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This clinical trial aims to test the effectiveness and safety of semaglutide, a GLP-1 receptor agonist, in treating moderate to severe alcohol use disorder (AUD) in Veterans. Participants who qualify will be randomly assigned to receive either semaglutide injections or placebo injections over a 28-week period, followed by a 4-week post-treatment safety assessment period. Participants receiving semaglutide will start with a low dose, gradually increasing to a maximum of 2.4 mg per week, depending on their tolerance. The primary measure of success will be a reduction in risky drinking, assessed through a reliable calendar-based interview method called the Timeline Follow-Back (TLFB), a well-validated calendar-based interview technique for recording daily alcohol consumption. The purpose of this research is to gather information on the effectiveness of semaglutide for treating AUD, potentially offering a new and more appealing treatment option.
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).
The proposed study is a randomized, double-blind, placebo-controlled, intent-to-treat, two-arm, parallel, superiority multicenter clinical trial. Veterans with moderate to severe AUD, as diagnosed by DSM-5 criteria, and seeking treatment will be invited to participate. Enrolled participants, meeting eligibility criteria, will be randomized in a 1:1 ratio to receive either semaglutide 2.4 mg or placebo injections using a stratified random block randomization method. The stratification factors are participating site and body mass index (BMI). The study will be conducted in four phases. Phase 1 will be Recruitment, Consent and Screening, Phase 2 will be Randomization and Dose Initiation (the first 4 weeks of treatment), Phase 3 will be the Endpoint Ascertainment Period (24 weeks), and Phase 4 is the Post-Treatment Safety Assessment (4 weeks). Study visits will occur every 4 weeks.
The primary outcome, a reduction in risky drinking, will be assessed by raters at a centralized assessment center (CAC), blinded to treatment assignment, using the Timeline Follow-Back (TLFB). The TLFB is a validated retrospective calendar-based interview technique to record daily alcohol consumption. The TLFB has been widely used in AUD research for its reliability in capturing detailed drinking patterns.
Intervention and Masking Semaglutide 2.4 mg: Participants assigned to the treatment group will undergo 28-week semaglutide treatment. The initial dosing period of 4 weeks (Phase 2) will be used for initiation of 0.25 mg for weeks 1 to 4. Further titration up to 2.4 mg weekly will occur starting at week 5 (Phase 3). Participants should be increased to their maximal tolerable dose. Increases will be considered only after the participant has been on the current dose for 4 weeks. Doses are not to exceed 2.4 mg weekly. Patients may have their dose reduced, maintain their current dose, or have slower titration 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.
Placebo: Participants assigned to the placebo group will receive a placebo pen, which mimics the treatment pens under the masking rule by following the same treatment procedure.
Sample Size and Study Duration This study plans to randomize 438 Veterans, with 219 participants assigned to each group. Recruitment is expected to be completed over 32 months.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Semaglutide | Experimental | Weekly subcutaneous injections of semaglutide up to 2.4 mg/week or maximum tolerated dose. Initial dosing starting at 0.25 for weeks 1-4. Further titration up to 2.4 mg weekly starting at week 5. |
|
| Placebo | Placebo Comparator | Weekly subcutaneous injections of placebo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Semaglutide | Drug | Weekly subcutaneous injections of semaglutide up to 2.4 mg/week or maximum tolerated dose. Initial dosing starting at 0.25 for weeks 1-4. Further titration up to 2.4 mg weekly starting at week 5. |
| Measure | Description | Time Frame |
|---|---|---|
| Two-level reduction in the World Health Organization (WHO) risk drinking level | Number of participants with at least a two-level reduction, from baseline risk level, in WHO risk drinking level. The WHO risk drinking levels categorize alcohol consumption into four groups: low (level 1; 0-2.86 standard drinks/day for men; 0-1.43 drinks/day for women), moderate (level 2; 2.87-4.29 standard drinks/day for men; 1.44-2.86 drinks/day for women), high (level 3; 4.3-7.14 standard drinks/day for men; 2.87-4.29 drinks/day for women), and very high (level 4; >7.15 drinks/day for men; >4.3 drinks/day for women). One standard drink is 14g of alcohol. A 2-level reduction, such as moving from very high to moderate risk, is considered a significant clinical improvement. | Change from Baseline to Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse events of special interest (Assessing safety and tolerability) | Safety and tolerability will be assessed using number of participants (assessing proportion) with adverse events of special interest (AESIs; adverse events reported in >2% of those exposed to the study drug in previous trials). | From randomization through week 32. |
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Inclusion Criteria:
Exclusion Criteria:
Medical and Psychiatric:
Laboratory
Concurrent Treatments:
Other
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| David W Oslin, MD | Contact | (215) 823-5870 | Dave.Oslin@va.gov | |
| Neil C Johnson, MA BA | Contact | (702) 202-8387 | 21265 | neil.johnson@va.gov |
| Name | Affiliation | Role |
|---|---|---|
| David W. Oslin, MD | Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA | Philadelphia | Pennsylvania | 19104-4551 | United States |
After the main results of this study have been published, de-identified data from the study may be shared with other VA investigators, other Federal health agencies, or academic institutions for the purpose of additional analyses provided this use has been approved by the appropriate VA oversight committee and there is an agreement in place that defines the limits of this use.
Non-identified study data may be made available to the FDA and Novo Nordisk for medication approval.
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Participants are randomized 1:1 to either Semaglutide or Placebo injections. The Semaglutide group will be titrated from 0.25 mg up to 2.4 mg/week based on flexible dosing.
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Participants assigned to the placebo group will receive a placebo pen, which mimics the treatment pens by following the same treatment procedure.
| Placebo | Drug | Weekly subcutaneous injections of placebo. |
|
| No heavy drinking days |
Number of participants with no heavy drinking days. Heavy drinking is defined as >4 standard drinks in a day for men and >3 for women. One standard drink is equal to 14 g of alcohol or approximately 12 oz beer, 5 oz wine, or 1.5 oz of liquor. The data will be derived from the Timeline Follow Back, which is a validated retrospective calendar-based interview technique to record daily alcohol consumption over a specified recall period (since the last assessment). |
| Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| Two-level reduction in the World Health Organization (WHO) risk drinking level by Race category | Number of participants by race category (White, Black, Other) with at least a two-level reduction, from baseline risk level, in WHO risk drinking level. Each month of the ascertainment phase (weeks 5-28), the WHO risk drinking level will be calculated. | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| Two-level reduction in the World Health Organization (WHO) risk drinking level by age category (<65, ≥ 65) at baseline | Number of participants by age category (<65, ≥ 65) at baseline with at least a two-level reduction, from baseline risk level, in WHO risk drinking level. Each month of the ascertainment phase (weeks 5-28), the WHO risk drinking level will be calculated. | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| Two-level reduction in the World Health Organization (WHO) risk drinking level by psychiatric comorbidity at baseline | Number of participants with a psychiatric comorbidity at baseline with at least a two-level reduction, from baseline risk level, in WHO risk drinking level. Each month of the ascertainment phase (weeks 5-28), the WHO risk drinking level will be calculated. | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| Two-level reduction in the World Health Organization (WHO) risk drinking level by presence of other psychiatric treatments (medication and/or psychotherapy) at baseline | Number of participants with psychiatric treatments (medication and/or psychotherapy) at baseline with at least a two-level reduction, from baseline risk level, in WHO risk drinking level. Each month of the ascertainment phase (weeks 5-28), the WHO risk drinking level will be calculated. | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| Two-level reduction in the World Health Organization (WHO) risk drinking level by impulsivity category (low, moderate, high) at baseline. | Number of participants by impulsivity category (low, moderate, high) at baseline with at least a two-level reduction, from baseline risk level, in WHO risk drinking level. Each month of the ascertainment phase (weeks 5-28), the WHO risk drinking level will be calculated. Impulsivity will be measured by the Barratt Impulsiveness Scale, which is a 30-item self-report instrument designed to access the personality/behavioral construct of impulsiveness. Items are scored on a 4-point scale: Rarely/Never = 1 Occasionally = 2 Often = 3 Almost Always/Always = 4. Total scores range from 30-120, with a higher score indicating a higher level of impulsivity. A score >/= 72 will be classified as high, 52-71 moderate, and < 52 low. | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| No heavy drinking days by Race category | Number of participants by race category (White, Black, Other) with no heavy drinking days. Heavy drinking is defined as >4 standard drinks in a day for men and >3 for women. One standard drink is equal to 14 g of alcohol or approximately 12 oz beer, 5 oz wine, or 1.5 oz of liquor. The data will be derived from the Timeline Follow Back, which is a validated retrospective calendar-based interview technique to record daily alcohol consumption over a specified recall period (since the last assessment). | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| No heavy drinking days by age category (<65, ≥ 65) at baseline | Number of participants by age category (<65, ≥ 65) at baseline with no heavy drinking days. Heavy drinking is defined as >4 standard drinks in a day for men and >3 for women. One standard drink is equal to 14 g of alcohol or approximately 12 oz beer, 5 oz wine, or 1.5 oz of liquor. The data will be derived from the Timeline Follow Back, which is a validated retrospective calendar-based interview technique to record daily alcohol consumption over a specified recall period (since the last assessment). | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| No heavy drinking days by psychiatric comorbidity at baseline | Number of participants with a psychiatric comorbidity at baseline with no heavy drinking days. Heavy drinking is defined as >4 standard drinks in a day for men and >3 for women. One standard drink is equal to 14 g of alcohol or approximately 12 oz beer, 5 oz wine, or 1.5 oz of liquor. The data will be derived from the Timeline Follow Back, which is a validated retrospective calendar-based interview technique to record daily alcohol consumption over a specified recall period (since the last assessment). | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| No heavy drinking days by presence of other psychiatric treatments (medication and/or psychotherapy) at baseline | Number of participants with psychiatric treatments (medication and/or psychotherapy) at baseline with no heavy drinking days. Heavy drinking is defined as >4 standard drinks in a day for men and >3 for women. One standard drink is equal to 14 g of alcohol or approximately 12 oz beer, 5 oz wine, or 1.5 oz of liquor. The data will be derived from the Timeline Follow Back, which is a validated retrospective calendar-based interview technique to record daily alcohol consumption over a specified recall period (since the last assessment). | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| No heavy drinking days by impulsivity category (low, moderate, high) at baseline. | Number of participants by impulsivity category (low, moderate, high) at baseline with no heavy drinking days. Heavy drinking is defined as >4 standard drinks in a day for men and >3 for women. One standard drink is equal to 14 g of alcohol or approximately 12 oz beer, 5 oz wine, or 1.5 oz of liquor. The data will be derived from the Timeline Follow Back, which is a validated retrospective calendar-based interview technique to record daily alcohol consumption over a specified recall period (since the last assessment). Impulsivity will be measured by the Barratt Impulsiveness Scale, which is a 30-item self-report instrument designed to access the personality/behavioral construct of impulsiveness. Items are scored on a 4-point scale: Rarely/Never = 1 Occasionally = 2 Often = 3 Almost Always/Always = 4. Total scores range from 30-120, with a higher score indicating a higher level of impulsivity. A score >/= 72 will be classified as high, 52-71 moderate, and < 52 low. | Weeks 5-28. Includes six repeated measurements every 4 weeks from week 5 to 28. |
| ID | Term |
|---|---|
| D000437 | Alcoholism |
| ID | Term |
|---|---|
| D019973 | Alcohol-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C000591245 | semaglutide |
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