The investigators approach is to conduct a Phase II Double-Blind randomised controlled trial with individuals with co-occurring Alcohol Use Disorder and overweight/obesity (AUD-OOB) to receive either a sub-cutaneous injection of Tirzepatide (2.5 mg for 4 weeks followed by 5 mg for 4 weeks) or visually matched sham saline injection, in combination with a structured behavioural intervention (Take Control CBT Module). The primary aim of the study is evaluate the efficacy of the intervention on the number of heavy drinking days (defined as 5+ standard drinks for men, 4+ standard drinks for women) during the final month of treatment (weeks 5 to 8) compared to baseline. The secondary aim of the study is to assess treatment effects on alcohol related (e.g. number drinks consumed per day, abstinent days) and cardio-metabolic outcomes (e.g. body weight in kg, waist circumference, blood pressure, HbA1c, total cholesterol etc...), and summarise safety outcomes associated with use (e.g. frequency and severity of side effects, number of serious adverse events, treatment related discontinuations). The study will also include neurobiological assessments such as functional magnetic resonance imaging (fMRI) and lab-based psychophysiology to assess the impact of tirzepatide on change in brain activity and autonomic responses to alcohol and food cues.
Aged 21 to 75 years
Meet DSM-5 criteria for alcohol use disorder (AUD) with at least moderate severity (≥4 symptoms in the past year)
≥60g ethanol/day for men
≥40g ethanol/day for women (based on the 28 days prior to the baseline visit)
Past-year DSM-5 diagnosis of another substance use disorder (except nicotine or mild cannabis use disorder)
Recent (past 30 days) self-reported illicit drug use (excluding cannabis), or a positive urine drug screen for non-cannabis substances
History of seizure, delirium tremens, or
Hospitalisation for withdrawal, or
Parallel
Tirzepatide
DrugSubcutaneous injection once weekly for 8 weeks: 2.5 mg/week initially for Weeks 1-4, then 5.0 mg/week for Weeks 5-8 (Dose escalation from 2.5 mg to 5.0 mg will occur at Week 5 unless the study physician advises continuation at the lower dose due to tolerability concerns. Delays or dose adjustments will be made per the physician's clinical judgment).
Take Control CBT Module
BehavioralThe Take Control intervention is a structured CBT intervention or manualised digital therapy designed to support alcohol reduction. Take Control will be completed using a computer interface with headphones in a private room. Participants will complete one module per week during treatment Weeks 1 to 8. Each module is approximately 30-45 minutes in length and will be completed independently by the participant under the supervision of a research assistant. Program content is fixed and self-paced, eliminating the need for fidelity monitoring of therapist behaviour. Take Control is an evidence-informed cognitive-behavioural intervention originally developed for use in pharmacotherapy trials for AUD and has demonstrated feasibility and acceptability in similar populations. The intervention content draws on established CBT strategies for alcohol reduction, including motivational enhancement, managing triggers, coping skills, and relapse prevention.
Placebo
Other interventionParticipants in the placebo condition will receive visually-matched sham injections, where by the placebo container and contents will be identical in appearance to Tirzepatide, except without the active ingrediant.
Heavy Drinking Days
Reduction in Heavy Drinking Days (HDD; defined as 4 or more drinks in a day for women and 5 or more drinks in a day for men). This will be measured by the Timeline Follow Back.
Number of drinks per drinking day consumed
Measured by Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels
Abstinent days
Measured by Timeline Follow Back
Alcohol Craving
As measured the Visual Analogue Scale (VAS) weekly and also at pre-, during-, and post- psychophysiological cue-reactivity task completion. Scored from to 0 to 100, where higher scores indicate more severe craving.
WHO drinking risk level scale.
The WHO drinking risk level scale categorizes alcohol consumption based on average daily intake of pure alcohol (in grams) and its associated health risk. There are 5 levels that differ based on gender: * For men, very high risk \>100 grams/day or; high risk as \>60 to 100 grams/day ; moderate risk as \>40 to 60 grams/day; and low risk as 1 to 40 grams/day. * For women, very high risk was defined as \>60 grams/day; high risk as \>40 to 60 grams/day; moderate risk as \>20 to 40 grams/day ; and low risk as 1 to 20 grams/day.
Changes in cigarette use
Measured according to the average number of cigarettes smoked per day, only among participants who reported regular smoking at baseline. Analysed with a mixed-effects models.
Changes in cannabis use
Measured according to the average number of days of cannabis used per week, only among participants who reported baseline use. Analysed with a mixed-effects models.
Changes in phosphatidylethanol (PEth), an objective biomarker of alcohol use
Changes in PEth (phosphatidylethanol) from baseline to Week 9 will be analysed using MMRM, with baseline PEth as a covariate. Collected at week 0, 9 (end-of-treatment) and optionally at week 12.
Changes in depressive symptom severity
Measured by cumulative scores on the Center for Epidemiologic Studies Depression Scale (CES-D). This scale consists of 20 items with a minimum score of 0 and a maximum score of 60. A higher score indicates greater depressive symptomatology. Items are rated according to how often the feeling or behavior occurred in the past week (e.g. 0 = Rarely or none of the time (less than 1 day; 1 = Some or a little of the time (1-2 days); 2 = Occasionally or a moderate amount of the time (3-4 days) and 3 = Most or all of the time (5-7 days))
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South West Sydney Local Health District
Lead sponsor
University of Sydney
Collaborator
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