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.
Individuals with co-occurring AUD and overweight or obesity (AUD-OOB) are an underserved population with high relapse rates and elevated cardiometabolic risk. Recent evidence suggests that Tirzepatide can simultaneously reduce alcohol intake in animal models and craving, drinks per day and heaving drinking days over a 9-week period in non-treatment seeking individuals with AUD. Tirzepatide's dual incretin mechanism offers the potential to simultaneously reduce alcohol use and improve metabolic health in this group, with a favourable safety profile and weekly dosing that supports adherence. As rates of AUD and obesity continue to rise, identifying pharmacological strategies that can address both conditions concurrently is a high public health priority. This is a phase II, randomised, double-blind, placebo-controlled clinical trial of 46 individuals designed to evaluate the effects of Tirzepatide on alcohol consumption, craving and cardiometabolic outcomes in adults with alcohol used disorder and overweight/obesity (AUD-OOB), to receive either a sub-cutaneous injection of tirzepatide (n=23) or a visually matched placebo (n=23). The trial will be conducted at a single clinical site in New South Wales, Australia. The Edith Collins Centre (ECC) will serve as the coordinating centre. In summary participants will: * Be randomized in a double-blind fashion to receive either tirzepatide or a visually matched placebo * Receive subcutaneous injections of tirzepatide (2.5mg for 4 weeks followed by 5mg for 4 weeks) or a matching placebo over an eight-week treatment period. * Visit the clinic weekly (for 8 weeks) for medication administration, clinical monitoring and brief behavioural support (delivered by the "Take Control" computerised CBT program). * Receive clinical assessments including alcohol use, cardiometabolic biomarkers (HbA1c, lipids, ASCVD) and alcohol biomarkers (PEth) at baseline (week 0), end of treatment (week 9) and follow-up (week 12). * Undergo neuroimaging (fMRI) and psychophysiology assessmenrts as a substudy at 2 timepoints: baseline (week 0) and between week 7-9. These tasks will assess neural and autonomic reactivity to alcohol and food-related cues, and will support a mechanistic understanding of tirzepatide's impact on reward sensitivity and stress responsivity-key predictors of relapse and treatment outcome The primary aim of this clinical trial is to examine the effects of weekly tirzepatide (2.5 mg for 4 weeks followed by 5 mg for 4 weeks) versus placebo injections, in combination with a structured behavioural intervention (Take Control) on alcohol consumption in adults with alcohol use disorder and overweight/obesity (AUD-OOB). The main question\[s\] it aims to answer are: 1. Main outcome: To determine the efficacy of Tirzepatide on alcohol related outcomes, the change in the number of heavy drinking days during the final four weeks of treatment (week 5 - 8, with a final assessment at week 9) will be assessed by comparison with baseline (28 days prior to baseline visit). Researchers will compare tirzepatide to placebo injections (a look-alike substance that contains no drug) to see if weekly tirzepatide administration can reduce the number of heavy drinking days. 2. Secondary Outcomes: i) To evaluate changes in additional alcohol-related outcomes: * Number of drinks per drinking day measured using the Timeline Follow Back * Number of abstinent days measured using the Timeline Follow Back * WHO drinking risk level * Weekly alcohol craving * Proportion of participants with zero heavy drinking days (Weeks 5-8) ii) To evaluate changes in cardiometabolic indices from baseline to Week 9: * Body weight * Waist circumference * Blood pressure * HbA1c * Total cholesterol * Triglycerides * 10-year ASCVD risk score iii) To assess safety outcomes associated the delivery of Tirzepatide, investigators will measure the: * Frequency and severity of side effects (graded using CTCAE V5.0 and monitored continuously throughout the intervention). * Number of serious adverse events (SAEs) * Treatment-related discontinuation Participants will complete additional neurobiological assessments including functional magnetic resonance imaging (fMRI) and laboratory-based psychophysiology at two timepoints: baseline (pre-treatment) and the final treatment visit (Week 8), which coincides with the final tirzepatide/placebo dose and final Take Control session. These measures will assess changes in brain activity and autonomic responses to alcohol and food cues.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
46
Subcutaneous 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).
The 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.
Participants 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.
Drug Health Services, Royal Prince Alfred Hospital
Sydney, New South Wales, Australia
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.
Time frame: 12 weeks (measured at baseline, during the final 4 weeks of treatment [weeks 5 - 8], end of treatment [week 9], and follow-up [week 12]).
Number of drinks per drinking day consumed
Measured by Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels
Time frame: 12 weeks (weekly, from baseline visit to final follow-up visit at week 12)
Abstinent days
Measured by Timeline Follow Back
Time frame: 12 weeks (weekly, from baseline visit to final follow-up visit at week 12)
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.
Time frame: 12 weeks (weekly, from baseline visit to final follow-up visit at week 12)
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.
Time frame: 12 weeks (weekly, from baseline visit to final follow-up visit at week 12)
Proportion of participants with zero heavy drinking days
Proportion of participants with zero heavy drinking days measured by the TLFB.
Time frame: 4 weeks (weeks 5 to 8)
Body weight
Changes in body weight in kilograms (kg) from baseline to week 9 (end of treatment).
Time frame: Measured at baseline [week 0] and at end of treatment [week 9].
Waist circumference
Changes in waist circumference in centimetres (cm) from baseline to week 9 (end of treatment).
Time frame: Measured at baseline [week 0] and at end of treatment [week 9]
Blood pressure
Systolic and diastolic blood pressure measured weekly from baseline to end of treatment (week 8).
Time frame: 9 weeks (weekly, from baseline visit to final dose at week 8)
HbA1c
Clinical metabolic monitoring for cardiometabolic risk and drug safety. Measures glycated haemoglobin in a blood in percentages (%). Collected at screening (Week 0) and again at the end-of-treatment visit (Week 9). Additional testing may be conducted at follow up (week 12) if clinically indicated.
Time frame: 3 weeks (Measured at baseline [week 0] and at end of treatment [week 9], and week 12 if clinically indicated)
10-year ASCVD risk score
A cardiometabolic biomarker providing an estimation of 10-year atherosclerotic cardiovascular disease (ASCVD) risk score, based on pooled cohort equations. This is a composite risk score derived from traditional cardiovascular risk factors, including gender, age, race, total cholesterol, total HDL cholesterol, systolic BP, previous receipt of treatment for high blood pressure (if SBP \> 120 mmHg), diabetes and smoking status. This is used to provide a risk score of atherosclerotic cardiovascular disease.
Time frame: Measured at baseline [week 0] and end of treatment [week 9].
Frequency and severity of side effects/adverse events (AEs)
Safety outcomes including adverse events (AEs), serious adverse events (SAEs), and vital sign abnormalities, will be summarised descriptively across the study period. Feasibility outcomes (e.g., recruitment and retention rates, session attendance) will be analysed using proportions with corresponding 95% confidence intervals.
Time frame: 12 weeks (at each visit)
Number of treatment-related discontinuation
As a measure of safety, the number of treatment-related discontinuations will be measured.
Time frame: 12 weeks (at each visit)
Total cholesterol
Clinical metabolic monitoring for total cholesterol in millimoles per litre (mmol/L). Collected at screening (Week 0) and again at the end-of-treatment visit (Week 9). Additional testing may be conducted at follow up (week 12) if clinically indicated.
Time frame: 3 weeks (Measured at baseline [week 0] and at end of treatment [week 9], and week 12 if clinically indicated)
Triglycerides
Clinical metabolic monitoring for triglycerides in blood sample, measured via millimoles per litre (mmol/L) as a measure of cardiometabolic risk and drug safety. Collected at screening (Week 0) and again at the end-of-treatment visit (Week 9). Additional testing may be conducted at follow up (week 12) if clinically indicated.
Time frame: 3 weeks (Measured at baseline [week 0] and at end of treatment [week 9], and week 12 if clinically indicated)
Changes in Positive and Negative Mood States
Mood states before/after ketamine sessions assessed by PANAS (Positive and Negative Affect Schedule). This will be measured during neuroimaging and psychophysiology sessions. Used to measure an individual's emotional state, assessing two dimensions: Positive Affect (PA; captures feelings like enthusiasm and alertness), and Negative Affect (NA; measures distress and negative emotions like anger and anxiety).
Time frame: Week 1 (prior to dose 1) and at EOT (end of treatment/week 8)
Alcohol craving measure 2
As measured by the Penn Alcohol Craving Scale (PACS). 5-item self-report questionnaire that evaluates alcohol craving over the past week. Measures frequency, intensity, duration of craving, perceived control over drinking, and overall craving severity. Each item is rated on a 7-point Likert scale (0-6). Total scores range from 0 to 30, with higher scores indicating greater craving.
Time frame: 12 weeks - measured weekly from baseline (week 1) to outcomes/discharge (week 12)
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