Evaluation of Long-term Efficacy and Safety of Cagrilintide and Semaglutide Combination Therapy Versus Placebo in Obesity Management

The primary objective of this study is to confirm the **superiority** of CagriSema s.c. 2.4 mg/2.4 mg compared to placebo, administered once weekly, as an adjunct to a reduced-calorie diet and increased physical activity, in achieving body weight reduction in participants with **obesity**. This is clinically relevant as effective weight management is crucial in reducing obesity-related health risks and improving overall health outcomes.

Secondary objectives include:

• Confirming the superiority of CagriSema over placebo on cardiometabolic parameters, specifically waist circumference, waist-to-height ratio, and systolic blood pressure.
• Comparing the effects on lipids, body mass index (BMI), glucose metabolism, glycaemic control, and other cardiovascular risk factors.
• Assessing improvements in pre-existing obesity-related complications and inflammation.
• Evaluating changes in body composition and clinical outcome assessments, including physical functioning, weight-related functioning, limitations in daily activities due to excess weight, and control of eating.
• Comparing the safety and tolerability of CagriSema versus placebo, and versus a dose tapering algorithm, as well as investigating safety and tolerability according to a flexible escalation regime in the former placebo group.

The clinical trial involves a total of **240 participants** diagnosed with **obesity**. The study population includes both male and female subjects, aged 18 years and older, with a **BMI** of 35.0 kg/m² or higher. Participants were selected based on their ability to provide informed consent and their willingness to adhere to a reduced-calorie diet and increased physical activity regimen. The trial does not include any vulnerable populations. The selection criteria ensure a diverse representation of adults who are generally in stable health, aside from their obesity condition. The trial aims to evaluate the efficacy of CagriSema in promoting weight reduction compared to a placebo, emphasizing lifestyle modifications as part of the intervention. The sponsor has not provided additional information regarding specific lifestyle habits or other health conditions of the participants.

The clinical trial is designed to evaluate the long-term efficacy and safety of a combination therapy involving **cagrilintide** and **semaglutide** in participants with obesity. This is a Phase III, randomized, double-blind, placebo-controlled trial. The trial aims to confirm the superiority of the combination therapy over placebo in reducing body weight when used as an adjunct to a reduced-calorie diet and increased physical activity. The trial is expected to commence recruitment on February 10, 2025, and conclude by November 17, 2028.

Participants will be randomly assigned to receive either the active treatment or placebo, administered via a prefilled auto-injector for subcutaneous injection once weekly. The trial will include several study visits, beginning with a screening visit to assess eligibility based on criteria such as age (≥18 years) and body mass index (BMI ≥35.0 kg/m²). Eligible participants will then proceed to the baseline visit, where they will be randomized and receive their first dose of the investigational product.

Subsequent follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. These visits will include assessments of body weight, waist circumference, blood pressure, and various metabolic parameters. The primary endpoint is the relative change in body weight, while secondary endpoints include achieving specific weight reduction targets and improvements in metabolic health markers.

The expected duration of participant involvement is up to 140 weeks, depending on the treatment group assignment. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the overall impact of the treatment on the participants' health outcomes.

The clinical trial involves the administration of several experimental medications, each formulated as a **solution for injection**. The primary experimental treatment is a combination of **cagrilintide** and **semaglutide**, both synthetically produced proteins. The trial includes multiple dosage formulations of this combination, each delivered via a prefilled auto-injector pen, known as the DV3384 pen-injector. This device is designed for single-patient, single-dose use, facilitating once-weekly subcutaneous injections through the same needle. The treatment period varies, with a maximum duration of 56 to 140 days, depending on the specific formulation.

The first formulation, "Cagrilintide B 6.8 mg/mL + semaglutide I 3.4 mg/mL DV3384," is administered subcutaneously once weekly. The second formulation, "Cagrilintide B 1.0 mg/mL + semaglutide I 0.5 mg/mL DV3384," follows the same administration route and frequency. Similarly, the third formulation, "Cagrilintide B 4.0 mg/mL + semaglutide I 2.0 mg/mL DV3384," is also administered subcutaneously once weekly. The fourth formulation, "Cagrilintide B 2.0 mg/mL + semaglutide I 1.0 mg/mL DV3384," and the fifth formulation, "Cagrilintide B 9.6 mg/mL + semaglutide I 4.8 mg/mL DV3384," are administered in the same manner, with the latter having a longer maximum treatment period of 140 days.

In addition to the experimental treatments, a **placebo** is utilized in the study, identified as the "Placebo/placebo DV3384 pen-injector." This placebo is intended to mimic the administration process of the active treatments, ensuring blinding and maintaining the integrity of the trial. The placebo is administered using the same DV3384 pen-injector device, although it contains no active substances.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the once-weekly administration protocol. The trial aims to evaluate the long-term efficacy and safety of these formulations in participants with obesity, with the primary objective of confirming the superiority of the active treatment over the placebo in terms of body weight reduction.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the relative change in body weight, which will be measured to evaluate the effectiveness of the treatment. Secondary endpoints include a variety of parameters such as the achievement of specific body weight reduction thresholds (≥ 20%, ≥ 25%, and ≥ 30%), changes in waist circumference, waist-to-height ratio, and systolic blood pressure (SBP). Additionally, the trial will assess changes in lipid profiles, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, triglycerides, free fatty acids, and non-HDL cholesterol.

Further secondary endpoints involve changes in **Body Mass Index (BMI)**, glycated hemoglobin (HbA1c), and fasting plasma glucose (FPG), as well as the achievement of specific glycemic targets. The development of type 2 diabetes (T2D) according to the American Diabetes Association (ADA) guidelines and changes in the ACC/AHA 10-year ASCVD risk score will also be evaluated. The trial will utilize dual-energy X-ray absorptiometry (DXA) to measure changes in total fat mass, visceral fat mass, and lean body mass. Patient-reported outcomes will be assessed using the SF-36 Physical Functioning score, IWQOL-Lite-CT, Impact of Weight on Daily Activities Questionnaire (IWDAQ), and Control of Eating Questionnaire (CoEQ). The number of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) will be recorded to evaluate safety alongside efficacy.