Does Semaglutide Reduce Alcohol Intake in Patients With Alcohol Use Disorder and Comorbid Obesity?

Study Overview
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Brief Summary
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This 26-week long, double-blinded randomized clinical trial aims to investigate the effects of the GLP-1 receptor agonist semaglutide s.c. vs placebo on alcohol consumption in 108 patients diagnosed with alcohol use disorder and comorbid obesity (BMI>30 kg/m2). Patients will be treated for 26 weeks with semaglutide subcutaneously (s.c.) once weekly or placebo. The medication will be provided as a supplement to standardised cognitive behavioural therapy. A subgroup of the patients will have two brain scans (Magnetic Resonance Spectroscopy (MRS) and functional Magnetic Resonance Imaging (fMRI)) conducted in one scan session at week 0 and 26. The primary endpoint is the percentage-point reduction in total number of heavy drinking days, defined as days with an excess intake of 48/60 grams of alcohol per day (women and men, respectively) from baseline to follow-up after 26 weeks of treatment, measured by the timeline followback (TLFB) method.

Official Title
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Does the Glucagon-like Peptide 1 (GLP-1) Receptor Agonist Semaglutide Reduce Alcohol Intake in Patients With Alcohol Use Disorder and Comorbid Obesity?

Conditions
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Alcohol Abuse, Alcohol Addiction, Alcohol Dependence, Alcohol Use Disorder

Intervention / Treatment
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* Drug: Semaglutide Injectable Product
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed oral and written consent Diagnosed with alcohol dependence according to the criteria of the International Classification of Diseases 10 (ICD-10), and diagnosed with alcohol use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Alcohol use disorder identification test (AUDIT) score >15 Body mass index (BMI) above or equal to 30 kg/m2 Age 18 - 70 years (both included) Heavy alcohol drinking defined as more than 6 days with alcohol consumption over 4 units (48 g alcohol) for women and 5 units (60 g alcohol) for men during a consecutive 30-day period, within 40 days prior to baseline evaluation, measured by the TLFB method. The 30-day period will be the 30 consecutive days with the biggest alcohol intake (most heavy drinking days and the largest amount of total alcohol) out of the 40 days. Exclusion Criteria: Severe psychiatric disease, defined as a diagnosis of schizophrenia, paranoid psychosis, bipolar disorder or mental retardation A history of delirium tremens or alcohol withdrawal seizures No serious withdrawal symptoms at inclusion (a score higher than 9 on the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)) at baseline examinations Present or former neurological disease, including traumatic brain injury Type 1 diabetes, type 2 diabetes in poor glycaemic control (defined as HbA1c ≥48 mmol/l or fasting plasma glucose above 7.0 mmol/l at inclusion) Females of childbearing potential who are pregnant, breast-feeding or have the intention of becoming pregnant within the next 9 months (26 weeks plus two months after discontinuation of semaglutide), or are not using contraceptives (during the whole study period) considered as highly effective (combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) intrauterine device, bilateral tubal occlusion, vasectomised partner, sexual abstinence). Pregnancy (serum human chorionic gonadotropin (hCG) > 3 U/L at inclusion) Impaired hepatic function (liver transaminases >3 times the upper limit) Impaired renal function (eGFR < 50 ml/min and/or plasma creatinine >150 μmol/l) Impaired pancreatic function (any history of acute or chronic pancreatitis and/or amylase > 2 times upper limit) Former medullary thyroid carcinoma (MTC) and/or family history with MTC and/or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) Cardiac problems defined as decompensated heart failure (NYHA class III or IV), unstable angina pectoris and/or myocardial infarction within the last 12 months Uncontrolled hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >110 mmHg) Concomitant pharmacotherapy against alcohol use disorder, i.e., disulfiram, naltrexone, acamprosate, or nalmefene, since the first of the 30 drinking days registered for inclusion at the TLFB-schedule. Receiving any investigational drug within the last three months Use of weight-lowering pharmacotherapy within the preceding 3 months Any other active substance use defined as a DUDIT-score >1 (except nicotine) Hypersensitivity to the active substance or any of the excipients Only for patients undergoing brain scans: o Contraindications for undergoing an MRI scan (magnetic implants, pacemaker, claustrophobia, etc.) Unable to speak and/or understand Danish Any condition that the investigator feels would interfere with trial participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: semaglutide<br>Wegovy once-weekly s.c.titrated to a maximum dose of 2.4 mg | Drug: Semaglutide Injectable Product<br>* Once weekly injections s.c with semaglutide (Wegovy)<br>* Other names: Wegovy;|
| Placebo Comparator: placebo<br>Saline s.c. once-weekly | Drug: Placebo<br>* Once weekly injections s.c with placebo (BD Posiflush)<br>* Other names: BD Posiflush (saline);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in heavy drinking days | Change in alcohol consumption, defined as the change in percentage of heavy drinking days during a period of 30 consecutive days, after 26 weeks of treatment adjusted for baseline (percentage points (pp)). A heavy drinking day is defined as more than 60/48 grams (men/women) of alcohol in one day, measured with the validated timeline follow-back (TLFB) method. | From baseline to 26 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in heavy drinking days adjusted for maximum tolerable semaglutide dose given | Change in heavy drinking days during a period of 30 consecutive days, after 26 weeks of treatment adjusted for baseline (percentage points (pp)) and maximum tolerable semaglutide dose given. | From baseline to 26 weeks of treatment | 
| Change in heavy drinking days adjusted for weightloss | Change in heavy drinking days during a period of 30 consecutive days, after 26 weeks of treatment adjusted for baseline (percentage points (pp)) and weight loss during the 26 weeks of treatment | From baseline to 26 weeks of treatment | 
| Total alcohol consumption | Change in total alcohol consumption /gram/last 30 consecutive days) | From baseline to 26 weeks of treatment | 
| Days without alcohol consumption | Number of days without alcohol consumption in the last 30 consecutive days | From baseline to 26 weeks of treatment | 
| Time to relapse | Time to relapse, defined as the time to first alcohol intake | From baseline to 26 weeks of treatment | 
| Time to relapse (heavy drinking day) | Time to first heavy drinking day | From baseline to 26 weeks of treatment | 
| World Health Organization (WHO) Risk Levels of Alcohol Consumption | Change in WHO alcohol risk level in the last 30 consecutive days, measured with the validated timeline follow-back (TLFB) method. | From baseline to 26 weeks of treatment | 
| Penn Alcohol Craving Scale (PACS) score | Change in Penn Alcohol Craving Scale (PACS) score. Minimum score = 0, maximum score =30. A high score means a worse outcome. | From baseline to 26 weeks of treatment | 
| Alcohol Use Disorder Identification Test (AUDIT) score | Change in Alcohol Use Disorder Identification Test (AUDIT) score. Minimum score = 0, maximum score =40. A high score means a worse outcome. | From baseline to 26 weeks of treatment | 
| Drug Use Disorders Identification Test (DUDIT) score | Change in Drug Use Disorders Identification Test (DUDIT) score. Minimum score = 0, maximum score =44. A high score means a worse outcome. | From baseline to 26 weeks of treatment | 
| Fibrosis-4 (FIB4) score | Change in Fibrosis-4 (FIB4) score, calculated from the parameters: the patient's age, blood aspartate aminotransferase levels (ASAT), thrombocytes and alanine transaminase (ALAT). A higher score means a worse outcome. | From baseline to 26 weeks of treatment | 
| Measure of life quality - World Health Organization Quality of Life brief (WHOQOL-BREF) score | Change in Measures of Health (WHOQOL-BREF) score. Minimum score = 26, maximum score =130. Higher scores mean a better outcome in items 1-2 + 10-25. A higher score in items 3-9 + 26 means a worse outcome. | From baseline to 26 weeks of treatment | 
| Fagerströms Test for Nicotine Dependence score | Change in Fagerströms Test for Nicotine Dependence score. Minimum score = 0, maximum score =10. A high score means a worse outcome. | From baseline to 26 weeks of treatment | 
| Gamma-glutamyl transferase (GGT) | Change in blood gamma-glutamyl transferase (GGT) | From baseline to 26 weeks of treatment | 
| Alanine transaminase (ALAT) | Change in blood alanine transaminase (ALAT) | From baseline to 26 weeks of treatment | 
| Phosphatidyl ethanol (PEth) | Change in plasma levels of phosphatidyl ethanol (PEth) | From baseline to 26 weeks of treatment | 
| Mean cell volume (MCV) | Change in blood mean cell volume (MCV) | From baseline to 26 weeks of treatment | 
| Body weight | Change in Body weight | From baseline to 26 weeks of treatment | 
| Blood pressure | Change in blood pressure (both systolic and diastolic) | From baseline to 26 weeks of treatment | 
| Pulse | Change in pulse | From baseline to 26 weeks of treatment | 
| Waist circumference | Change in waist circumference | From baseline to 26 weeks of treatment | 
| Glycaemic control parameters | Change in HbA1c | From baseline to 26 weeks of treatment | 
| MRS brain gamma-aminobutyric acid (GABA) levels | Change in brain GABA levels (cortical, caudate, and putamen) assessed by MRS brain scans | From baseline to 26 weeks of treatment | 
| fMRI alcohol cue-reactivity | Change in brain alcohol cue-response in reward-processing brain regions (ventral and dorsal striatum, puta-men, nucleus accumbens, and caudate), including the septal area assessed by fMRI brain scans | From baseline to 26 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-1, Glucagon-like peptide 1, semaglutide, fMRI, MRS