Evaluation of the Efficacy and Safety of Cagrilintide and Semaglutide in Combination for Weight Reduction in Patients with Overweight or Obesity

The primary objective of this study is to confirm the **superiority** of CagriSema in reducing body weight compared to placebo, when used as an adjunct to a reduced-calorie diet and increased physical activity in participants with overweight or obesity. This is clinically relevant as effective weight management is crucial in reducing the risk of comorbidities associated with obesity, such as cardiovascular disease and type 2 diabetes.

Secondary objectives include: - Confirming the superiority of CagriSema versus placebo in achieving ≥20%, ≥25%, and ≥30% weight reduction. - Confirming the superiority of CagriSema versus cagrilintide and semaglutide on body weight. - Confirming the superiority of CagriSema versus placebo on waist circumference, systolic blood pressure, and physical functioning. - Comparing the safety and tolerability of CagriSema versus placebo, semaglutide, and cagrilintide.

The clinical trial involves a total of **2314 participants** diagnosed with **overweight and obesity**. The study population includes both male and female subjects, aged 18 years and older. Participants were selected based on specific criteria, including a **BMI** of 30.0 kg/m² or higher, or a BMI of 27.0 kg/m² or higher with at least one obesity-related complication such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. The trial does not include a vulnerable population. Participants are required to adhere to a reduced-calorie diet and increased physical activity as part of the study protocol. The selection process ensures a diverse representation of individuals who meet the outlined health and lifestyle criteria.

The clinical trial is designed to evaluate the **efficacy** and safety of cagrilintide in combination with semaglutide, administered subcutaneously once weekly, in participants with overweight or obesity. This is a randomized, double-blind, placebo-controlled trial, which aims to confirm the superiority of the combination therapy over placebo as an adjunct to a reduced-calorie diet and increased physical activity. The trial is expected to commence recruitment on November 3, 2023, and conclude by October 19, 2026. Participants will be involved in the study for the duration of the trial, with specific visits scheduled to monitor progress and safety.

The sequence of study visits includes an initial screening visit to assess eligibility based on criteria such as age, **body mass index (BMI)**, and the presence of obesity-related complications. Eligible participants will be randomized to receive either the active treatment or placebo. Follow-up visits will occur at regular intervals to evaluate primary endpoints, including relative change in body weight and achievement of at least 5% weight reduction. Secondary endpoints will assess further weight reduction milestones, changes in waist circumference, systolic blood pressure, and quality of life scores, as well as the incidence of treatment-emergent adverse events.

The end-of-study visit will mark the completion of the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment's impact. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or choose to withdraw consent. The trial's methodology ensures rigorous data collection and analysis to support the evaluation of the investigational treatment's safety and efficacy in the target population.

The clinical trial involves the administration of **CagriSema**, a combination of cagrilintide B and semaglutide I, both synthetically produced proteins. The experimental medication is delivered using the DV3384 pen-injector, a single patient, single dose, prefilled auto-injector. This device is designed for once-weekly subcutaneous injection, allowing both active substances to be administered through the same needle. The pharmaceutical form of the medication is a prefilled auto-injector, and the route of administration is subcutaneous. The frequency of administration is once weekly. Participant compliance is monitored through the use of the prefilled auto-injector, ensuring accurate dosing and adherence to the treatment schedule.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is administered using the same DV3384 pen-injector, which is also a single patient, single dose, prefilled auto-injector intended for once-weekly subcutaneous injection. The placebo is used to evaluate the efficacy and safety of the experimental treatment by providing a comparator for body weight reduction outcomes. The administration schedule and monitoring for the placebo group are identical to those of the experimental group, ensuring consistency in the trial protocol.

The efficacy of the clinical trial investigating the combination of cagrilintide and semaglutide (CagriSema) in participants with overweight or obesity will be assessed using both primary and secondary endpoints. The primary endpoints include the relative change in body weight and the achievement of a weight reduction of at least 5%. Secondary endpoints encompass a broader range of measures, including the achievement of weight reductions of 20%, 25%, and 30%, changes in waist circumference, changes in systolic blood pressure, and improvements in quality of life as measured by the Impact of Weight on Quality Of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score and the SF-36 V2 Health Survey Acute (SF-36v2) Physical Functioning score. Additionally, the number of Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) will be recorded.

The trial will utilize a single patient, single dose, prefilled auto-injector, the DV3384 pen-injector, for the administration of the investigational products. This device is intended for once-weekly subcutaneous injections. The trial is designed to confirm the superiority of CagriSema over placebo as an adjunct to a reduced-calorie diet and increased physical activity. The trial is categorized as a phase III study, focusing on the safety and efficacy of the treatment in the specified population. The estimated recruitment start date is November 3, 2023, with an estimated end date of October 19, 2026.