Cessation or Reduction of Alcohol Consumption in Veterans: A Randomized Controlled Trial for Alcohol Use Disorder (CRAVE)

Background:

AUD is one of the leading causes of disability worldwide. The prevalence of AUD is high, affecting 10.9% of US adults and 5.1% of adults worldwide. Oral naltrexone, the most widely prescribed medication for AUD, has a number needed to treat (NNT) to prevent a return to heavy drinking of 12, and thus is only modestly effective. Indeed, less than 2% of adults with AUD receive medication in a given year. Though the Department of Veterans Affairs promotes pharmacotherapy as a best practice, there are over 400,000 Veterans within the Veterans Health Administration (VHA) who have a diagnosis of AUD, with only about 40,000 being actively treated with pharmacotherapy (source: VA Quality Dashboard accessed 1/31/2025). As there have been no new Food and Drug Administration (FDA) approved medications in nearly two decades, there is an urgent need for novel treatments for AUD with superior efficacy and higher patient appeal. Based upon very promising clinical experience, retrospective studies, preclinical data, and recent pilot clinical trial results, the proposed clinical trial is designed to provide definitive evidence regarding the efficacy of the GLP-1 RA, semaglutide, compared to placebo for the treatment of AUD. This research will offer urgently needed information on the efficacy of GLP-1 RAs in the treatment of AUD in a diverse sample and is directly in line with the strategic priorities (SP) for VA Research codified by the Office of Research and Development (ORD) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Study Design:

This is a randomized, double-blinded, intent-to-treat, two-arm, parallel, superiority multisite clinical trial in which 622 participants will be randomized into the semaglutide treatment or placebo arm in a 1:1 ratio. Randomization will be stratified according to BMI (<30 or ≥ 30) and participating site. Veterans with DSM-5-diagnosed moderate to severe AUD who are seeking treatment will be invited to participate in this trial. After eligibility screening, participants will be randomized to either the semaglutide group or the placebo group.

The study will be conducted in three phases. Phase 1 will be Recruitment, Consent and Screening, Phase 2 will be Randomization and Intervention (6 months of treatment), which includes dose escalation and the primary endpoint ascertainment period (the last 28 days of the intervention period), and Phase 3 is the Post Treatment Safety Assessment (4 weeks).

Study Objectives:

Primary Objective: To evaluate the efficacy of semaglutide 2.4 mg compared to placebo in achieving the World Health Organization's (WHO) two-level alcohol risk reduction (WHO-2LRR), from baseline risk level, in the WHO risk drinking level in the treatment of moderate to severe AUD. The primary outcome will be measured during the last 28 days of the intervention period.

Secondary Objectives:

1. To compare the safety and tolerability of semaglutide 2.4 mg versus placebo.
2. To evaluate the efficacy of semaglutide on reducing the proportion of subjects reporting no heavy drinking days (NHDD) during the last 28 days of the intervention period.
3. To evaluate the efficacy of semaglutide on a WHO-2LRR during the last 56 days of the intervention period.
4. To assess moderation effects of race, age, sex, BMI, impulsivity, psychiatric comorbidity, or presence of other psychiatric treatments (medication and/or psychotherapy) on semaglutide treatment effects compared to placebo.

Exploratory Objectives:

The following objectives aim to provide a comprehensive assessment of semaglutide's impact on various aspects of patients' well-being and recovery from AUD, compared to placebo:

• WHO-2LRR and NHDD: Evaluate the risk level change over the entire course of the intervention (monthly repeated measures). Similarly, assess the presence of no heavy drinking each month over the entire intervention period.
• Clinical Global Impression - Improvement (CGI-I): Assess overall improvement of AUD symptoms.
• Health-Related Quality of Life (HRQoL): Evaluate the effect on improvement in health-related quality of life as measured by the Veterans RAND 12-Item Health Survey (VR-12).
• Progress in Addiction Treatment: Measure progress in addiction treatment using the Brief Addiction Monitor-Revised (BAM-R).
• Alcohol Craving: Assess the improvement in alcohol craving as measured by the Penn Alcohol Craving Scale (PACS).
• Psychiatric Distress as measured by
• Depressive symptoms: Measure reductions in psychiatric distress related to depression using the Patient Health Questionnaire (PHQ-9).
• Anxiety symptoms: Measure reductions in psychiatric distress related to anxiety using the Generalized Anxiety Disorder-7 (GAD-7).
• Post-Traumatic Stress Disorder (PTSD): Measure reductions in psychiatric distress related to PTSD using the PTSD Checklist (PCL-5) among participants with PTSD.
• Alcohol-Related Problems and Consequences: Assess the improvement in alcohol-related problems and consequences as measured by the Short Inventory of Problems (SIP-2R).
• Health Care Utilization (HCU): Evaluate reductions in health care utilization.

Intervention and Masking:

Participants assigned to the semaglutide 2.4 mg group will undergo 24 weeks of treatment (Phase 2). Phase 2 will be used to initiate a dose of 0.25 mg with further dose escalation up to 2.4 mg weekly starting at week 5. Participants will be increased to their maximal tolerable dose. Increases will be considered only after the participant has been on the current dose for 4 weeks (dose escalation schedule is 0.25, 0.5, 1.0, 1.7, and 2.4 mg). Doses are not to exceed 2.4 mg weekly. Patients may have their dose reduced, maintain their current dose, or have a slower dose escalation to ensure tolerability and increase retention in the study. Doses are delivered via a pen, a cartridge-based device that calibrates medication delivery based on the desired dose. An extremely small needle (4-mm, 32-gauge needle - the size of 2 human hairs) is used to deposit the medication subcutaneously. Participants assigned to the placebo group will receive a placebo that mimics the same treatment procedure.

Throughout the study, the investigators will maintain double-blind conditions regarding the medication condition. To enhance the ability to maintain blinded assessment of the primary outcome, the assessment will be collected by a Central Assessment Center.

Sample Size and Study Duration:

This study plans to randomize 622 Veterans, with 311 participants assigned to each group. The study duration will be minimally 47 months for study start-up, approximately 32 months for recruitment, dose escalation, endpoint assessment and follow-up for safety, three months for data cleaning, and nine months for data analysis and reporting.