Tirzepatide Combined With Cognitive-Behavioural Therapy (CBT) for Adults With Alcohol Use Disorder (AUD) and Overweight/Obesity (OOB)

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 Покажи пълното описание...

Inclusion Criteria: 1. Aged 21 to 75 years 2. Meet DSM-5 criteria for alcohol use disorder (AUD) with at least moderate severity (≥4 symptoms in the past year) 3. Have an average daily alcohol consumption of: * ≥60g ethanol/day for men * ≥40g ethanol/day for women (based on the 28 days prior to the baseline visit) 4. Body mass index (BMI) ≥27 kg/m² 5. Currently motivated to reduce or stop drinking but not engaged in formal AUD treatment 6. Able and willing to attend weekly clinic visits and complete all study procedures 7. Fluent in English and able to provide informed consent 8. Stable housing situation (not transient or homeless) Exclusion Criteria: 1. Past-year DSM-5 diagnosis of another substance use disorder (except nicotine or mild cannabis use disorder) 2. Recent (past 30 days) self-reported illicit drug use (excluding cannabis), or a positive urine drug screen for non-cannabis substances 3. History of significant alcohol withdrawal, defined by: * History of seizure, delirium tremens, or * Hospitalisation for withdrawal, or * CIWA-Ar score \>9, or * PAWS score \>4 at screening 4. Currently engaged in pharmacological or behavioral treatment for AUD, or prior engagement within the past 3 months 5. History or current diagnosis of: * Type 1 or Type 2 diabetes * Diabetic complications (e.g. retinopathy) * HbA1c ≥6.5% at screening 6. Significant psychiatric illness, including: * Current active suicidal ideation (per C-SSRS) * Lifetime history of psychosis or bipolar disorder * Unstable depression or anxiety interfering with daily functioning 7. Chronic or acute pancreatitis 8. Significant liver disease or abnormal liver function tests (ALT, AST, ALP, bilirubin \>3× ULN) 9. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) type I/II 10. Estimated glomerular filtration rate (eGFR) \<30 mL/min 11. Recent significant weight loss (\>5% of body weight in past 30 days) 12. Use of any weight loss medication (e.g., orlistat, bupropion-naltrexone) or AUD medication (e.g., naltrexone, acamprosate, topiramate, varenicline) in the past 3 months 13. Use of tirzepatide or any GLP-1 receptor agonist in the past 6 months 14. Pregnant or breastfeeding, or not using effective contraception (females of childbearing potential) 15. Inability to attend weekly visits due to work/travel/schedule conflicts 16. Participation in another clinical trial involving an investigational product 17. Shared household with a current or past participant in this trial 18. Scheduled for surgery requiring anaesthesia within 90 days of enrolment that would interfere with participation or follow-up 19. History of muscle wasting, bone disorders (e.g. sarcopenia) 20. Active gastrointestinal conditions that could interfere with treatment (e.g., severe GERD) 21. Uncontrolled hypertension, recent heart attack or stroke (within 6 months) Extra Exclusion criteria for Those Participants Agreeing to Participate in Neuroimaging \& Psychophysiology Tasks: 22. Presence of any MRI-incompatible metal implants or devices, including pacemakers, aneurysm clips, insulin pumps, or cochlear implants 23. History of brain surgery or penetrating head trauma 24. Prior occupation as a machinist, welder, or metal worker (due to risk of metal fragments) 25. Non-removable piercings or dental hardware that would interfere with MRI 26. History of claustrophobia likely to interfere with scanning compliance aa. Neurological disorders (e.g., epilepsy, multiple sclerosis) likely to confound neuroimaging data bb. Inability to lie still or tolerate MRI procedures cc. Patient weighting over 159kg (MRI scan limit) dd. Any other condition or medication judged by the investigator to preclude safe participation