drug: Prednisolone
Corticosteroid

No Intervention: Standard of Care (Lille ≥ 0.45)
Standard of care therapy (continue prednisolone, stop all therapy and/or offer palliative care)
Experimental: Mycophenolate + Prednisolone (Lille ≥ 0.45)
Prednisolone (40 mg/day) and mycophenolate mofetil for 21 days (500 mg BID for first 4 days followed by 1000 mg BID for the next 17 days).
Drug: Mycophenolate mofetil
Immunosuppressive agent
Other Name: CellCept®

Drug: Prednisolone
Corticosteroid




Primary Outcome Measures :
  1. Survival [ Time Frame: Day 8 to Day 29 ]
    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.

  2. Change in Bilirubin [ Time Frame: Day 8 to Day 29 ]
    To determine whether treatment with prednisolone and rilonacept (Arcalyst®) (anti-interleukin-1 [IL-1]) is better than treatment with prednisolone (standard of care) among patients with alcoholic hepatitis who respond to 1 week of prednisolone (i.e., Lille score of <0.45). Primary outcome is change in bilirubin between Day 8 (start of treatment) and Day 29 (end of treatment).


Secondary Outcome Measures :
  1. Safety [ Time Frame: Week 24 ]
    To determine adverse events, especially infection and renal failure, for each treatment group.

  2. MELD and DF Score [ Time Frame: Day 8 to Day 29 ]
    To determine the change in MELD score and in Maddrey's discriminant function between Day 8 and Day 29 for each treatment group.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01903798


Locations
United States, California
VA Long Beach Healthcare System
Long Beach, California, United States, 90822
LAC USC Medical Center
Los Angeles, California, United States, 90033
Harbor-UCLA Medical Center
Torrance, California, United States, 90509
Sponsors and Collaborators
Southern California Institute for Research and Education
University of Southern California
Los Angeles Biomedical Research Institute
VA Long Beach Healthcare System
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
Principal Investigator: Timothy R. Morgan, MD VA Long Beach Healthcare System

Responsible Party: Timothy Morgan, MD, Chief, Hepatology, VA Long Beach Healthcare System
ClinicalTrials.gov Identifier: NCT01903798     History of Changes
Other Study ID Numbers: SCAHC Clinical Trial
1U01AA021886 ( U.S. NIH Grant/Contract )
First Posted: July 19, 2013    Key Record Dates
Last Update Posted: May 10, 2018
Last Verified: April 2016

Additional relevant MeSH terms:
Hepatitis, Alcoholic
Hepatitis
Hepatitis A
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Liver Diseases, Alcoholic
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mycophenolic Acid
Prednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors