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

Who can take part

• Veteran
• World Health Organization's (WHO) risk drinking level of Very High or High in the 28 days prior to screening (based on screening TLFB)
• Current diagnosis of moderate or severe alcohol use disorder (AUD), i.e., meeting at least 4 of 11 DSM-5 AUD criteria, based on semi-structured diagnostic exam, the Mini-International Neuropsychiatric Interview (MINI)
• Able and willing to provide informed consent
• Has a desire to reduce their alcohol consumption

Who cannot take part

• Psychiatric diagnosis, the Mini-International Neuropsychiatric Interview (MINI); Current serious psychiatric illness (any psychotic disorder, bipolar 1 disorder, psychotic major depression, antisocial personality disorder, bulimia, or anorexia); Current DSM-5 diagnosis of a Substance use disorder (SUD), other than moderate-to-severe alcohol, any nicotine, or mild cannabis use disorders
• Other assessments (local site); At the time of randomization, moderate-to-severe alcohol withdrawal (Clinical Institute Withdrawal Assessment for Alcohol (CIWA-AR) >8); Body mass index (BMI) <21 kilograms/square meter (kg/m2); 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 Co-Investigator (Co-I), make it unlikely the participant can participate in or complete the 24-week active phase of the study; Pregnant, actively breastfeeding, or female of childbearing potential who is unwilling to use a highly effective method of contraception as defined by the NIH; Currently enrolled in another therapeutic or investigational clinical trial without a preexisting dual enrollment agreement; Participant is incarcerated
• Medical History (medical history form); Type 1 diabetes; 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 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 stage 3 fibrosis or stage 4 cirrhosis from a liver biopsy; 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; Current drug-induced liver disease; History of alpha1 antitrypsin deficiency related liver disease; History of autoimmune liver disease; History of hemochromatosis; History of Wilson's disease; Presence of gastroparesis; History of acute gallbladder disease in the prior 6 months; Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2); Unstable body weight defined as >5% change in body weight (documented or self-report; intentional or not) in the 90 days prior to randomization; 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; Known history of prior hypersensitivity reaction to semaglutide, any of the product components, or any other GLP-1 analogue
• Concurrent Treatments (medical history form):; Current (within the past 30 days) use of pharmacotherapy for alcohol use disorder (AUD), including oral or intramuscular naltrexone, acamprosate, disulfiram, topiramate; 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, meglitinides, thiazolidinediones 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)
• Laboratory; Hemoglobin A1c (HbA1c)>10; Estimated glomerular filtration rate (eGFR) <30 milliliters/minute (mL/min); Albumin < 3.5 grams/deciliter (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/ liter (L) 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