Integrated Therapies for Alcohol Use in Alcohol-associated Liver Disease (ITAALD) Trial

Overview

This is a multicenter, randomized, double-blinded, placebo-controlled trial focused on the treatment of severe alcohol-associated hepatitis (sAH) and alcohol use disorder (AUD). The primary purpose of the study is to determine whether subjects receiving sAH therapy in addition to AUD treatments will have better alcohol and liver-related outcomes at 6 months compared to sAH therapy plus usual care for AUD. Patients assigned to the AUD treatment will receive Acamprosate and counseling whereas those assigned to AUD standard care will receive brief advice and referral to a 12-step program. The secondary purpose of the study is to determine if F-652 is safe and effective in treating sAH when compared to prednisone. Subjects will receive F-652 on days 1 and 7 or prednisone for 28 days. Outcomes will be measured by overall survival at 90 days.

Objectives: 1. To determine whether interventions directed to treat AUD integrated with sAH therapies will improve a composite endpoint of alcohol and liver-related events at 6 months compared to usual care for AUD (primary endpoint). 2. To compare 90-day survival in patients receiving F-652 with those receiving up to 28 days of prednisone using the Day-7 Lille score as a stopping rule (secondary endpoint). 3. To compare one-year overall survival in patients receiving either IL-22 or prednisone with or without acamprosate (secondary endpoint). Trial design and conduct The Investigators will conduct a prospective, multicenter, sequentially randomized trial in 216 patients with sAH using a sequentially randomized design for proof of concept. The trial will assess whether integrated treatment of sAH and AUD reduces alcohol- and liver-related events and mortality. The trial design resembles a 2X2 factorial study, but the AUD treatment assignment \[acamprosate + motivational interviewing (MI) + motivational enhancement therapy (MET)\] versus usual care (UC), defined as a brief intervention with advice not to drink alcohol-containing beverages and referral to a 12-step program, is done on Day 7 after the start of the sAH treatment. Only survivors of the first 7 days will be randomized to receive the AUD intervention or UC. The study will be conducted at six clinical sites in the United States selected by the National Institute of Alcoholic Abuse and Alcoholism (NIAAA) and supported by a Data Coordinating Center at Indiana University (DCC). The DCC will also manage the biorepository. The study will be conducted according to Good Clinical Practice (GCP) and in compliance with local, state, and federal regulatory requirements. Adverse events during the trial will be identified, recorded, assessed for causality, and reported in accordance with FDA guidance. In addition to general assessment, the investigators will specifically focus on (1) rates and types of infection as well as their severity, (2) potential development of drug-induced liver injury, (3) injection site reactions, and (4) hematological adverse events. This study will be approved by an appropriately convened single IRB, Advarra, and will be monitored by an NIAAA-appointed Data and Safety Monitoring Board (DSMB). The Investigators will conduct this study under an Investigational New Drug (IND) application from the United States Food and Drug Administration (FDA). It is anticipated that a centrally located investigational pharmacy at Indiana University will dispense the study medications to all participating sites under close coordination from the DCC. The study will provide the participants with F-652, prednisone, matching placebos, and acamprosate. Duration of Trial by Phase Treatment phase: up to 6 months Follow-up phase: up to two years Interventions to be tested F-652 vs. prednisone as treatment for sAH. AUD interventions (acamprosate + MI + MET) versus usual care for AUD treatment. Group assignment: The Investigators will sequentially randomize the study participants into four treatment groups. On day 1, participants will be randomized to receive either F-652 or prednisone at a 1-to-1 ratio. Those randomized to receive F-652 will also receive a prednisone placebo; those randomized to receive prednisone will receive the F-652 placebo. Prednisone or prednisone placebo will be stopped if the Day-7 Lille score is \>0.45. On day 7, survivors will be randomized to receive either the AUD intervention (acamprosate + MI + MET) or usual care at a 1-to-1 ratio. Block randomization will be used to ensure balanced group sizes in randomization. So, there will be four treatment combinations: ARM 1: F-652 on days 1 and 7 and matching placebos for prednisone for 28 days and acamprosate for 6 months. MI will be delivered during the hospitalization; MET sessions will be delivered in the first 3 months. ARM 2: F-652 on days 1 and 7 and matching placebo for prednisone for 28 days and usual care for AUD. ARM 3: Prednisone for 28 days and matching placebos for F-652 on days 1 and 7 and acamprosate for 6 months. MI will be delivered during the hospitalization; MET sessions will be delivered in the first 3 months. ARM 4: Prednisone for 28 days and matching placebo for F-652 on days 1 and 7 and usual care for AUD. Distribution of study drug and placebo Participants or guardians will be instructed on drug timing and dose of these experimental treatments after discharge from the hospital. Study personnel will ensure participants and guardians are knowledgeable about the frequency and amount before the end of the study visit, and an instructional document will be provided.