Tirzepatide Combined With Cognitive-Behavioural Therapy (CBT) for Adults With Alcohol Use Disorder (AUD) and Overweight/Obesity (OOB)
Overview
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- South West Sydney Local Health District
- Enrollment
- 46
- Locations
- 1
- Primary Endpoint
- Heavy Drinking Days
Overview
Brief Summary
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.
Detailed Description
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:
- 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.
- 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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Masking Description
Randomisation will be carried out using a computer-generated list prepared by an independent biostatistician who is not involved in participant recruitment or assessment. The randomisation schedule will be securely uploaded to REDCap and accessible only to unblinded pharmacy staff responsible for study drug dispensing. Investigators enrolling participants will remain blinded and will not have access to the allocation list at any stage. Unblinding will only be permissible in the event of a medical emergency where knowledge of the participant's treatment assignment is essential to inform clinical care. Such unblinding will be conducted by the study pharmacist and must be documented and justified in the participant's trial record.
Eligibility Criteria
- Ages
- 21 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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)
- •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)
- •Body mass index (BMI) ≥27 kg/m²
- •Currently motivated to reduce or stop drinking but not engaged in formal AUD treatment
- •Able and willing to attend weekly clinic visits and complete all study procedures
- •Fluent in English and able to provide informed consent
- •Stable housing situation (not transient or homeless)
Exclusion Criteria
- •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 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
- •Currently engaged in pharmacological or behavioral treatment for AUD, or prior engagement within the past 3 months
- •History or current diagnosis of:
- •Type 1 or Type 2 diabetes
Arms & Interventions
Tirzepatide: subcutaneous administration of Tirzepatide plus CBT ("Take Control" program)
1 x Screening, Baseline Clinical Assessments, Neuroimaging (T0) and Psychophysiology, Randomisation (Visit 1, Week 0)
From Dose 1 (Visit 2, week 1) to Dose 4 (Visit 5, week 4), with "Take Control" CBT module: 2.5mg Tirzepatide dose administration, and a 15-20 minutes computer-based CBT module.
From Dose 5 (Visit 6 , week 5) to Dose 8 (Visit 9, week 8) with "Take Control" CBT module: 5.0mg dose administration (unless contraindicated by study physician), and a 15-20 minutes computer-based CBT module.
Neuroimaging substudy (Visit 10, week 8): After the final medication and CBT module, participants complete final neuroimaging timepoint (T1).
End-of-treatment (Visit 11, week 9 & Visit 12, week 12): One and four weeks after the last dose and neuroimaging, participants will complete psychophysiology assessments using the same tasks as baseline.
Intervention: Tirzepatide (Drug)
Tirzepatide: subcutaneous administration of Tirzepatide plus CBT ("Take Control" program)
1 x Screening, Baseline Clinical Assessments, Neuroimaging (T0) and Psychophysiology, Randomisation (Visit 1, Week 0)
From Dose 1 (Visit 2, week 1) to Dose 4 (Visit 5, week 4), with "Take Control" CBT module: 2.5mg Tirzepatide dose administration, and a 15-20 minutes computer-based CBT module.
From Dose 5 (Visit 6 , week 5) to Dose 8 (Visit 9, week 8) with "Take Control" CBT module: 5.0mg dose administration (unless contraindicated by study physician), and a 15-20 minutes computer-based CBT module.
Neuroimaging substudy (Visit 10, week 8): After the final medication and CBT module, participants complete final neuroimaging timepoint (T1).
End-of-treatment (Visit 11, week 9 & Visit 12, week 12): One and four weeks after the last dose and neuroimaging, participants will complete psychophysiology assessments using the same tasks as baseline.
Intervention: Take Control CBT Module (Behavioral)
Placebo: subcutaneous administration of placebo plus CBT ("Take Control" program)
1 x Screening, Baseline Clinical Assessments, Neuroimaging (T0) and Psychophysiology, Randomisation (Visit 1, Week 0)
From Dose 1 (Visit 2, week 1) to Dose 4 (Visit 5, week 4), with "Take Control" CBT module: matched placebo dose administration OR matched placebo, and a 15-20 minutes computer-based CBT module.
From Dose 5 (Visit 6 , week 5) to Dose 8 (Visit 9, week 8) with "Take Control" CBT module: matched placebo administration, and a 15-20 minutes computer-based CBT module.
Neuroimaging substudy (Visit 10, week 8): After the final medication and CBT module, participants complete final neuroimaging timepoint (T1).
End-of-treatment (Visit 11, week 9 & Visit 12, week 12): One and four weeks after the last dose and neuroimaging, participants will complete psychophysiology assessments using the same tasks as baseline.
Intervention: Take Control CBT Module (Behavioral)
Placebo: subcutaneous administration of placebo plus CBT ("Take Control" program)
1 x Screening, Baseline Clinical Assessments, Neuroimaging (T0) and Psychophysiology, Randomisation (Visit 1, Week 0)
From Dose 1 (Visit 2, week 1) to Dose 4 (Visit 5, week 4), with "Take Control" CBT module: matched placebo dose administration OR matched placebo, and a 15-20 minutes computer-based CBT module.
From Dose 5 (Visit 6 , week 5) to Dose 8 (Visit 9, week 8) with "Take Control" CBT module: matched placebo administration, and a 15-20 minutes computer-based CBT module.
Neuroimaging substudy (Visit 10, week 8): After the final medication and CBT module, participants complete final neuroimaging timepoint (T1).
End-of-treatment (Visit 11, week 9 & Visit 12, week 12): One and four weeks after the last dose and neuroimaging, participants will complete psychophysiology assessments using the same tasks as baseline.
Intervention: Placebo (Other)
Outcomes
Primary Outcomes
Heavy Drinking Days
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]).
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.
Secondary Outcomes
- Proportion of participants with zero heavy drinking days(4 weeks (weeks 5 to 8))
- Number of drinks per drinking day consumed(12 weeks (weekly, from baseline visit to final follow-up visit at week 12))
- Alcohol Craving(12 weeks (weekly, from baseline visit to final follow-up visit at week 12))
- Abstinent days(12 weeks (weekly, from baseline visit to final follow-up visit at week 12))
- Waist circumference(Measured at baseline [week 0] and at end of treatment [week 9])
- Blood pressure(9 weeks (weekly, from baseline visit to final dose at week 8))
- Total cholesterol(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(Week 1 (prior to dose 1) and at EOT (end of treatment/week 8))
- Alcohol craving measure 2(12 weeks - measured weekly from baseline (week 1) to outcomes/discharge (week 12))
- WHO drinking risk level scale.(12 weeks (weekly, from baseline visit to final follow-up visit at week 12))
- Body weight(Measured at baseline [week 0] and at end of treatment [week 9].)
- 10-year ASCVD risk score(Measured at baseline [week 0] and end of treatment [week 9].)
- HbA1c(3 weeks (Measured at baseline [week 0] and at end of treatment [week 9], and week 12 if clinically indicated))
- Frequency and severity of side effects/adverse events (AEs)(12 weeks (at each visit))
- Number of treatment-related discontinuation(12 weeks (at each visit))
- Triglycerides(3 weeks (Measured at baseline [week 0] and at end of treatment [week 9], and week 12 if clinically indicated))
Investigators
Kirsten Morley BPsych MPH PhD
Professor
South West Sydney Local Health District