A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Dose-Escalation, Proof-of-Concept Study Evaluating the Safety, Tolerability, Efficacy and Pharmacokinetics of INT-787 in Subjects With Severe Alcohol Associated Hepatitis
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Intercept Pharmaceuticals
- Enrollment
- 80
- Locations
- 31
- Primary Endpoint
- Lille model response based on Lille score by treatment group
Overview
Brief Summary
The purpose of this trial is to assess dose related safety, efficacy, and pharmacokinetics (PK) of INT-787 in participants with severe alcohol-associated hepatitis (sAH).
Detailed Description
This is a Phase 2a, randomized, double-blind, placebo-controlled, dose-escalation, proof-of-concept study to evaluate the safety, tolerability, efficacy, and PK of INT-787 in participants, initially admitted to the hospital, with severe alcohol-associated hepatitis (sAH). The study aims to demonstrate and provide rationale for the selection of optimal dose(s) of INT-787 in the target population of participants with sAH. INT-787 will be evaluated for safety and tolerability prior to dose escalation. Overall efficacy, compared to placebo, will be assessed for each dose cohort.
Additionally, PK measurements at various study timepoints will allow the Sponsor to better understand the systemic exposure of INT-787 and the relationship between exposure and efficacy and safety. Such insights in participants with more advanced liver disease will provide valuable information for future clinical trials of INT-787.
The placebo-treated participants will provide important natural history information on outcomes in this participant population with sAH treated with supportive care. The placebo-treated participants within cohorts are meant to blind the study drug administration while the data across dose cohorts will be used in the overall analysis.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Males or females aged 18 to 65 years (inclusive)
- •Clinical diagnosis of sAH based on all the following:
- •History of ongoing excess alcohol (\>60 g/day \[male\] or \>40 g/day \[female\]) use for ≥6 months, with \<60 days of abstinence prior to the onset of jaundice
- •Serum total bilirubin \>3.0 mg/dL
- •Aspartate aminotransferase (AST) ≥50 U/L
- •AST/Aspartate aminotransferase (ALT) ratio ≥1.5
- •Onset of jaundice within prior 8 weeks
- •Cohort 1 through Cohort 4: Maddrey's Discriminant Factor (mDF) ≥32 and ≤70
- •Cohort 5 and Cohort 6: mDF ≥32
- •Cohort 1 through Cohort 4: MELD score ≥18 to ≤25 (inclusive) and Cohort 5 and Cohort 6: MELD score ≥21 to ≤30
Exclusion Criteria
- •Participants taking products containing obeticholic acid in the 30 days prior to randomization
- •Participants taking \>2 doses of systemic corticosteroids within 30 days prior to randomization.
- •Participants who have been inpatient at a referral hospital for \>7 days prior to transfer.
- •Pregnancy, planned pregnancy, potential for pregnancy (e.g., unwillingness to use effective birth control during the study), or current or planned breast feeding.
- •Abstinence from alcohol consumption for \>2 months before Day
- •AST or ALT \>400 U/L.
- •Cohort 1 through Cohort 4: mDF \<32 or \>
- •Cohort 5 and Cohort 6: mDF \<32
- •Cohort 1 through Cohort 4: MELD score \<18 or \>
- •Cohort 5 and Cohort 6: MELD \<21 or \>30
Arms & Interventions
INT-787
Participants will be randomized to receive INT-787 (in Dose Escalation Cohorts [Cohorts 1 through 4] and Extension Phase Cohorts [Cohorts 5 and 6])
Intervention: INT-787 (Drug)
Placebo
Participants will be randomized to receive matching placebo
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Lille model response based on Lille score by treatment group
Time Frame: Day 7
The Lille score response rate will be analyzed as a categorical variable. Participants with Lille score \<0.45 will be counted as responders and those with Lille score ≥0.45 will be counted as non-responders.
Secondary Outcomes
- Change from Baseline in total bilirubin(Baseline and at Day 7, 14, 21, 28, 56 and 84)
- Difference in 28-day, 56-day, and 84-day all-cause mortality or liver transplantation (TFS) between INT-787 and placebo(Day 28, 56, 84)
- Number of participants with treatment emergent adverse events (TEAEs), serious adverse events (SAEs) and treatment emergent adverse event of special interest (AESIs)(During the study period, up to 12 weeks)
- Change from baseline in the Model for End-Stage Liver Disease (MELD) score at 28-days by treatment group(Baseline and at Day 28)
- Number of participants reporting infectious adverse events by System organ class (SOC)/ preferred term by treatment group(During the study period, up to 12 weeks)