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

Exclusion Criteria54

• Medical and Psychiatric:
• Type 1 diabetes
• 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 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)
• Body mass index (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 alpha1 antitrypsin deficiency related liver disease
• Current 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 judgement 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
• 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, 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)
• 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
• Currently enrolled in another therapeutic or investigational clinical trial
• Participant is incarcerated