Integrated Therapies for Alcohol Use in Alcohol-associated Liver Disease (ITAALD) Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 216
- 试验地点
- 6
- 主要终点
- Death
研究概览
简要总结
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.
详细描述
Objectives:
- 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).
- 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).
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18, <70
- •Definitive or probable diagnosis of sAH as defined by the NIAAA criteria4, 5 A. Onset of jaundice (defined as serum total bilirubin >3 mg/dL) within the prior 8 weeks B. Ongoing average consumption of > 40 gm (for females) and > 60 gm (for males) alcohol daily for 6 months or more with less than 8 weeks of abstinence before onset of jaundice; OR If, in the investigator's judgment, alcohol use may have been underreported, available clinical evidence-including collateral history, medical records, prior documentation of alcohol use, alcohol biomarkers such as PEth, or other relevant evidence-indicates that the participant met the protocol-defined alcohol consumption requirement within the 8 weeks before screening.
- •C. AST > 50 IU/L, D. AST: ALT > 1.5 E. ALT and AST values < 400 IU/L F. Liver biopsy findings consistent with AH
- •*In patients with possible AH or AH with confounding factors such as possible ischemic hepatitis, possible DILI, uncertain history of alcohol use (e.g., patient denies excessive alcohol use), and atypical/abnormal laboratory tests (e.g., AST < 50 IU/L or > 400 IU/L, AST/ALT ratio < 1.5), antinuclear antibody > 1:160 or SMA > 1:80, a standard of care liver biopsy will be considered during current hospital admission to confirm AH and exclude competing etiologies.
- •Females of childbearing (reproductive) potential must have a negative serum or urine pregnancy test at screening.
排除标准
- •Active listing for liver transplantation before screening
- •MELD score <20 or > 35
- •Uncontrolled infection (persistent positive blood or other body fluid cultures despite 48 hours of antibiotic therapy)
- •Progressive hemodynamic compromise requiring intravenous pressors
- •Pneumonia as evidenced by clinical and/or radiological examination (will not perform radiology if not indicated by clinical exam)
- •Renal failure defined by estimated GFR (CKD-EPI) <35 mL/min.
- •Clinically active C. diff infection
- •Evidence of other liver diseases (such as autoimmune hepatitis, primary biliary cholangiopathy, primary sclerosing cholangitis, ischemic, sepsis- or drug-induced liver disease)
- •History or presence of cancer (including hepatocellular carcinoma) other than non-melanoma skin cancer
- •Prior exposure to systemic corticosteroid (glucocorticoid) or TNF-alpha inhibitors for more than 4 days within the previous 30 days prior to screening, specifically for the treatment of sAH.
- •Clinically significant pancreatitis- abdominal pain, elevated lipase (> 3 X ULN), and at least edema of pancreas with fat-stranding on CT scan
- •Active gastrointestinal bleeding defined as hematemesis or melena with a decrease in hemoglobin more than 2 g/dl in 24 hours due to gastrointestinal bleeding, or with a decrease in mean arterial BP to < 65 mmHg
- •Significant concomitant medical illnesses (such as uncontrolled congestive heart failure or COPD or progressive multi-organ failure) as determined by the study investigator
- •Uncontrolled mental illness as determined by the study investigator
- •Uncontrolled HBV, HIV, or HCV infection with persistent viremia. However, subjects with controlled (undetectable viral load) HIV and HBV on viral suppressive therapies will be enrolled and subjects with history of HCV will be enrolled if they have evidence of SVR within one year prior to enrollment
- •Active illicit opiates, cocaine, ketamine, or methamphetamine use in the last 30 days via patient report or medical chart review.
- •Uncontrolled diabetes mellitus with A1c > 9
- •Pregnancy or breastfeeding
- •Known allergy or intolerance to therapeutic agents to be tested
- •Unwillingness to stop alcohol use and to undergo AUD treatment
- •Unwillingness to either abstain from sexual intercourse, or if sexually active, use a reliable method of birth control during the study and for at least 30 days after the last dose of the study medication. Examples of acceptable birth control methods include double barrier method such as condom and occlusive cap (diaphragm or cervical cap) with spermicidal foam/gel/film/cream/suppository; birth control pills, patches, injections, or implants; intrauterine device (IUD); vasectomy and tubal ligation.
- •Participant has any condition or circumstance that adversely affects the participant, could cause noncompliance with treatment or visits, may impact the interpretation of clinical data, could cause bias, or may otherwise contraindicate the participant's participation in the study.
研究组 & 干预措施
Prednisone, IL-22 (F-652) Placebo, and usual care
Prednisone for 28 days and matching placebo for F-652 on days 1 and 7 and usual care for AUD.
干预措施: IL-22 (F-652) Placebo (Drug)
IL-22 (F-652), Prednisone Placebo, Acamprosate, MI and MET
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
干预措施: Acamprosate (Drug)
IL-22 (F-652), Prednisone Placebo, Acamprosate, MI and MET
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
干预措施: IL-22 (Drug)
Prednisone, IL-22 (F-652) Placebo, and usual care
Prednisone for 28 days and matching placebo for F-652 on days 1 and 7 and usual care for AUD.
干预措施: Prednisone (Drug)
IL-22 (F-652), Prednisone Placebo, and usual care
F-652 on days 1 and 7 and matching placebo for prednisone for 28 days and usual care for AUD.
干预措施: Prednisone placebo (Drug)
IL-22 (F-652), Prednisone Placebo, Acamprosate, MI and MET
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
干预措施: Prednisone placebo (Drug)
Prednisone, IL-22 (F-652) Placebo, Acamprosate, MI, and MET
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
干预措施: Prednisone (Drug)
IL-22 (F-652), Prednisone Placebo, Acamprosate, MI and MET
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
干预措施: Motivational Enhancement Therapy (MET) (Behavioral)
Prednisone, IL-22 (F-652) Placebo, Acamprosate, MI, and MET
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
干预措施: Motivational Interviewing (MI) (Behavioral)
IL-22 (F-652), Prednisone Placebo, and usual care
F-652 on days 1 and 7 and matching placebo for prednisone for 28 days and usual care for AUD.
干预措施: IL-22 (Drug)
Prednisone, IL-22 (F-652) Placebo, Acamprosate, MI, and MET
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
干预措施: IL-22 (F-652) Placebo (Drug)
IL-22 (F-652), Prednisone Placebo, Acamprosate, MI and MET
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
干预措施: Motivational Interviewing (MI) (Behavioral)
IL-22 (F-652), Prednisone Placebo, and usual care
F-652 on days 1 and 7 and matching placebo for prednisone for 28 days and usual care for AUD.
干预措施: Usual Care (Behavioral)
Prednisone, IL-22 (F-652) Placebo, and usual care
Prednisone for 28 days and matching placebo for F-652 on days 1 and 7 and usual care for AUD.
干预措施: Usual Care (Behavioral)
Prednisone, IL-22 (F-652) Placebo, Acamprosate, MI, and MET
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
干预措施: Motivational Enhancement Therapy (MET) (Behavioral)
Prednisone, IL-22 (F-652) Placebo, Acamprosate, MI, and MET
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
干预措施: Acamprosate (Drug)
结局指标
主要结局
Death
时间窗: 6 months
Number (%) of participants who die from any cause
Liver transplant
时间窗: 6 months
Number (%) of participants who receive liver transplant
Ascites
时间窗: 6 months
Number (%) of participants with new onset of clinically detectable
Hepatic encephalopathy
时间窗: 6 months
Number (%) of participants with hepatic encephalopathy ≥ New Haven grade 2
Portal hypertensive bleeding
时间窗: 6 months
Number (%) of participants with gastroesophageal varices or portal gastropathy
Liver-related hospital admission
时间窗: 6 months
Number (%) of participants with liver-related hospital admission for ascites, hepatic encephalopathy, infection, GI bleeding
Increase in MELD score > 5 points
时间窗: 6 months
Number (%) of participants with increase in MELD score \> 5 points
Return to drinking
时间窗: 6 months
Number (%) of participants that return to drinking defined as \<100% abstinence-using timeline follow back questionnaire
次要结局
- Transplant-free survival(30 days, 90 days, 180 days, 1 year, and 2 years)
- Overall Survival(30 days, 90 days, 180 days, 1 year, and 2 years)
研究者
Samer Gawrieh
Professor of Medicine. Director, Hepatology Clinical and Research Fellowship Program Clinical Director, NIAAA Alcoholic Hepatitis Network DCC
Indiana University