E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atherosclerotic cardiovascular disease Chronic kidney disease Systemic inflammation |
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E.1.1.1 | Medical condition in easily understood language |
Cardiovascular disease Chronic kidney disease Inflammation |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051615 |
E.1.2 | Term | Atherosclerotic cardiovascular disease |
E.1.2 | System Organ Class | 100000004866 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067394 |
E.1.2 | Term | hs-CRP increased |
E.1.2 | System Organ Class | 100000004848 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011418 |
E.1.2 | Term | CRP increased |
E.1.2 | System Organ Class | 100000004848 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the superiority of ziltivekimab 15 mg s.c. once-monthly in reducing the risk of MACE (as defined by the primary endpoint) compared to placebo, both added to standard of care, in participants with established ASCVD, CKD and systemic inflammation. |
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E.2.2 | Secondary objectives of the trial |
- To demonstrate the superiority of ziltivekimab 15 mg s.c. once-monthly compared to placebo, both added to standard of care, in participants with established ASCVD, CKD and systemic inflammation, with regards to the following: • reducing the risk of expanded MACE (as defined by the confirmatory secondary endpoint) • reducing the risk of heart failure (as defined by the confirmatory secondary endpoint) • reducing all-cause mortality • delaying the progression of CKD (as defined by the confirmatory secondary endpoint) - To compare the effects of ziltivekimab 15 mg s.c. once-monthly versus placebo, both added to standard of care, in participants with established ASCVD, CKD and systemic inflammation, with regards to the following: • reducing systemic inflammation (defined by the secondary and exploratory endpoints) • improving patient reported outcomes (PRO) • not increasing severe infections (as defined by secondary safety endpoints) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The title is the same as main title : 'ZEUS - Effects of ziltivekimab versus placebo on cardiovascular outcomes in participants with established atherosclerotic cardiovascular disease, chronic kidney disease and systemic inflammation'.
No new primary and secondary objectives added for the sub-study |
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E.3 | Principal inclusion criteria |
- 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) - Serum hs-CRP greater than or equal to 2 mg/L at screening (visit 1) - Evidence of 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). |
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E.4 | Principal 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 screening (visit 1). - 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). |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Time to first occurrence of 3-point MACE, a composite endpoint consisting of: - CV death ( Based on EAC-confirmed events, including undetermined cause of death) - non-fatal MI ( Based on EAC-confirmed events, acute MI only) - non-fatal stroke ( Based on EAC-confirmed events, including ischaemic, haemorrhagic and undetermined stroke) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From randomisation (month 0) to end-of-study (up to 48 months (Maximum treatment duration is dependent on event rates and is estimated to be approximately 48 months including a 3-month follow-up period) |
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E.5.2 | Secondary end point(s) |
1. Time to first occurrence of expanded MACE, a composite endpoint consisting of: - CV death (Based on EAC-confirmed events, including undetermined cause of death) - non-fatal MI ( Based on EAC-confirmed events, acute MI only) - non-fatal stroke ( Based on EAC-confirmed events, including ischaemic, haemorrhagic and undetermined stroke) - hospitalisation for unstable angina pectoris requiring urgent coronary revascularisation ( Based on EAC-confirmed events) 2. Number of hospitalisations for heart failure (Based on EAC-confirmed events) or urgent heart failure visit (Based on EAC-confirmed events) 3. Time to occurrence of all-cause mortality (Based on EAC-confirmed events) 4. Time to first occurrence of a composite CKD endpoint consisting of: - onset of persistent (“Persistent” is defined as 2 consecutive samples meeting the criteria. The 2 samples must be at least 4 weeks apart) greater than or equal to 40% reduction in eGFR (CKD-EPI) compared with baseline - kidney failure defined as: a) death from kidney failure (Based on EAC-confirmed events, defined as a non-CV death that is due to the direct consequences of severely impaired kidney function. Undetermined cause of death in participants with eGFR below15 mL/min/1.73 m^2 will be considered kidney death) b) onset of persistent (“Persistent” is defined as 2 consecutive samples meeting the criteria. The 2 samples must be at least 4 weeks apart) eGFR below 15 mL/min/1.73 m^2 (CKD-EPI) c) initiation of chronic kidney replacement therapy (maintenance dialysis or kidney transplantation) (Based on EAC-confirmed events) 5. Time to first occurrence of each of the individual components (Based on EAC-confirmed events) of the expanded MACE endpoint and the kidney composite endpoint 6. Time to first occurrence of MIs (acute MI only) (fatal and non-fatal) (Based on EAC-confirmed events) 7. Time to first occurrence of stroke (including ischaemic, haemorrhagic and undetermined stroke) (fatal and non-fatal) (Based on EAC-confirmed events) 8. Time to first occurrence of a composite MACE endpoint consisting of: - all-cause mortality (Based on EAC-confirmed events) - non-fatal MI (Based on EAC-confirmed events, acute MI only), - non-fatal stroke (Based on EAC-confirmed events, including ischaemic, haemorrhagic and undetermined stroke) 9. Time to first occurrence of an expanded composite kidney endpoint consisting of: - CV death (Based on EAC-confirmed events, including undetermined cause of death) - onset of persistent (“Persistent” is defined as 2 consecutive samples meeting the criteria. The 2 samples must be at least 4 weeks apart) greater than or equal to 40% reduction in eGFR (CKD-EPI) compared with baseline - kidney failure defined as: a) death from kidney failure (Based on EAC-confirmed events, defined as a non-CV death that is due to the direct consequences of severely impaired kidney function. Undetermined cause of death in participants with eGFR below 15 mL/min/1.73 m^2 will be considered kidney death) b) onset of persistent (“Persistent” is defined as 2 consecutive samples meeting the criteria. The 2 samples must be at least 4 weeks apart) eGFR below 15 mL/min/1.73 m^2 (CKD-EPI) c) initiation of chronic kidney replacement therapy (maintenance dialysis or kidney transplantation)(Based on EAC-confirmed events) 10. Time to first occurrence of coronary revascularisation 11. Change in UACR 12. Change in eGFR (CKD-EPI) 13. Annual rate of change in eGFR (CKD-EPI) (total eGFR slope) 14. Change in hs-CRP 15. Change in NT-pro-BNP 16. Change in left ventricular ejection fraction (LVEF) 17. Number of events of atrial fibrillation 18. Number of hospitalisations with infection as primary cause (Based on EAC-confirmed events) or death due to infection (Based on EAC-confirmed events) 19. Change in Short Form 36 (SF-36) Physical Component Score (PCS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.- 10. From randomisation (month 0) to end-of-study (up to 48 months (Maximum treatment duration is dependent on event rates and is estimated to be approximately 48 months including a 3-month follow-up period.)) 11.- 12. From randomisation (month 0) to (24 months) 13. From randomisation (month 0) to end-of-study (up to 48 months (Maximum treatment duration is dependent on event rates and is estimated to be approximately 48 months including a 3-month follow-up period.)) 14.- 16. From randomisation (month 0) to (24 months) 17.-18. From randomisation (month 0) to end-of-study (up to 48 months (Maximum treatment duration is dependent on event rates and is estimated to be approximately 48 months including a 3-month follow-up period.)) 19. From randomisation (month 0) to (24 months) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 191 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
China |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
South Africa |
Taiwan |
United States |
European Union |
Russian Federation |
Serbia |
Turkey |
Ukraine |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 14 |