Evaluation of Tirzepatide on Alcohol Consumption and Reward Processing in Patients with Schizophrenia and Alcohol Use Disorder

The primary objective of this study is to evaluate the effects of **tirzepatide** compared to placebo on alcohol consumption in patients diagnosed with **schizophrenia** and **alcohol use disorder**. This is clinically relevant as it explores the potential of tirzepatide, a medication primarily used for glucose regulation, in addressing comorbid conditions that significantly impact patient health and quality of life. The study aims to provide insights into whether tirzepatide can reduce alcohol intake, which is a critical factor in managing these patients' overall health and treatment outcomes.

The clinical trial involves participants diagnosed with **schizophrenia** and **alcohol use disorder**. The study population includes both male and female subjects, aged between 18 and 70 years. Participants are required to have a Body Mass Index (BMI) of 23 kg/m² or higher and must have experienced heavy alcohol consumption, defined as four or more heavy drinking days within a consecutive 21-day period during the 28 days preceding the baseline evaluation. The trial population was selected based on specific diagnostic criteria, including an Alcohol Use Disorder Identification Test (AUDIT) score greater than 15. The study includes a vulnerable population, and informed consent is a prerequisite for participation. The sponsor has not provided information regarding the total number of participants.

The clinical trial is designed to evaluate the effects of **tirzepatide** compared to placebo on alcohol consumption in patients diagnosed with schizophrenia and alcohol use disorder. This is a randomized, double-blind, placebo-controlled trial conducted over a period of 26 weeks. The trial will involve multiple study visits, beginning with an inclusion visit where participants will be screened for eligibility based on criteria such as age, diagnosis, and alcohol consumption patterns. Participants must provide informed consent and meet specific inclusion criteria, including a diagnosis of alcohol dependence and schizophrenia spectrum disorder, an Alcohol Use Disorder Identification Test (AUDIT) score greater than 15, and a body mass index (BMI) of 23 kg/m² or higher.

Following the inclusion visit, participants will be randomly assigned to receive either tirzepatide or a placebo, administered subcutaneously using a pre-filled pen. The primary endpoint is the change in alcohol consumption, specifically the percentage change in heavy drinking days after 16 weeks of treatment, adjusted for baseline values. Secondary endpoints include changes in total alcohol consumption, alcohol craving scores, and various health parameters over 16 and 26 weeks. Study visits will occur at baseline, 16 weeks, and 26 weeks to assess these endpoints using validated methods such as the Timeline Followback (TLFB) method and the Penn Alcohol Craving Scale (PACS).

The expected length of participant involvement is up to 26 weeks, with conditions for early termination including withdrawal of consent or adverse events. The trial aims to provide insights into the potential of tirzepatide as a treatment for reducing alcohol intake in this patient population, with the estimated recruitment start date set for March 1, 2025, and an estimated end date of December 31, 2028. The trial is categorized as Phase 4, exploring a new indication for an existing product with marketing authorization.

The clinical trial involves the administration of **tirzepatide**, an investigational medication, in various dosages. Tirzepatide is provided as a **solution for injection** in a pre-filled pen, known commercially as Mounjaro. The available dosages for this trial include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg per dose. Each dosage is administered subcutaneously using the KwikPen device. The maximum daily dose is 2.14 mg, with a total maximum dose of 240 mg over a treatment period of up to 26 weeks. The active substance, tirzepatide, is a protein-based compound, and its administration is intended to evaluate its effects on alcohol consumption in patients with schizophrenia and alcohol use disorder.

In addition to the experimental medication, the trial includes the use of **sodium chloride** as a placebo. Sodium chloride is provided as a solution for infusion, specifically in pre-filled saline syringes (BD PosiFlush™, BD Worldwide) containing 3 ml each. The placebo is administered via subcutaneous injection, with a maximum daily dose of 0.43 ml and a total maximum dose of 72 ml over a 24-week period. The inclusion of sodium chloride serves as a comparator to assess the efficacy of tirzepatide in the study population.

The efficacy of **tirzepatide** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the change in alcohol consumption, specifically measured as a percent change in heavy drinking days after 16 weeks of treatment with tirzepatide or placebo. This will be adjusted for baseline values and recorded using the validated Timeline-Follow-Back (TLFB) method.

Secondary endpoints will include a variety of measures to assess changes from baseline to after 16 weeks and 26 weeks of treatment. These measures include total alcohol consumption, number of days without alcohol, and World Health Organisation (WHO) alcohol risk level, all measured using the TLFB method. Additionally, changes in alcohol craving scores will be evaluated using the Penn Alcohol Craving Scale (PACS), and changes in Alcohol Use Disorders Identification Test (AUDIT) and Drug Use Disorders Identification Test (DUDIT) scores will be recorded.

Further assessments will include changes in quality of life using the Schizophrenia Quality of Life Scale (SQLS), Clinical Global Impression Severity Scale (CGI-S), and Global Assessment of Psychosocial Disability (GAPD). Symptom severity of schizophrenia will be measured using the six-item Positive and Negative Syndrome Scale (PANSS-6). Other parameters include changes in the Patient Health Questionnaire (PHQ-9) score, smoking habits using the Fagerström Test for Nicotine Dependence, and various blood parameters such as GGT, ALAT, MCV, and phosphatidyl ethanol (PEth) levels.

Additional measures will assess changes in body weight, waist circumference, blood pressure, pulse, glycemic parameters (HbA1c), risk of liver fibrosis using the FIB-4 index, and proteomics. For a subgroup of participants, fMRI will be conducted to evaluate changes in BOLD signals in response to alcohol cues and resting state fMRI. Changes in blood cotinine levels, average number of cigarettes smoked per day, and preferred substance of use will also be monitored. Qualitative interviews will be conducted for a subgroup to evaluate differences in trial participation experiences. Biomarkers of recent cannabis exposure and changes in drug use frequency will also be assessed.