Randomized Study of Cagrilintide + Semaglutide Combination vs Semaglutide Monotherapy for Weight Loss in Adults with Obesity (± Type 2 Diabetes)

The primary objective is to demonstrate the superiority of the combination of semaglutide plus cagrilintide administered at a dose of 0 mg/0 mg compared with semaglutide plus cagrilintide 2.4 mg/2.4 mg and semaglutide alone on body weight reduction in participants with obesity (with or without type 2 diabetes) when used as adjunct to a reduced‑calorie diet and increased physical activity.

Secondary objectives include:

• Comparison of the two combination regimens on blood pressure and cardiometabolic biomarkers;
• Assessment of impact on quality of life;
• Evaluation of effects on glucose metabolism;
• Comparison of safety and tolerability between the treatment arms.

The trial enrolled a total of 1,360 adult participants aged 18 years and older, inclusive of all gender identities. All subjects had a body mass index (BMI) of at least 35 kg/m² and were classified as having obesity, with sub‑groups either without type 2 diabetes (HbA1c < 6.5 %) or with type 2 diabetes (HbA1c < 10 %). Participants were selected on the basis of these BMI and glycemic criteria, and were required to be generally healthy aside from the specified metabolic condition. The study population was instructed to follow a reduced‑calorie diet and to increase physical activity as part of the intervention protocol.

The study is a Phase III, multicenter, randomized, double‑blind, controlled trial comparing two subcutaneous dose regimens of the investigational combination cagrilintide‑semaglutide with a subcutaneous semaglutide comparator in adults with obesity (BMI ≥ 35 kg/m²) with or without type 2 diabetes. Eligible participants undergo a screening visit to confirm inclusion criteria, followed by randomization and initiation of weekly injections. Subsequent study visits occur at weeks 4, 12, 24, 36, and 52, during which efficacy (relative change in body weight, BMI, waist circumference, metabolic parameters) and safety assessments (adverse events, laboratory values) are performed. The final end‑of‑study visit is scheduled at week 52, marking the completion of approximately one year of participant involvement, with the overall trial recruitment period spanning from May 2026 to April 2028. Participants may be withdrawn early for predefined reasons such as serious adverse events, pregnancy, non‑adherence to the investigational product or protocol, or voluntary withdrawal of consent, and data up to the point of discontinuation will be included in the analysis.

The investigational product, identified as cagrilintide + semaglutide, is supplied as a solution for injection for subcutaneous administration. Two dose strengths are evaluated: 0 mg/0 mg and 2.4 mg/2.4 mg of the combined active substances, delivered once weekly. The formulation contains both cagrilintide and semaglutide in a single injection. Dosing is titrated according to the assigned treatment arm, and participants receive instructions to self‑administer the injection on the same day each week. Compliance is monitored through injection logs, electronic diaries, and periodic review of returned medication containers.

The comparator arm uses semaglutide alone, also provided as a solution for injection for subcutaneous use. The assigned dose is 0 mg administered once weekly, consistent with the study’s dosing schedule. Participants receive the same reduced‑calorie diet and increased‑physical‑activity recommendations as the investigational arms. Adherence to the weekly injection schedule is tracked via the same compliance measures employed for the test product.

All participants are instructed to maintain a standardized lifestyle intervention targeting weight reduction in the context of obesity with or without type 2 diabetes. Monitoring of dosing intervals, injection technique, and any missed doses is performed at each scheduled visit.

Efficacy will be evaluated primarily by the relative change in body weight from baseline to the end of treatment. Secondary efficacy assessments include additional measures of weight and metabolic outcomes, such as change in body mass index (BMI), achievement of weight‑loss thresholds of ≥20 %, ≥25 % and ≥30 % relative to baseline, and achievement of BMI categories < 30 kg/m², < 27 kg/m², and normal BMI (18.5 ≤ BMI < 25). Anthropometric parameters comprise change in waist circumference and attainment of a waist‑to‑height ratio < 0.53. Lipid profile changes will be expressed as ratios to baseline for total cholesterol, HDL‑C, LDL‑C, VLDL‑C, triglycerides, free fatty acids, and non‑HDL cholesterol. Patient‑reported outcomes will be captured using the SF‑36v2 physical function scale and the IWQOL‑Lite‑CT physical function instrument. Glycemic control will be assessed by change in HbA1c and the proportion of participants achieving HbA1c < 6.5 % (sub‑study 2) or normal HbA1c < 5.7 %.