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Cessation or Reduction of Alcohol Consumption in Veterans: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of a GLP-1 Receptor Agonist Semaglutide in U.S. Veterans With Alcohol Use Disorder (CRAVE) Phase 3 438 Randomized Double-Blind Placebo-Controlled Veterans

Not yet recruiting
Clinical Trial NCT07218354 (CRAVE) is designed to study Treatment for Alcohol Use Disorder. This Phase 3 interventional study is not yet recruiting. Enrollment is planned to begin on May 1, 2026 until the study accrues 438 participants. Led by VA Office of Research and Development, this study is expected to complete by May 26, 2029. The latest data from ClinicalTrials.gov was last updated on January 7, 2026.
Brief Summary
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 ...Show More
Detailed Description
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 Depa...Show More
Official Title

CSP #2041 - Cessation or Reduction of Alcohol Consumption in VEterans: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of a GLP-1 Receptor Agonist Semaglutide in U.S. Veterans With Alcohol Use Disorder (CRAVE)

Conditions
Alcohol Use Disorder
Other Study IDs
  • CRAVE
  • 2041
NCT ID Number
NCT07218354
Start Date (Actual)
2026-05-01
Last Update Posted
2026-01-07
Completion Date (Estimated)
2029-05-26
Enrollment (Estimated)
438
Study Type
Interventional
PHASE
Phase 3
Status
Not yet recruiting
Keywords
Alcohol use Disorder
Semaglutide
Alcohol
GLP-1
Primary Purpose
Treatment
Design Allocation
Randomized
Interventional Model
Parallel
Masking
Quadruple
Arms / Interventions
Participant Group/ArmIntervention/Treatment
ExperimentalSemaglutide
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.
Semaglutide
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 ComparatorPlacebo
Weekly subcutaneous injections of placebo.
Placebo
Weekly subcutaneous injections of placebo.
Primary Outcome Measures
Outcome MeasureMeasure DescriptionTime 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.
Secondary Outcome Measures
Outcome MeasureMeasure DescriptionTime 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.
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.
Participation Assistant
Eligibility Criteria

Eligible Ages
Adult, Older Adult
Minimum Age
18 Years
Eligible Sexes
All
Accepts Healthy Volunteers
Yes
  • Veteran.
  • WHO risk drinking level of Very High or High in the 30 days prior to screening.
  • Current diagnosis of moderate or severe AUD (i.e., meeting at least 4 of 11 DSM-5 AUD criteria) based on semi-structured diagnostic exam.
  • Able and willing to provide informed consent.

Medical and Psychiatric:

  • Type 1 diabetes.
  • Current serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe or psychotic major depression, borderline or antisocial personality disorder, eating disorder).
  • Current DSM-5 diagnosis of a SUD (other than moderate-to-severe alcohol, any nicotine, or mild cannabis use disorders).
  • At the time of randomization, moderate-to-severe alcohol withdrawal (Clinical Institute Withdrawal Assessment for Alcohol (CIWA-AR) >8).
  • BMI <21 kg/m2.
  • Unstable body weight defined as >5% change in body weight (documented or self-report; intentional or not) in the 90 days prior to randomization.
  • History of acute or chronic pancreatitis.
  • History of diabetic ketoacidosis.
  • History of proliferative diabetic retinopathy.
  • History of ascites, advanced liver fibrosis, compensated cirrhosis with portal hypertension, decompensated cirrhosis, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, or hepatocellular carcinoma (HCC).
  • History of stage 3 fibrosis or stage 4 cirrhosis from a liver biopsy.
  • Presence of gastroparesis.
  • History of acute gallbladder disease in the prior 6 months.
  • History of advanced fibrosis or cirrhosis, including (but not limited to) transient elastography (liver stiffness) of >12 kPa, FIB-4 2.67, ELF 9.8, MRE 3.63 kPa.
  • History of esophageal varices on endoscopy or imaging.
  • History of nodular liver, cirrhosis, splenomegaly, varices or splenic venous shunting or collaterals on prior imaging.
  • History or acute alcohol hepatitis (by liver biopsy or elevated bilirubin > 1.5 times the upper limit of normal).
  • History of primary biliary cholangitis.
  • History of primary sclerosing cholangitis.
  • History of autoimmune liver disease.
  • History of hemochromatosis.
  • History of Wilson's disease.
  • History of alpha-10 antitrypsin-related liver disease.
  • History of drug-induced liver disease.
  • Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2).
  • Acute high risk of suicide requiring hospitalization at the time of screening or randomization.
  • Medical, psychiatric, behavioral, or logistical conditions which, in the judgment of the Local Site Investigator (LSI) or Sub-Investigator (Sub-I), make it unlikely the participant can participate in or complete the 28-week active phase of the study.
  • Recent major cardiovascular event in the 90 days prior to randomization (myocardial infarction, stroke, New York Heart Association class IV heart failure, transient ischemic attack (TIA), or unstable angina.

Laboratory

  • Hemoglobin A1c (HbA1c)>10.
  • Estimated glomerular filtration rate (eGFR) <30 mL/min.
  • Albumin < 3.5 g/dl.
  • Aspartate aminotransferase (AST) >3 the Upper Limit of Normal (ULN).
  • Alanine aminotransferase (ALT) >3 the ULN.
  • Lipase > 2 times the upper limit of normal.
  • Alkaline phosphatase > 1.5 times the ULN.
  • Total bilirubin > 1.5 times the ULN except with documented Gilbert's syndrome.
  • International Normalized Ratio (INR) > 1.3 unless due to anticoagulation therapy.
  • Platelet count <150,000/µL unless consistent with baseline and reflects the participant's habitual thrombocyte level, and there was no presence of portal hypertension.
  • Hepatitis B surface antigen positive.
  • Hepatitis C virus RNA positive - participants treated and cured of hepatitis C must have at least 2 years of negative testing.
  • Anti-HIV antibody positive test with uncontrolled or unstable treatment.
  • Positive urine drug screen for substances other than cannabis and prescribed medications.
  • Positive urine pregnancy test at screening in those considered of childbearing potential.

Concurrent Treatments:

  • Current (within the past 30 days) use of pharmacotherapy for AUD (including oral or intramuscular naltrexone, acamprosate, disulfiram, topiramate).
  • Known history of prior hypersensitivity reaction to semaglutide, any of the product components, or any other GLP-1 analogue.
  • Current (within the past 30 days) use of the following medications with glucose-lowering properties: GLP-1 analogues; sulfonylurea; insulin and insulin products; dipeptidyl peptidase-4 (DPP-4) inhibitors; sodium-glucose cotransporter-2 (SGLT-2) inhibitors or other medications that may interact with semaglutide.
  • Recent changes in dose (within 2 months of randomization) of psychiatric medications (i.e., antidepressants, antianxiety, mood stabilizing).

Other

  • Pregnant, actively breastfeeding, or female of childbearing potential who is unwilling to use a highly effective method of contraception as defined by the NIH \[67\].
  • Currently enrolled in another therapeutic or investigational clinical trial.
  • Participant is incarcerated.
VA Office of Research and Development logoVA Office of Research and Development
Study Central Contact
Contact: David W Oslin, MD, (215) 823-5870, [email protected]
Contact: Neil C Johnson, MA BA, (702) 202-8387, [email protected]
1 Study Locations in 1 Countries

Pennsylvania

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, Philadelphia, Pennsylvania, 19104-4551, United States
David W Oslin, MD, Contact, 215-823-5870, [email protected]
David W. Oslin, MD, Study Chair