Clinical Trial of Rybelsus (Semaglutide) Among Adults With Alcohol Use Disorder (AUD)

Study Overview
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Brief Summary
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This study is a randomized controlled trial of oral semaglutide among treatment-seeking individuals with AUD. The investigators will randomly assign 50 participants to receive semaglutide (titrated to 7 milligrams (mg) per day) or matched placebo for 8 weeks. The primary aims are to assess the safety and tolerability of semaglutide in this population and to evaluate its effects, relative to placebo, on alcohol cue-elicited craving and alcohol consumption.

Detailed Description
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A screening visit will be conducted at which written informed consent will be obtained and inclusion/exclusion criteria will be assessed. Subsequently, eligible participants will be randomly assigned to take oral semaglutide or matched placebo for 8 weeks, with the semaglutide dose titrated from 3 milligrams (mg)/day for the first 4 weeks to 7 milligrams (mg)/day for the second 4 weeks. Participants will complete 7 additional clinic visits (weekly during the first 4 weeks of the treatment period and biweekly during the second 4 weeks). At each visit, participants will also engage in a computerized behavioral intervention. At screening and again at the Week 6 visit, participants will complete an alcohol cue reactivity task. At the Week 1 visit, before ingesting the first dose of study medication, and again at the Week 8 visit, participants will complete a functional MRI session.

Official Title
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Randomized, Controlled Trial of Rybelsus (Semaglutide) Among Adults With Alcohol Use Disorder (AUD)

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Drug: Semaglutide 3 MG [Rybelsus]
* Drug: Semaglutide 7 MG [Rybelsus]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21 or older. Meets Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for current AUD of at least moderate severity, as assessed by the Mini International Neuropsychiatric Interview (MINI). Seeking pharmacological treatment for AUD and wants to stop or cut down on drinking. Has a body mass index (BMI) of at least 25 kg/m2. Able to read and understand questionnaires and informed consent. Lives within 50 miles of the study site. Please contact clinical site for additional inclusion criteria. Exclusion Criteria: Current DSM-5 diagnosis of any other substance use disorder of moderate or greater severity, except for Nicotine Use Disorder, as assessed by MINI. Urine drug screen at screening positive for any substance except cannabis. Current DSM-5 bipolar disorder, major depressive episode, or panic disorder, as assessed by MINI. Current or lifetime eating disorder (anorexia, bulimia, or binge eating disorder) or psychotic disorder, as assessed by MINI. Current suicidal ideation or homicidal ideation. Current use of other psychotropic medications except antidepressants (for which dose must be stable for at least the past 2 months). Current or past-month use of AUD pharmacotherapy, including (e.g., oral naltrexone, acamprosate, or disulfiram) or current or past 60-day use of injectable naltrexone. Current psychotherapy in which the primary focus is AUD. Attendance at Alcoholics Anonymous (AA) meetings is not exclusionary. Current or past-month use of weight control medications. Current or past-month use of metformin for any indication. Any prior use of semaglutide or other GLP-1 agonists. History of severe alcohol withdrawal (e.g., seizure, delirium tremens), as evidenced by self- report and assessment with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar). Current or lifetime Type 1 or Type 2 diabetes diagnosis, or HbA1c >6.5%. Current or lifetime kidney disease or creatinine clearance <80 mL/min for participants <=55 years of age (<65 mL/min for those >55). Personal history of gastrointestinal disease (e.g., gastroparesis) or pancreatitis. Personal or family history of medullary thyroid carcinoma and/or multiple endocrine neoplasia syndrome type 2 Current or past hepatocellular disease, as indicated by verbal report or elevations of serum amylase, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of the normal range at screening. Uncontrolled hypertension (systolic BP >160 mmHg or diastolic >100 mmHg). Biological females of childbearing potential who are pregnant (by plasma HCG), nursing, or who are not using a reliable form of contraception. Lack of a stable living situation. (If participating in MRI sessions) Contraindications to MRI scanning, ferrous metal in the body including intracranial, intraorbital, or intraspinal metal, pacemakers, cochlear implants, other non-MRI-compatible devices, or other devices that could compromise the quality of the MRI images such as a permanent top retainer or braces. (If participating in MRI sessions) Severe claustrophobia or morbid obesity that preclude placement in the MRI scanner.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Double-blind placebo controlled clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants in this Arm will take a medically inert placebo. To ensure pill equivalence between groups, tablets will be packaged in the same capsule; thus, each participant will take one capsule per day. Participants will be instructed to ingest the capsule orally each morning. | Drug: Placebo<br>* A medically inert placebo medication will be taken for 8 weeks.<br>|
| Active Comparator: Semaglutide 3 milligrams and 7 milligrams<br>Participants in this Arm will study medication for a total of 8 weeks - on semaglutide 3 milligrams per day for 4 weeks, then 7 milligrams per day for 4 weeks. To ensure pill equivalence between groups, tablets will be packaged in the same capsule; thus, each participant will take one capsule per day. Participants will be instructed to ingest the capsule orally each morning. | Drug: Semaglutide 3 MG [Rybelsus]<br>* Semaglutide 3 mg will be taken for the first 4 weeks of the 8-week trial.<br>* Other names: Rybelsus 3 mg;Drug: Semaglutide 7 MG [Rybelsus]<br>* Semaglutide 7 mg will be taken for the second 4 weeks of the 8-week trial.<br>* Other names: Rybelsus 7 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cue Craving Visual Analog Score | The primary efficacy endpoint will be the magnitude of change between screening and Week 6 in the cue-craving VAS score on the first VAS item (How strong is your craving to drink alcohol?) administered after the alcohol cue presentation. Scores range from 0 (none) to 20 (extremely strong). Higher scores indicate a higher level of craving. | 7 weeks - change between screening and Week 6 visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of drinks per day | The number of standard alcoholic drinks participants consume per day during the last 4 weeks of the treatment period (Week 5-8), as reported on the Timeline Follow-Back Interview. | 4 weeks | 
| Percentage of heavy drinking days | The percentage of heavy drinking days during the last 4 weeks of the treatment period (Week 5-8), as reported on the Timeline Follow-Back Interview. | 4 weeks |