Semaglutide Therapy for Alcohol Reduction (STAR)

Study Description:

This study will test the safety/tolerability and early efficacy of subcutaneous (s.c.) semaglutide at the dose of 2.4 mg/week or maximum tolerated dose (MTD) as a potential new treatment for alcohol use disorder (AUD).

Objectives:

We propose to test early efficacy and safety/tolerability of semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, as a novel pharmacotherapy to reduce alcohol use and related measures. This will be a Phase 2a, pilot, proof-of-concept, outpatient study combined with experimental medicine human laboratory procedures.

Endpoints:

The primary aims will be to determine whether semaglutide reduces alcohol drinking from baseline to endpoint, as measured by total number of standard alcohol-containing drinks consumed per week (drinks per week, DPW). Semaglutide is safe and tolerable in individuals with AUD, as measured by the frequency/severity of adverse events and the proportion of participants who reach maximum dose, and B) semaglutide reduces alcohol drinking from baseline to endpoint, as measured by total number of standard alcohol-containing drinks consumed per week (drinks per week, DPW).

The following secondary aims will also be examined:

• Whether semaglutide is safe and tolerable, as assessed by the number and severity of adverse events and the proportion of participants who reach the target dose.
• Whether semaglutide reduces other self-reported alcohol-related outcomes (e.g., heavy drinking days, drinks per drinking days, World Health Organization (WHO) drinking levels)
• Whether semaglutide reduces blood Phosphatidylethanol (PEth) levels as a biomarker of alcohol use
• Whether semaglutide reduces alcohol and/or food cue-elicited craving assessed in a bar-like laboratory
• Whether semaglutide reduces and/or changes food choices in a virtual reality buffet-like laboratory

• INCLUSION CRITERIA:

This study will enroll adult individuals with a current diagnosis of AUD. Participants will be recruited without any preference to sex, race, religion, or other social variables, but sociodemographic data will be collected for sample characterization and potential use in the analyses. Since self-reported psychological measures that have been validated in English constitute major part of the study assessments, participants need to be able to speak, read, write, and understand English to be in the study.

The information needed to assess eligibility will be collected under an IRB-approved NIDA IRP

screening protocol, led by the Office of the Clinical Director (OCD) at the NIDA IRP to assess

potential research participants' eligibility for entering clinical protocols. Additional details can be found in the NIDA screening protocol documents. Furthermore, NIH medical records (from other NIH clinical protocols) and outside medical records may also be used, if available, to determine whether participants fulfill the eligibility criteria.

To be eligible for this study, an individual must meet all of the following criteria:

• At least 18 years old
• Alcohol Use Disorder (minimum 2 symptoms on a validated diagnostic tool, e.g., the Mini-International Neuropsychiatric Interview (MINI) or the Structured Clinical Interview for DSM Disorders (SCID))
• Self-reported drinking, according to alcohol Timeline Follow-Back (TLFB), of > 7 drinks per week for females or > 14 drinks per week for males during the 28-day period prior to screening plus at least four days with > 3 drinks for females or > 4 drinks for males during the 28-day period prior to screening
• Most recent Clinical Institute Withdrawal Assessment for Alcohol - revised (CIWA-Ar) score < 10
• Able to speak, read, write, and understand English as demonstrated by ability to understand and sign the NIDA screening protocol consent
• Normal or corrected-to-normal (e.g., wearing glasses or contacts) vision and normal or corrected-to-normal (e.g., with the use of a hearing aid) hearing

Exclusion criteria

An individual who meets any of the following criteria will be excluded from enrolling in this study:

• BMI < 23 kg/m^2 or BMI >= 50 kg/m^2
• Evidence of malnutrition as determined by the Nutrition Risk Screening 2002 (NRS-2002)
• Most recent blood tests: creatinine >= 2 mg/dL, eGFR <45 mL/min/1.73 m^2, triglycerides > 500 mg/dl, ALP > 4x the upper limit of normal, clinically abnormal lipase levels per study clinician
• Present diagnosis of diabetes mellitus or blood hemoglobin A1c (HbA1c) >= 6.5 %
• Current (within the past 30 days) use of the following medications with glucose lowering properties: GLP-1 analogues, sulfonylurea, insulin, metformin, thiazolidinediones, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors
• Current or prior use of semaglutide or tirzepatide
• Current (within the past 30 days) use of weight-lowering medications
• Current (within the past 30 days) use of FDA-approved pharmacotherapy for AUD (oral or intramuscular naltrexone, acamprosate, disulfiram)
• Current (within the past 30 days) use of medications with known interaction with semaglutide
• Personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Known ongoing history of alcohol ketoacidosis, gastroparesis, pancreatitis (either acute or chronic), pancreatic carcinoma, gallbladder disease, jaundice, Mallory-Weiss syndrome (esophageal tears secondary to vomiting), esophageal varices, cirrhosis
• Known history of gastric bypass surgery
• Known history of prior hypersensitivity reaction to semaglutide, any of the product components, or any other GLP-1 analogue
• Known history of suicidal attempts (within the past 24 months) or active suicidal ideation
• Known history of clinically significant vestibular disorders or motion sickness
• Known history of clinically significant noise-induced hearing loss or tinnitus
• Contraindication(s) for brain fMRI
• Unstable cardiovascular conditions (e.g., arrhythmias, clinically significant ECG abnormalities)
• Physical and/or mental health conditions that are clinically unstable, as determined by the study clinicians, including (but not limited to) major depressive disorder or generalized anxiety disorder unstable during the past three months or other psychiatric conditions (e.g., schizophrenia, bipolar disorder) unstable during the past twelve months prior to screening.
• Female who is pregnant, breast-feeding, or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method
• Any other reason or clinical condition that the investigators judge may interfere with study participation and/or be unsafe for a participant