Evaluation of Semaglutide as an Adjunctive Therapy for Metabolic Control in Patients with Schizophrenia Spectrum Disorders on Antipsychotics

The primary objective of this study is to evaluate the effect of **semaglutide** administered subcutaneously at a dose of 2.4 mg once weekly, compared to a placebo, on body weight in patients with schizophrenia spectrum disorders who are using antipsychotic medications. These patients have a body mass index (BMI) of 30 kg/m² or higher, or a BMI of 27 kg/m² or higher with prediabetes, as determined by fasting plasma glucose (FPG) levels between 5.6 and 6.9 mmol/l and/or HbA1c levels between 39-47 mmol/mol on two separate occasions at least 24 hours apart. This objective is clinically relevant as it addresses the challenge of managing weight gain, a common side effect of antipsychotic treatment, which can exacerbate metabolic disorders and increase the risk of cardiovascular diseases.

The secondary objectives include comparing the effect of semaglutide on several metabolic and health parameters: - Fasting blood glucose, HbA1c, triglycerides, and cholesterol levels - Time until discontinuation of antipsychotic drug treatment - Perceived body image - Cognition - Economic outcomes - Body fat measures - Heart rate and blood pressure - Development of type 2 diabetes mellitus - Depressive symptoms. These secondary objectives aim to provide a comprehensive understanding of the broader impacts of semaglutide on metabolic control and overall health in this patient population.

The clinical trial focuses on **metabolic control** in patients using antipsychotic medications, specifically targeting individuals diagnosed with schizophrenia spectrum disorders. The study population comprises both male and female participants aged between 18 and 70 years. Participants are required to have a **body mass index (BMI)** of 30 kg/m² or higher, or a BMI of 27 kg/m² or higher with the presence of prediabetes, as determined by fasting plasma glucose levels between 5.6 and 6.9 mmol/l and/or HbA1c levels between 39-47 mmol/mol. The trial does not involve a vulnerable population. Participants must have been using antipsychotic drugs for at least three weeks prior to the study and have a treatment plan for continued use over the next six months. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is representative of individuals with the specified medical conditions and lifestyle factors relevant to the trial's objectives.

The clinical trial is designed as an **interventional**, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy of **semaglutide** as an add-on treatment for metabolic control in patients using antipsychotic medications. The trial aims to compare the effects of semaglutide 2.4 mg administered subcutaneously once weekly against a placebo in patients diagnosed with schizophrenia spectrum disorders who have a body mass index (BMI) of 30 kg/m² or higher, or a BMI of 27 kg/m² or higher with prediabetes. The primary endpoint is the change in body weight from baseline to week 26. Secondary endpoints include changes in HbA1c, fasting plasma glucose, fasting serum insulin, lipids, cognition, and quality of life, among others.

The trial is expected to last until August 31, 2027, with participant recruitment starting on October 1, 2023. Participants will be involved in the study for a maximum of 26 weeks. The study visits are structured as follows: an initial screening visit to determine eligibility, followed by baseline assessments at week 0. Subsequent follow-up visits will occur at regular intervals to monitor progress and collect data on the primary and secondary endpoints. The end-of-study visit will take place at week 26, where final assessments will be conducted.

Inclusion criteria require participants to be between 18 and 70 years old, provide informed consent, and meet specific BMI and prediabetes criteria. Exclusion criteria are not explicitly detailed in the provided data. Participants may be terminated early from the study if they withdraw consent, experience adverse effects, or if the investigator deems it necessary for safety reasons. The trial is categorized as a phase III study, focusing on a patient population previously excluded from earlier studies conducted before drug approval.

The clinical trial involves the administration of **semaglutide**, marketed under the name Wegovy, as the experimental medication. Wegovy is provided as a **solution for injection** in a pre-filled pen, with a concentration of 2.4 mg. The active substance, semaglutide, is a GLP-1 agonist of protein origin. The medication is administered via **subcutaneous injection** once weekly. The maximum daily dose is 0.34 mg, with a total maximum dose of 37.76 mg over the treatment period. The trial is designed to assess the efficacy of semaglutide in patients with schizophrenia spectrum disorders and a BMI of 30 kg/m² or higher, or a BMI of 27 kg/m² or higher with prediabetes. The treatment period extends up to 26 weeks.

The study also includes a **placebo** that matches the active treatment in appearance and administration method. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the active treatment, via subcutaneous injection, and follows the same dosing schedule. This allows for a direct comparison of the effects of semaglutide against the placebo, providing a robust assessment of the drug's efficacy in the target population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in body weight from baseline to week 26 of the study. This will be measured to evaluate the effect of semaglutide as an add-on treatment for metabolic control in patients with schizophrenia spectrum disorders.

Secondary endpoints include changes from baseline at week 0 to week 26 in several metabolic and cognitive parameters. These include **HbA1c** levels, fasting plasma glucose (FPG), fasting serum insulin, insulin C-peptide, and lipid profiles such as total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, free fatty acids, and triglycerides. Cognitive changes will be assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). Additionally, the time until discontinuation of antipsychotic drug treatment will be evaluated through interviews and serum level measurements.

Other secondary endpoints involve changes in the Stunkard scale, economic outcomes assessed through incremental cost-effectiveness ratio (ICER) and cost-utility analysis, and quality of life changes measured by the Manchester Short Assessment of Quality of Life (MANSA). Further assessments include changes in waist and hip circumference, waist-to-hip ratio, heart rate, blood pressure, the proportion of participants with type 2 diabetes mellitus (T2DM) at week 26, and ratings on the Calgary Depression Scale for Schizophrenia (CDSS). These efficacy parameters will be collected and analyzed at specified timepoints, primarily from baseline to week 26, using validated scales and laboratory tests.