A randomised placebo-controlled superiority trial of GLP-1 receptor agonist for the treatment of alcohol use disorder in people with chronic liver disease and obesity: Controlling Unhealthy Relationships with Both alcohol and obesity (CURB trial)

Research question Does 36 weeks of treatment with semaglutide reduce alcohol use in people with alcohol use disorder (AUD), obesity and chronic liver disease? Background Alcohol use is the third leading cause of death in the UK, with alcohol-specific deaths up by 45% since 2019, costing the NHS £4.9 billion annually and £27.4 billion to society. It is the primary cause of liver disease in the UK. Prevalence of obesity is also rising, present in 50% of people with alcohol-related liver disease. Alcohol and obesity have a synergistic impact on liver-related mortality, yet there are no interventions addressing both together. Semaglutide, a GLP-1 receptor agonist (GLP1RA), is an effective treatment for type 2 diabetes and obesity. Preliminary data show that GLP1RAs reduce alcohol use in people with AUD. GLP1RAs have not yet been tested to treat AUD in people with obesity and liver disease. Aim To assess the efficacy of semaglutide (vs placebo) to reduce alcohol use in people with moderate to severe AUD, obesity and liver disease. Objectives In people with moderate to severe AUD, obesity and chronic liver disease to determine whether 36 weeks of semaglutide reduces alcohol use and improves clinical and patient-reported outcomes vs placebo. Methods We will conduct a multicentre double-blind placebo-controlled randomised superiority trial with internal pilot, embedded qualitative evaluation and mechanistic sub-study. We will recruit 268 participants with moderate to severe AUD, obesity and liver fibrosis or compensated cirrhosis from 15 UK hospitals and community alcohol services. Participants will receive semaglutide with a target dose of 2.4mg weekly or matched placebo for 36 weeks. All participants will receive treatment as usual including psychosocial therapy where provided. The primary outcome is alcohol consumption during the prior 28 days assessed at week 36, measured using the timeline follow-back method. Secondary outcomes include serum alcohol biomarker (phosphatidylethanol), liver fibrosis, weight, quality of life and mental wellbeing. Participants will attend in-person visits at baseline and at weeks 8, 16, 24 and 36, and remote visits every 2-4 weeks. A qualitative sub-study will explore intervention experiences in relation to any psychosocial therapy received, comprising semi-structured interviews with 40 participants following completion of the trial. Timelines Project duration; 50 months 1-9: Study set-up and approvals 10-20: Recruitment to internal pilot 21-35: Recruitment to full trial 36-45: Completion of follow-up 46-50: Analysis, write-up and dissemination Impact and dissemination This study has the potential to improve outcomes of over 20,000 people with AUD, obesity and liver disease in the UK. We will produce a lay summary to distribute to patients and the public. We will publish our findings in open access journals and present them to the clinical community at international conferences.