Title: An adaptive-design randomised placebo-controlled trial of baclofen in the treatment of alcohol use disorder in patients with liver cirrhosis (BASIS)
Funder: Department of Health and Social Care

Abstract: Aim of the Research_x000D_ Our proposed trial will evaluate whether baclofen is an effective treatment option in patients with alcohol-related liver cirrhosis, and which dose(s) is/are safe and effective. _x000D_ _x000D_ Background_x000D_ The question “What are the most effective ways to help people with alcohol-related liver disease stop drinking?” was considered a top priority by the James Lind Alliance. In patients with alcohol-related liver cirrhosis, stopping alcohol consumption (abstinence) can lead to improvements in how the liver works, resulting in longer life expectancy. Therefore, helping people to stop drinking is the most important aim of treatment. However, there are limited medications to support abstinence from alcohol in individuals with cirrhosis. Recently, the drug, baclofen, has shown promising but not conclusive results in small research projects. A wide variety of doses have been used, but it remains unclear, which, if any, might be the most appropriate dose. This study aims to address these knowledge gaps and provide evidence on which doses of baclofen work best in patients with alcohol-related liver cirrhosis._x000D_ _x000D_ Design and methods_x000D_ This trial will test 3 different doses of baclofen and a placebo (dummy treatment) in patients with alcohol-related cirrhosis over 26 weeks. We will include a 2-week run-in period to identify participants who do not wish to change their drinking behaviour at this time. Participants will be randomised after the run-in period to one of the four treatment arms using double-blind methods, meaning neither the participant nor the researchers will know which treatment has been allocated. We will use an adaptive design for this trial, which will allow us to remove some of the baclofen arms that do not seem to be working well, making the trial more efficient. A 9-month internal pilot will be conducted to ensure that the trial is feasible, and strategies used for opening sites, recruitment and retention are optimised. The maximum total sample size required is 400, with equal numbers in each treatment arm. We will also undertake blood sampling to determine the relationship between the amount of baclofen in the bloodstream to and how participants respond. This will help us to identify the best dose for each individual._x000D_ _x000D_ Patient and public involvement_x000D_ We have been fortunate in having support from patient groups who have helped shape and refine our methods to ensure that no patient is disadvantaged by being part of this study, and that we maximise recruitment, engagement and follow-up. They have also considered the effect size of the trial, and deemed that a scenario where, for every 4 people treated, 1 would benefit (number needed to treat of 4; absolute difference of 25%) as the most acceptable when considering the vulnerability of the patient group and what is realistically achievable from the treatment. The PPI co-applicants have agreed to be further involved in the project through trial groups, ethical considerations, developing strategies to maximise engagement, and dissemination. _x000D_ _x000D_ Dissemination_x000D_ Dissemination will be through traditional academic routes (e.g. peer-reviewed journals and conference presentations), national and international societies and consortia, and public facing materials as approved by the PPI co-applicants. These public facing documents include lay summaries and a podcast of the primary findings to help improve accessibility to the outcomes.

Lay abstract: Research Questions_x000D_ 1. Does baclofen improve treatment outcomes for alcohol use disorder (AUD) in patients with cirrhosis?_x000D_ 2. What is the most effective dose of baclofen in improving treatment outcomes for AUD in patients with cirrhosis?_x000D_ _x000D_ Background_x000D_ Continued alcohol consumption in the presence of cirrhosis accelerates the time to death. Baclofen has been considered as a promising alcohol anti-craving agent in the treatment of AUD. It has the advantage of being predominantly excreted renally and thus is considered relatively safer than other alcohol anti-craving medications in patients with established liver disease. However, there is limited evidence regarding baclofen’s efficacy for the treatment of AUD in patients with cirrhosis._x000D_ _x000D_ Aims/Objectives_x000D_ Aims:_x000D_ 1) Investigate the effect of baclofen compared with placebo in the treatment of AUD in patients with alcohol-related cirrhosis;_x000D_ 2) Determine which dose(s) of baclofen is/are most effective in improving AUD treatment outcomes in patients with alcohol-related cirrhosis;_x000D_ 3) Assess the relationship between variability in baclofen exposure and efficacy and safety parameters._x000D_ _x000D_ Objectives:_x000D_ i) Conduct a four-arm, double-blind trial whereby patients are randomly assigned to one of three doses of baclofen or placebo and subsequently followed-up for 24 weeks to record rates of continued abstinence, with an in-built internal pilot in the initial phase;_x000D_ ii) Compare the primary and secondary outcomes between placebo and the three baclofen groups;_x000D_ iii) Monitor and compare the safety profile of the baclofen arms, including dose dependency, in comparison to the placebo arm;_x000D_ iv) Obtain sparse PK sampling data from patients to inform a population pharmacokinetic/pharmacodynamic (PK/PD) model to explore the relationship between baclofen exposure and efficacy and safety outcomes._x000D_ _x000D_ Methods_x000D_ A 26-week randomised controlled, adaptive-design, double-blind, multi-centre four-arm trial of baclofen compared to placebo in patients with alcohol-related cirrhosis. The trial will comprise a 2-week pre-randomisation run-in and 24-weeks of treatment. The primary outcome is continued abstinence for 24 weeks post randomisation. The four trial arms will be: Baclofen at doses of 10 mg TDS, 20 mg TDS, and 30 mg TDS, and placebo. An adaptive design has been selected to remove intervention arms that demonstrate poor efficacy. A 9-month internal pilot will be conducted to ensure trial feasibility and optimal delivery. The maximum total sample size required for randomisation is 400, with equal numbers in each arm. A PK/PD sub-study will be conducted to quantify and understand variability in exposure at the same doses, and how this relates to clinical outcome measures._x000D_ _x000D_ Timelines_x000D_ 48 months_x000D_ _x000D_ Impact/dissemination_x000D_ If proven effective, baclofen would provide a pharmacological therapy in a group with limited options for promoting abstinence. The importance of abstinence is underlined by its association with a ~40% reduced risk of death in the proceeding 5 years and potentially beyond. We would also expect baclofen to help reduce inequalities in mortality from alcohol-related cirrhosis. Those from lower socio-economic backgrounds are firstly at greater risk of developing cirrhosis and then at greater risk of death once diagnosed. Dissemination will be through traditional academic routes, national and international societies and consortia, and public facing materials as approved by the PPI co-applicants.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL