A Study to Test the Effect of BI 456906 on Cardiovascular Safety in People With Overweight or Obesity (SYNCHRONIZE™ - CVOT)

Study Overview
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Brief Summary
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This study is open to adults who are at least 18 years old and have a body mass index (BMI)bof 27 kg/m2 or more. People can take part if they have cardiovascular or chronic kidney disease. People who have at least 2 health problems related to their weight or risks of cardiovascular disease can participate. Participants must have previously tried to lose weight by changing their diet. The purpose of this study is to find out whether people with overweight or obesity who take a medicine called BI 456906 (survodutide) are less or more likely to develop serious cardiovascular problems. It also aims to find out whether health parameters like blood pressure improve. Overweight and obesity are linked to cardiovascular disease. Survodutide is a medicine that is developed to help people with obesity or overweight to lose weight. Participants are divided into 3 groups of almost equal size. 2 groups get different doses of survodutide and 1 group gets placebo. Placebo looks like survodutide but does not contain any medicine. Every participant has a 2 in 3 chance of getting survodutide. Participants inject survodutide or placebo under the skin once a week. All participants also receive counselling on diet and physical activity. Participants are in the study for up to 2 years and 3 months. During this time, it is planned that participants visit the study site up to 21 times and attend remote visits by video calls. During these visits, the doctors check participants' cardiovascular and overall health. The results are compared between survodutide and placebo groups. The study staff also takes note of any unwanted effects.

Official Title
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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

Conditions
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Obesity

Intervention / Treatment
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* Drug: BI 456906
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age ≥18 years at the time of signing informed consent, and at least the legal age of consent in countries where it is >18 years. Body mass index (BMI) ≥27 kg/m2 at screening with established cardiovascular disease (CVD) and/or at least 2 weight-related complications or risk factors for CVD OR BMI ≥30 kg/m2 at screening with established CVD or chronic kidney disease (CKD), and/or at least 2 weight-related complications or risk factors for CVD. Further inclusion criteria apply. Exclusion criteria: Previous treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists within 3 months before screening. Type 1 diabetes. Less than 3 months between the last dose of GLP-1R agonists and GLP-1R agonist/insulin/glucose-dependent insulinotropic polypeptide (GIP) combinations and screening. Known clinically significant gastric emptying abnormality (e.g., severe diabetic gastroparesis or gastric outlet obstruction). Further exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 456906 3.6 mg<br> | Drug: BI 456906<br>* once weekly subcutaneous injection<br>* Other names: survodutide;|
| Experimental: BI 456906 6.0 mg<br> | Drug: BI 456906<br>* once weekly subcutaneous injection<br>* Other names: survodutide;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* once weekly subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of any of the adjudicated components of the composite endpoint consisting of: CV death, non-fatal stroke, non-fatal MI, ischaemia related coronary revascularisation, or HFE (to demonstrate non-inferiority) | Heart failure events (HFE) includes hospitalisation for heart failure (HHF), emergency room visit, urgent care visit, or urgent outpatient heart failure (HF) visit (5-point major adverse cardiac event (5P-MACE)) CV-Cardiovascular MI-Myocardial infarction | up to Week 114 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of any of the adjudicated components of the composite endpoint consisting of: CV death, non-fatal stroke, or non-fatal MI (3-point major adverse cardiac event (3P-MACE)) (to demonstrate non-inferiority) |  | up to Week 114 | 
| Absolute change in systolic blood pressure (SBP) (mmHg) from baseline to Week 72 |  | Baseline and at Week 72 | 
| Absolute change in waist circumference (cm) from baseline to Week 72 |  | Baseline and at Week 72 | 
| Absolute change in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) from baseline to Week 72 in trial participants with HF at baseline | KCCQ-TSCC scale score range is from 0 to 100 where low score means patient not doing well and higher score means patient doing better. | At Baseline and at Week 72 | 
| Time to first occurrence of any of the adjudicated components of the composite endpoint consisting of: CV death, non-fatal stroke, non-fatal MI, ischaemia related coronary revascularisation, or HFE (to demonstrate superiority) |  | up to Week 114 | 
| Percentage change in body weight from baseline to Week 72 |  | Baseline and at Week 72 | 
| Absolute change in diastolic blood pressure (DBP) (mmHg) from baseline to Week 72 |  | Baseline and at Week 72 | 
| Absolute change in aspartate aminotransferase (AST) (U/L) from baseline to Week 72 |  | Baseline and at Week 72 | 
| Absolute change in alanine aminotransferase (ALT) (U/L) from baseline to Week 72 |  | Baseline and at Week 72 | 
| Absolute change in glycosylated haemoglobin A1c (HbA1c) (mmol/mol) from baseline to Week 72 in trial participants with type 2 diabetes mellitus (T2DM) |  | Baseline and at Week 72 | 
| Absolute change in HbA1c (%) from baseline to Week 72 in trial participants with T2DM |  | Baseline and at Week 72 | 
| Time to onset of T2DM in trial participants without T2DM at baseline |  | up to Week 114 | 
| Time to first occurrence of any of the adjudicated components of the composite endpoint consisting of: CV death, non-fatal stroke, non-fatal MI, or ischaemia related coronary revascularisation (4-point major adverse cardiac event (4P-MACE)) |  | up to Week 114 | 
| Time to first occurrence of any of the adjudicated components of the composite endpoint consisting of: CV death, non-fatal stroke, non-fatal MI, or HFE (3P-MACE+ HFE) |  | up to Week 114 | 
| Time to first occurrence of any of the adjudicated components of the composite endpoint consisting of: CV death, non-fatal stroke, or non-fatal MI (3P-MACE) |  | up to Week 114 | 
| Time to first occurrence of CV death or HFE |  | up to Week 114 | 
| Time to first occurrence of CV death or HHF |  | up to Week 114 | 
| Time to first occurrence of HFE |  | up to Week 114 | 
| Time to CV death |  | up to Week 114 | 
| Time to all-cause mortality |  | up to Week 114 | 
| Time to first occurrence of non-fatal MI |  | up to Week 114 | 
| Time to first occurrence of non-fatal stroke |  | up to Week 114 | 
| Time to first occurrence of ischaemia related coronary revascularisation |  | up to Week 114 | 
| Achievement of body weight reduction ≥5% from baseline to Week 72 |  | Baseline and at Week 72 | 
| Achievement of body weight reduction ≥10% from baseline to Week 72 |  | Baseline and at Week 72 | 
| Achievement of body weight reduction ≥15% from baseline to Week 72 |  | Baseline and at Week 72 | 
| A composite of death, number HFEs (including HHFs, urgent HF visits, and unplanned outpatient visits), time to first HFE and change from baseline in KCCQ-TSS at 72 weeks assessed by the win ratio in trial participants with HF at baseline | Win ratio will be assessed as below: The primary efficacy endpoint will be analyzed using the clinical benefit approach comparing every participant in the BI 456906 arm to every participant in the placebo arm to determine a winner. A winner in the pair-wise comparison has a delayed time to the occurrence of death; if that cannot be determined, a winner has fewer HFEs; if the number of HFEs is the same a winner has a delayed time to the occurrence of first HFE; if that rule does not determine a winner, a winner has a more favorable (less increase or more decrease) change in KCCQ-CSS between baseline and at 72 weeks, otherwise the pair will be recorded as tied. The estimated net benefit (win ratio is then calculated as the total number of wins in the BI 456906 group across all strata divided by the total number of losses) will be provided. KCCQ-TSCC scale score range is from 0 to 100 where low score means patient not doing well and higher score means patient doing better. | At baseline and at 72 Weeks |