ZEUS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease, Chronic Kidney Disease and Inflammation

Study Overview
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Brief Summary
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This study is conducted to see if ziltivekimab reduces the risk of having cardiovascular events (for example heart attack and stroke) in people with cardiovascular disease, chronic kidney disease and inflammation. Participants will either get ziltivekimab (active medicine) or placebo (a dummy medicine which has no effect on the body). This is known as the study medicine. Which treatment participants get is decided by chance. Participants chance of getting ziltivekimab or placebo is the same. Ziltivekimab is not yet approved in any country or region in the world. It is a new medicine doctors cannot prescribe. Participants will get the study medicine in a pre filled syringe. Participants will need to use the pre filled syringe to inject the study medicine into a skinfold once-monthly. The study is expected to last for up to 4 years. Participants will have up to 20 clinic visits. Participants will have blood and urine samples taken at most of the clinic visits. Participants will have their heart examined using sound waves (echocardiography) and electrodes (electrocardiogram). Women cannot take part if pregnant, breast-feeding or planning to get pregnant during the study period.

Official Title
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ZEUS - Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Participants With Established Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease and Systemic Inflammation

Conditions
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Cardiovascular Risk, Chronic Kidney Disease, Inflammation

Intervention / Treatment
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* Drug: Ziltivekimab B
* Drug: Ziltivekimab C
* Drug: Placebo (Ziltivekimab B)
* Drug: Placebo (Ziltivekimab C)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic kidney disease defined by one of the below: Estimated glomerular filtration rate (eGFR) greater than or equal to (>=) 15 and below 60 mL/min/1.73 m^2 (using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation) Urinary albumin-to-creatinine ratio (UACR) >= 200 milligrams per gram (mg/g) and eGFR >= 60 mL/min/1.73 m2 (using the CKD-EPI creatinine equation) Serum high-sensitivity C-reactive protein (hs-CRP) greater than or equal to 2 milligram per liter (mg/L) Evidence of atherosclerotic cardiovascular disease (ASCVD) by one or more of the following: a) Coronary heart disease defined as at least one of the following: i. Documented history of MI ii. Prior coronary revascularisation procedure iii. greater than or equal to 50% stenosis in major epicardial coronary artery documented by cardiac catheterisation or CT coronary angiography b) Cerebrovascular disease defined as at least one of the following: i. Prior stroke of atherosclerotic origin ii. Prior carotid artery revascularisation procedure iii. greater than or equal to 50% stenosis in carotid artery documented by X-ray angiography, MR angiography, CT angiography or Doppler ultrasound. c) Symptomatic peripheral artery disease (PAD) defined as at least one of the following: i. Intermittent claudication with an ankle-brachial index (ABI) below or equal to 0.90 at rest ii. Intermittent claudication with a greater than or equal to 50% stenosis in peripheral artery (excluding carotid) documented by X-ray angiography, MR angiography, CT angiography or Doppler ultrasound iii. Prior peripheral artery (excluding carotid) revascularisation procedure iv. Lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g. trauma or osteomyelitis). Exclusion Criteria: Clinical evidence of, or suspicion of, active infection at the discretion of the investigator. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris, or transient ischaemic attack within 60 days prior to randomisation (visit 2). Planned coronary, carotid or peripheral artery revascularisation known on the day of randomisation (visit 2). Major cardiac surgical, non-cardiac surgical, or major endoscopic procedure (thoracoscopic or laparoscopic) within the past 60 days prior to randomisation (visit 2) or any major surgical procedure planned at the time of randomisation (visit 2).

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: Ziltivekimab<br>Participants will receive 15 milligrams (mg) of either Ziltivekimab B or Ziltivekimab C subcutaneously using single-use pre-filled DV3430-C1 manual syringe or single-dose DV3430-C3 pen-injector respectively once monthly for up to 4 years. | Drug: Ziltivekimab B<br>* Administered subcutaneously (s.c., under skin) once-monthly using single-use pre-filled DV3430-C1 manual syringe and added to standard of care.<br>Drug: Ziltivekimab C<br>* Administered subcutaneously (s.c., under skin) once-monthly using single-dose DV3430-C3 pen-injector and added to standard of care.<br>|
| Placebo Comparator: Placebo<br>Participants will receive 15 mg of either placebo (Ziltivekimab B) or placebo (Ziltivekimab C) subcutaneously using single-use pre-filled DV3430-C1 manual syringe or single-dose DV3430-C3 pen-injector respectively once monthly for up to 4 years. | Drug: Placebo (Ziltivekimab B)<br>* Administered subcutaneously (s.c., under skin) once-monthly using single-use pre-filled DV3430-C1 manual syringe and added to standard of care.<br>Drug: Placebo (Ziltivekimab C)<br>* Administered subcutaneously (s.c., under skin) once-monthly using single-dose DV3430-C3 pen-injector and added to standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of 3-point Major Adverse Cardiovascular Event (MACE), a composite endpoint consisting of: Cardiovascular (CV) death, non-fatal Myocardial Infarction (MI) and non-fatal stroke. | Months | From randomisation (month 0) to end-of-study (up to 48 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of expanded MACE, a composite endpoint consisting of: CV death, non-fatal MI, non-fatal stroke and hospitalisation for unstable angina pectoris requiring urgent coronary revascularisation | Months | From randomisation (month 0) to end-of-study (up to 48 months) | 
| Number of heart failure hospitalisations or urgent heart failure visits or CV deaths | Count | From randomisation (month 0) to end-of-study (up to 48 months) | 
| Time to occurrence of all-cause mortality. | Months | From randomisation (month 0) to end-of-study (up to 48 months) | 
| Time to first occurrence of composite Chronic Kidney Disease (CKD) endpoint consisting of onset of persistent at least 40% reduction in estimated glomerular filtration rate(eGFR) CKD-Epidemiology Collaboration (EPI) compared with baseline, kidney failure | Months | From randomisation (month 0) to end-of-study (up to 48 months) | 
| Time to first occurrence of each of the individual components of the expanded MACE endpoint and the kidney composite endpoint. | Months | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Time to first occurrence of MI (fatal and non-fatal). | Months | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Time to first occurrence of stroke (fatal and non-fatal). | Months | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Time to first occurrence of a composite MACE endpoint consisting of: all-cause mortality, non-fatal MI and non-fatal stroke. | Months | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Time to first occurrence of an expanded composite kidney endpoint consisting of: CV death, onset of persistent at least 40% reduction in eGFR (CKD-EPI) compared with baseline, kidney failure. | Months | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Time to first occurrence of coronary revascularisation | Months | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Change in Urinary Abumin-to-Ceatinine ratio (UACR). | Percentage | From randomisation (month 0) to 2 years (24 months). | 
| Change in eGFR (CKD-EPI)) | mL/min/1.73 m^2 | From randomisation (month 0) to 2 years (24 months) | 
| Annual rate of change in eGFR (CKD-EPI) (total eGFR slope) | mL/min/1.73 m^2/ year | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Change in high-sensitivity C-reactive protein (hs-CRP) | Percentage | From randomisation (month 0) to 2 years (24 months | 
| Change in N-terminal-pro-brain natriuretic peptide ( NT-pro-BNP) | Percentage | From randomisation (month 0) to 2 years (24 months) | 
| Change in left ventricular ejection fraction (LVEF) | Percentage | From randomisation (month 0) to 2 years (24 months) | 
| Number of events of atrial fibrillation | Count | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Change in haemoglobin | Grams per deciliter (g/dL) | From randomisation (month 0) to 2 years (24 months) | 
| Number of hospitalisations with infection as primary cause or death due to infection. | Count | From randomisation (month 0) to end-of-study (up to 48 months). | 
| Change in Short Form 36 (SF-36) Physical Component Score (PCS) | Score on scale | From randomisation (month 0) to 2 years (24 months) |