The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers

Phase 1

Terminated

Conditions: Alcohol Use Disorder

Interventions: Drug: Exenatide
Other: Sham injection

Registration Number: NCT03645408

Lead Sponsor: Boston Medical Center

Brief Summary: A double-blind, randomized, placebo-controlled, crossover design trial was used to test the effect of exenatide on alcohol self-administration and craving following a priming dose of alcohol. The specific objective of this research was to determine whether exenatide has effects on alcohol consumption.

Detailed Description: This proposal was intended to answer the call for accelerating drug development by exploring the potential of a glucagon-like peptide-1 (GLP-1) agonist, exenatide, as a candidate medication for the treatment of Alcohol Use Disorder. There is now substantial preclinical evidence that GLP-1 agonists can attenuate behaviors that model both the consumption and seeking of several commonly abused substances including alcohol, cocaine, and nicotine. This study was intended to accelerate medication development for Alcohol Use Disorder by testing a commercially-available and well-tolerated agent at a fraction of the cost of new drug discovery. None of the FDA-approved Alcohol Use Disorder medications or off-label Alcohol Use Disorder medications target this GLP-1 pathway, making exenatide a promising compound for Alcohol Use Disorder drug development.

The primary aim of this study was to test the effects of exenatide on alcohol self-administration and craving among heavy drinkers. In this within-subjects crossover design, 3 heavy drinkers were randomized to exposure order (exenatide or sham injection) prior to completing two alcohol self-administration trials. Subjects received a priming drink of alcohol and had access to 8 drinks over a 2-hour period. The investigators anticipated that subjects would consume less alcohol following the administration of exenatide compared to when they received a sham injection. Significant exenatide-induced reductions in drinking would be considered to be an indication that this drug may have value as an Alcohol Use Disorder medication. This study may provide a rationale for phase II randomized controlled trials testing exenatide with a treatment-seeking Alcohol Use Disorder population. These results may also help to spur further clinical investigation of the effects of exenatide and other available GLP-1 agonists on the factors implicated in the regulation of alcohol consumption.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8

Inclusion Criteria

21-55 years of age.
Able to verify age with a state or federal picture identification.
Exceeds safe weekly drinking limits [4 standard drink units (SDUs) for women or 21 SDUs for men per week]
Reports at least one episode of binge drinking (>3 SDUs for women, >4 SDUs for men) an average of once per week in the four weeks prior to baseline screening.
Meets Diagnostic And Statistical Manual Of Mental Disorders, Fifth Edition (DSM-5)criteria for mild alcohol use disorder or greater severity.

Exclusion Criteria

Seeking treatment for alcohol problems.
Clinical Institute Withdrawal Assessment at ≥10
DSM-5 diagnosis of current major depression, bipolar disorder, schizophrenia, bulimia/anorexia, dementia, or a substance use disorder other than alcohol, nicotine, marijuana or caffeine.
If female, pregnant, nursing, have plans to become pregnant.
If female, does not agree to use an accepted form of birth control.
Has a medical contraindication to the use of exenatide.
Has medical or mental condition for which further alcohol exposure at the planned dose range would be contraindicated.
Current risk of suicidality (MINI suicidality score greater than 8 (low risk) or Yes to the ideation question #4 of the C-SSRS).
BMI is less than 18 or greater than or equal to 30.
History of diabetes.
Baseline hemoglobin A1c ≥ 6.5%
Baseline non fasting glucose >200
Significantly elevated serum lipase levels.
Impaired renal function (GFR <80 mL/min).
Pancreatitis, gastroparesis or other severe gastrointestinal disease.
Has had gastric bypass surgery
Subject is currently taking warfarin.
Has received alcohol counseling or other non-pharmacologic intervention to treat AUD in the past 90 days.
Has taken medications that are used to treat alcohol use disorder (AUD) in the past 90 days.
Subjects with a history of thyroid cancer or other thyroid disease.
Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, methadone, or methamphetamines.
Prior history of anaphylaxis or angioedema with another GLP-1 receptor agonist.
Prior use of exenatide
Liver function values AST or ALT are twice the normal limit
Unable to comfortably abstain from nicotine for a period of 8 hours.
Has Chronic obstructive pulmonary disease (COPD), history of solid organ transplant, sickle cell disease, severe heart disease or other health condition for which exposure to COVID-19 represents an unreasonable risk as determined by the study staff physician using accepted COVID-19 guidance (e.g. Centers for Disease Control, etc.).
Subject has prior history of Drug-induced thrombocytopenia

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo then Exenatide	Exenatide	This is a within subjects design study in which each subject receives both study drug and placebo. Subjects in this arm received a sham injection on the day of the first alcohol self-administration trial. The sham injection was a needle stick using a syringe with no drug injected. Subjects in this arm then received a 5 mcg dose of immediate release exenatide on the day of the second alcohol self-administration trial. The 5mcg dose of exenatide was approved as the first dose administered to patients at the start of their treatment with this drug for FDA-approved indications. Note that the volume of fluid injected for a 5mcg dose is so small that subjects would not sense this volume of fluid (or lack thereof) during the injection. Subjects were shielded from seeing the injection to maintain the blind.
Placebo then Exenatide	Sham injection	This is a within subjects design study in which each subject receives both study drug and placebo. Subjects in this arm received a sham injection on the day of the first alcohol self-administration trial. The sham injection was a needle stick using a syringe with no drug injected. Subjects in this arm then received a 5 mcg dose of immediate release exenatide on the day of the second alcohol self-administration trial. The 5mcg dose of exenatide was approved as the first dose administered to patients at the start of their treatment with this drug for FDA-approved indications. Note that the volume of fluid injected for a 5mcg dose is so small that subjects would not sense this volume of fluid (or lack thereof) during the injection. Subjects were shielded from seeing the injection to maintain the blind.
Exenatide then Placebo	Exenatide	This is a within subjects design study in which each subject receives both study drug and placebo. Subjects in this arm received a 5 mcg dose of immediate release exenatide on the day of the first alcohol self-administration trial. The 5mcg dose of exenatide was approved as the first dose administered to patients at the start of their treatment with this drug for FDA-approved indications. Subjects in this arm then received a sham injection on the day of the second alcohol self-administration trial. The sham injection was a needle stick using a syringe with no drug injected. Note that the volume of fluid injected for a 5mcg dose is so small that subjects would not sense this volume of fluid (or lack thereof) during the injection. Subjects were shielded from seeing the injection to maintain the blind.
Exenatide then Placebo	Sham injection	This is a within subjects design study in which each subject receives both study drug and placebo. Subjects in this arm received a 5 mcg dose of immediate release exenatide on the day of the first alcohol self-administration trial. The 5mcg dose of exenatide was approved as the first dose administered to patients at the start of their treatment with this drug for FDA-approved indications. Subjects in this arm then received a sham injection on the day of the second alcohol self-administration trial. The sham injection was a needle stick using a syringe with no drug injected. Note that the volume of fluid injected for a 5mcg dose is so small that subjects would not sense this volume of fluid (or lack thereof) during the injection. Subjects were shielded from seeing the injection to maintain the blind.

Primary Outcome Measures

Name	Time	Method
Alcohol Consumption	2 hours	Alcohol consumption was measured by using a graduated cylinder to determine the amount of alcohol given to the subject that was not consumed. The amount not consumed was then subtracted from the total amount of alcohol served to the subject in order to calculate the amount consumed. This outcome was measured in standard drink units (SDUs). A standard drink contains approximately 0.6 fluid ounces of pure alcohol.

Secondary Outcome Measures