REDEFINE 3: A Research Study to See the Effects of CagriSema in People Living With Diseases in the Heart and Blood Vessels

Study Overview
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Brief Summary
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This study will look at the effects of CagriSema on cardiovascular events (for example heart attack and stroke) in people living with cardiovascular disease. Participants will either get CagriSema or a dummy medicine (also called placebo) which has no effect on the body. Which treatment participants will get will be decided by chance. Participant's chance of getting CagriSema or placebo is the same. Participants will inject the study medicine once a week. The study medicine will be injected briefly with a thin needle, typically in the stomach, thighs or upper arms. The study will last for up to 4.5 years.

Official Title
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The Cardiovascular Safety and Efficacy of Cagrilintide 2.4 mg s.c. in Combination With Semaglutide 2.4 mg s.c. (CagriSema 2.4 mg/2.4 mg s.c.) Once-weekly in Participants With Established Cardiovascular Disease

Conditions
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Cardiovascular Disease

Intervention / Treatment
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* Drug: Cagrilintide
* Drug: Semaglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Age above or equal to 55 years at the time of signing informed consent Body mass index (BMI) greater than or equal to (>=) 25.0 kilograms per meter square (kg/m^2) Established CVD as evidenced by at least one of the following: Prior myocardial infarction Prior stroke (ischemic or haemorrhagic stroke) Symptomatic peripheral arterial disease (PAD) defined as at least one of the following: Intermittent claudication with an ankle-brachial index (ABI) less than (<) 0.85 at rest Intermittent claudication with a >= 50% stenosis in a lower extremity peripheral artery documented by X-ray angiography, magnetic resonance (MR) angiography, computed tomography (CT) angiography or Doppler ultrasound Prior revascularization procedure of a lower extremity peripheral artery Lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g., trauma or osteomyelitis) For participants with T2D at screening the following inclusion criteria also apply: Diagnosed with type 2 diabetes mellitus (T2D) >= 180 days before screening HbA1c 6.5%-10% (48-86 millimoles per mole [mmol/mol]) (both inclusive), as measured by central laboratory at screening Treatment with either: Lifestyle intervention alone 1-3 marketed oral antidiabetic drugs (OADs) (metformin, α-glucosidase inhibitors (AGI), glinides, sodium-glucose co-transporter 2 inhibitor (SGLT2i), dipeptidyl peptidase 4 (DPP4)-inhibitors, thiazolidinediones, or sulphonylureas (SU) as a single agent or in combination) according to local label Basal insulin alone or in combination with up to two marketed OADs, all according to local label Exclusion Criteria: Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 60 days before screening Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Heart failure classified as being in New York Heart Association (NYHA) Class IV at screening Treatment with any glucagon-like peptide-1 (GLP-1) receptor agonist (RA) or a medication with GLP-1 activity within 90 days before screening End stage renal disease defined as estimated glomerular filtration rate (eGFR) < 15 millileters per minutes per 1.73^2 (mL/min/1.73 m^2), as measured by the central laboratory at screening Chronic or intermittent haemodialysis or peritoneal dialysis

Ages Eligible for Study
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Minimum Age: 55 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: CagriSema 2.4 mg/2.4 mg<br>Participants will receive 2.4 milligrams (mg) cagrilintide and 2.4 mg semaglutide subcutaneously (s.c.) once-weekly after a dose escalation period of 16 weeks during the maintenance period of 219 weeks. | Drug: Cagrilintide<br>* Participants will receive 2.4 mg cagrilintide s.c. once-weekly after a dose escalation period of 16 weeks for 219 weeks.<br>Drug: Semaglutide<br>* Participants will receive 2.4 mg semaglutide s.c. once-weekly after a dose escalation period of 16 weeks for 219 weeks.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo matched to cagrilintide and placebo matched to semaglutide s.c. once weekly for 235 weeks. | Drug: Placebo<br>* Participants will receive placebo matched to cagrilintide and placebo matched to semaglutide subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of major adverse cardiovascular event (MACE), a composite endpoint consisting of: cardiovascular (CV) death, non-fatal myocardial infarction, non-fatal stroke | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to occurrence of CV death | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Time to first occurrence of a composite heart failure endpoint consisting of: CV death, heart failure, hospitalisation and urgent heart failure visit | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Time to first occurrence of a composite endpoint: Onset of persistent ≥40% reduction in eGFRcr (CKD-EPI), Onset of persistent eGFRcr (CKD-EPI) <15 mL/min/1.73 m2, Initiation of chronic kidney replacement therapy, Kidney death and CV death | CKD-EPI is Chronic Kidney Disease Epidemiology Collaboration. Measured in days. | From baseline (week -3) to end of study (up to 242 weeks or more) | 
| Time to first occurrence of all-cause death | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Time to first occurrence of an expanded MACE composite endpoint consisting of: CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation and unstable angina requiring hospitalisation | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Time to first occurrence of a composite endpoint consisting of: all-cause death, non-fatal myocardial infarction and non-fatal stroke | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Time to first occurrence of myocardial infarction (fatal and non-fatal) | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Time to first occurrence of stroke (fatal and non-fatal) | Measured in days. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Relative change in body weight | Measured in percentage (%). | From baseline (week 0) to 120 weeks | 
| Change in waist circumference | Measured in centimeters (cm). | From baseline (week 0) to 120 weeks | 
| Change in systolic blood pressure (SBP) | Measured in millimeters of mercury (mmHg). | From baseline (week 0) to 120 weeks | 
| Change in diastolic blood pressure (DBP) | Measured in mmHg. | From baseline (week 0) to 120 weeks | 
| Relative change in lipids: Total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, triglycerides and free fatty acids | Measured in percentage. | From baseline (week 0) to 120 weeks | 
| Change in glycated haemoglobin (HbA1c) | Measured in percentage-points. | From baseline (week 0) to 120 weeks | 
| Change in Short Form 36 v2.0 acute (SF-36v2) | SF-36v2.0 is a 36-item commonly used generic clinical outcome assessment (COA) instrument measuring health-related quality of life and general health status across disease areas. The SF-36v2.0 for adults with a 1 week recall period (i.e. acute version) measures the individual overall health-related quality of life in 8 health domains (physical functioning, role-physical, bodily pain, general health, social functioning, role emotional, vitality and mental health). Furthermore, it includes two aggregated scores: a physical component summary score and a mental component summary score. Range of score for domains and component summary scores : 1-100 (Higher scores indicated a better health state). | From baseline (week 0) to 120 weeks | 
| Number of treatment emergent serious adverse events (TESAEs) | Measured in count of events. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Number of event adjudication committee (EAC)-confirmed malignant neoplasms | Measured as count of events. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Number of severe hypoglycaemic episodes (level 3) (only for participants with type 2 diabetes mellitus [T2D] at screening) | Measured as count of events. | From baseline (week 0) to end of study (up to 242 weeks or more) | 
| Change from baseline in high-sensitivity C-reactive protein (hsCRP) | Measured in milligram per liter (mg/L) | From baseline (week 0) to 120 weeks | 
| Change from baseline in tumour necrosis factor alpha (TNF-α) | Measured in picograms per milliliter (pg/mL) | From baseline (week 0) to 120 weeks | 
| Change from baseline in Interleukin 6 (IL-6) | Measured in pg/mL. | From baseline (week 0) to 120 weeks | 
| Change from baseline in Interleukin 1 beta (IL-1β) | Measured in pg/mL. | From baseline (week 0) to 120 weeks | 
| Change in pain intensity rated by Numerical Rating Scale (NRS) | The NRS rates average pain intensity in the last 24 hours on a scale from 0 to 10, with 0 meaning 'No pain' and '10' meaning 'Pain as bad as you can imagine'. | From baseline (week 0) to 120 weeks | 
| Change in Pittsburgh Sleep Quality Index (PSQI) | The Pittsburgh Sleep Quality Index is a 19-item, self-rated questionnaire, assessed various aspects of sleep, sleep quality, and sleep disturbances. The PSQI is composed of 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these 7 components yields 1 global score. An overall score ranges from 0 to 21, where lower scores denote a healthier sleep quality. | From baseline (week 0) to 120 weeks | 
| Change in neuropathy status by baseline neuropathy group (painful neuropathy, painless neuropathy or no neuropathy) | Measured in percentage. | From baseline (week 0) to 120 weeks |