Alcoholic Hepatitis
Conditions
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).
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.
Interventions
DRUGPrednisolone
Corticosteroid
DRUGRilonacept
DRUGMycophenolate mofetil
Immunosuppressive agent
Sponsors
University of Southern California
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
VA Long Beach Healthcare System
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Southern California Institute for Research and Education
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival at Day 29 of the Assigned Treatment | 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. 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. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Patients Reported Ascites | Week 24 |
Countries
United States
Participant flow
Recruitment details
4 participants were randomized. 3 in the standard of care (with Prednisolone) and 1 in mycophenolate + prednisolone arm. Out of 3 randomized to the SOC arm, 2 had a Lille score of \<.45 and one had a Lille score of \>.45. The participant who was randomized to mycophenolate + prednisolone had a Lille score of \>.45.
Participants by arm
| Arm | Count |
|---|---|
| Continue Prednisolone (Lille <0.45) Continue prednisolone 40 mg/day (current standard of care) for 21 days.
Prednisolone: Corticosteroid | 2 |
| 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).
Rilonacept: Interleukin-1 blocker
Prednisolone: Corticosteroid | 0 |
| Standard of Care (Lille ≥ 0.45) Standard of care therapy (continue prednisolone, stop all therapy and/or offer palliative care) | 1 |
| 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).
Mycophenolate mofetil: Immunosuppressive agent
Prednisolone: Corticosteroid | 1 |
| Total | 4 |
Baseline characteristics
| Characteristic | Continue Prednisolone (Lille <0.45) | Rilonacept + Prednisolone (Lille <0.45) | Standard of Care (Lille ≥ 0.45) | Mycophenolate + Prednisolone (Lille ≥ 0.45) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Age, Continuous | 45.6 years STANDARD_DEVIATION 9.7 | — | 71.2 years STANDARD_DEVIATION 0 | 58 years STANDARD_DEVIATION 0 | 52 years STANDARD_DEVIATION 13.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | — | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | — | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | — | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | — | 1 Participants | 0 Participants | 3 Participants |
| Region of Enrollment United States | 2 participants | — | 1 participants | 1 participants | 4 participants |
| Sex: Female, Male Female | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | — | 1 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 0 | 1 / 1 | 0 / 1 |
| other Total, other adverse events | 0 / 2 | 0 / 0 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 0 | 1 / 1 | 1 / 1 |
Outcome results
Primary
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.
Time frame: Day 8 to Day 29
Population: There was no participant randomized to rilonocept +prednisolone arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Continue Prednisolone (Lille <0.45) | Survival at Day 29 of the Assigned Treatment | 2 Participants |
| Rilonacept + Prednisolone (Lille <0.45) | Survival at Day 29 of the Assigned Treatment | 0 Participants |
| Standard of Care (Lille ≥ 0.45) | Survival at Day 29 of the Assigned Treatment | 1 Participants |
| Mycophenolate + Prednisolone (Lille ≥ 0.45) | Survival at Day 29 of the Assigned Treatment | 1 Participants |
Secondary
Number of Patients Reported Ascites
Time frame: Week 24
Population: No patient was randomized to Rilonacept +prednisolone arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Continue Prednisolone (Lille <0.45) | Number of Patients Reported Ascites | 0 Participants |
| Rilonacept + Prednisolone (Lille <0.45) | Number of Patients Reported Ascites | 0 Participants |
| Standard of Care (Lille ≥ 0.45) | Number of Patients Reported Ascites | 1 Participants |
| Mycophenolate + Prednisolone (Lille ≥ 0.45) | Number of Patients Reported Ascites | 0 Participants |