A Phase 3, randomised, double-blind, parallel-group, event-driven, cardiovascular safety study with BI 456906 administered subcutaneously compared with placebo in participants with overweight or obesity with established cardiovascular disease (CVD) or chronic kidney disease, and/or at least two weight-related complications or risk factors for CVD

The primary objective of this study is to demonstrate the **non-inferiority** of survodutide compared with placebo. This is assessed by the hazard ratio based on a Cox regression for the time to the first occurrence of any of the adjudicated components of the primary composite endpoint. These components include cardiovascular (CV) death, non-fatal stroke, non-fatal myocardial infarction (MI), ischaemia-related coronary revascularisation, or heart failure events (HFE), collectively referred to as 5P-MACE. This objective is clinically relevant as it evaluates the cardiovascular safety of survodutide in individuals with overweight or obesity, who are at increased risk for cardiovascular events.

The secondary objectives are as follows:

• To demonstrate the non-inferiority of survodutide compared with placebo by means of the hazard ratio based on a Cox regression for time to first occurrence of any of the adjudicated components of the composite endpoint, defined as CV death, non-fatal stroke, or non-fatal MI (3P-MACE).
• To demonstrate the superiority of survodutide for the difference of adjusted mean for absolute change from baseline in systolic blood pressure (SBP) to Week 72.
• To demonstrate the superiority of survodutide for the difference of adjusted mean for absolute change from baseline in waist circumference, reflective of visceral fat, to Week 72.
• To demonstrate the superiority of survodutide for the difference of adjusted mean for absolute change from baseline to Week 72 in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) in trial participants with heart failure (HF) at baseline.
• To demonstrate the superiority of survodutide compared with placebo by means of the hazard ratio based on a Cox regression for time to first occurrence of any of the adjudicated components of the primary composite endpoint, defined as CV death, non-fatal stroke, non-fatal MI, ischaemia-related coronary revascularisation, or HFE (5P-MACE).

The clinical trial involves a total of **3458 participants** diagnosed with **obesity**. The study population includes both male and female subjects, aged 18 years and older, with a **Body Mass Index (BMI)** of at least 27 kg/m². Participants were selected based on the presence of established cardiovascular disease (CVD) or chronic kidney disease (CKD), or the presence of at least two weight-related complications or risk factors for CVD. The trial includes individuals from a vulnerable population, ensuring a comprehensive assessment of the intervention's impact across diverse health statuses. Lifestyle factors such as diet and physical activity were considered, although specific habits were not detailed. The selection criteria ensure a focus on individuals with significant health concerns related to obesity and its complications.

The clinical trial is a **randomized**, **double-blind**, parallel-group, event-driven study designed to evaluate the cardiovascular safety of **BI 456906** administered subcutaneously compared to placebo in participants with overweight or **obesity**. The trial targets individuals with established cardiovascular disease (CVD) or chronic kidney disease, and/or at least two weight-related complications or risk factors for CVD. The primary objective is to demonstrate the non-inferiority of **survodutide** compared with placebo by assessing the time to the first occurrence of any adjudicated components of the primary composite endpoint, which includes cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, ischemia-related coronary revascularization, or heart failure events (5P-MACE).

The trial is expected to commence recruitment on January 16, 2024, and conclude by April 2, 2026. Participants will be involved in the study for a maximum treatment period of 92 weeks. The study visits are structured as follows: an initial inclusion (screening) visit to assess eligibility based on criteria such as age, body mass index (BMI), and medical history related to CVD or chronic kidney disease. Subsequent visits will include regular follow-up assessments to monitor the safety and efficacy of the treatment, with specific evaluations at predetermined intervals. The end-of-study visit will finalize the participant's involvement, ensuring all necessary data is collected and any post-treatment care is addressed.

Participants may be withdrawn from the study early if they experience adverse events that compromise their safety, fail to adhere to the study protocol, or choose to withdraw consent. The trial will utilize a **solution for injection** form of the investigational product, administered via **subcutaneous use**. The study's design ensures rigorous monitoring and data collection to support the primary and secondary endpoints, which include various cardiovascular and metabolic health outcomes. The trial's methodology and procedures are aligned with regulatory standards to ensure the integrity and reliability of the results.

The clinical trial involves the administration of **BI 456906**, a **solution for injection** developed by Boehringer Ingelheim International. This experimental medication is administered via **subcutaneous use**. The active substance, **BI 456906**, is of protein origin and is not a paediatric formulation. The maximum treatment period for this medication is 4 weeks, with no specified maximum daily or total dose amount. The pharmaceutical form is consistent across all administrations, ensuring uniformity in the delivery method.

Another formulation of **BI 456906** is also used in the trial, with a maximum treatment period of 84 weeks. This formulation maintains the same pharmaceutical form, **solution for injection**, and is administered subcutaneously. The active substance remains the same, and the formulation is not intended for paediatric use. The dosing schedule and compliance are monitored to ensure adherence to the trial protocol.

A third formulation of **BI 456906** is included, with a maximum treatment period of 92 weeks. This formulation is identical in pharmaceutical form and administration route to the previous formulations. The active substance is consistent, and the formulation is not designed for paediatric use. The trial protocol includes measures to monitor participant compliance with the dosing schedule.

The trial also includes a **placebo** group, which serves as a comparator to the experimental treatments. The placebo is not specified in terms of pharmaceutical form or administration route, as it is intended to mimic the experimental treatments without containing the active substance. The use of a placebo is critical for assessing the efficacy and safety of **BI 456906** in the context of the trial's objectives.

The efficacy of the investigational product **survodutide** will be assessed in a Phase 3, randomized, double-blind, parallel-group, event-driven clinical trial. The primary endpoint for evaluating efficacy is the time to the first occurrence of any of the adjudicated components of the composite endpoint, which includes cardiovascular (CV) death, non-fatal stroke, non-fatal myocardial infarction (MI), ischaemia-related coronary revascularisation, or heart failure events (HFE), collectively referred to as 5P-MACE. This will be analyzed using a Cox regression model to determine the hazard ratio of survodutide compared to placebo.

Secondary endpoints include the time to the first occurrence of any components of the 3P-MACE (CV death, non-fatal stroke, or non-fatal MI), changes in systolic blood pressure (SBP), waist circumference, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) in participants with heart failure, and percentage change in body weight from baseline to Week 72. Additional secondary endpoints involve changes in diastolic blood pressure (DBP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hemoglobin A1c (HbA1c) levels, as well as the time to onset of type 2 diabetes mellitus (T2DM) in participants without T2DM at baseline.

Measurements for these endpoints will be collected at various time points, including baseline and Week 72, using validated scales and laboratory tests. The trial aims to demonstrate the non-inferiority of survodutide compared to placebo in terms of cardiovascular safety and efficacy in participants with overweight or obesity and established cardiovascular disease or chronic kidney disease, and/or at least two weight-related complications or risk factors for cardiovascular disease.