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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05021835
Recruitment Status : Recruiting
First Posted : August 26, 2021
Last Update Posted : December 2, 2021
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Cardiovascular Risk Chronic Kidney Disease Inflammation Drug: Ziltivekimab Drug: Placebo (ziltivekimab) Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: ZEUS - Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Participants With Established Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease and Systemic Inflammation
Actual Study Start Date : August 30, 2021
Estimated Primary Completion Date : September 24, 2025
Estimated Study Completion Date : October 15, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: ziltivekimab 15 mg
Participants will receive ziltivekimab 15 mg for up to 4 years.
Drug: Ziltivekimab
Administered subcutaneously (s.c., under skin) once-monthly and added to standard of care

Placebo Comparator: Placebo (ziltivekimab)
Participants will receive placebo (ziltivekimab) for up to 4 years.
Drug: Placebo (ziltivekimab)
Administered subcutaneously (s.c., under skin) once-monthly and added to standard of care




Primary Outcome Measures :
  1. Time to first occurrence of 3-point major adverse cardiovascular event (MACE), a composite endpoint consisting of: Cardiovascular (CV ) death (Based on EAC-confirmed events; including undetermined cause of death) [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]
    Months

  2. Time to first occurrence of 3-point MACE, a composite endpoint consisting of: non-fatal myocardial infarction(MI) ( Based on EAC-confirmed events; including undetermined cause of death; acute MI only) [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]
    Months

  3. Time to first occurrence of 3-point MACE, a composite endpoint consisting of: non-fatal stroke (Based on EAC-confirmed events; including ischaemic, haemorrhagic and undetermined stroke) [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]
    Months


Secondary Outcome Measures :
  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 [ Time Frame: 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) ]
    Months

  2. Time to first occurrence of expanded MACE, a composite endpoint consisting of: non-fatal MI (Based on EAC-confirmed events; acute MI only) [ Time Frame: 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) ]
    Months

  3. Time to first occurrence of expanded MACE, a composite endpoint consisting of: non-fatal stroke (Based on EAC-confirmed events; including ischaemic, haemorrhagic and undetermined stroke) [ Time Frame: 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) ]
    Months

  4. Time to first occurrence of expanded MACE, a composite endpoint consisting of: hospitalisation for unstable angina pectoris requiring urgent coronary revascularisation (Based on EAC-confirmed events) [ Time Frame: 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) ]
    Months

  5. Number of hospitalisations for heart failure (Based on EAC-confirmed events) or urgent heart failure visit (Based on EAC-confirmed events) [ Time Frame: 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) ]
    Count

  6. Time to occurrence of all-cause mortality (Based on EAC-confirmed events) [ Time Frame: 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) ]
    Months

  7. Time to first occurrence of a composite CKD endpoint consisting of:onset of persistent greater than or equal to 40% reduction in eGFR (CKD-EPI) compared with baseline [ Time Frame: 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) ]
    Months ("Persistent" is defined as 2 consecutive samples meeting the criteria. The 2 samples must be at least 4 weeks apart)

  8. Time to first occurrence of a composite CKD endpoint consisting of kidney failure defined as:death from kidney failure [ Time Frame: 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) ]
    Months (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)

  9. Time to first occurrence of a composite CKD endpoint consisting of:kidney failure defined as onset of persistente eGFR below 15 mL/min/1.73 m^2 (CKD-EPI) [ Time Frame: 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) ]
    Months

  10. Time to first occurrence of a composite CKD endpoint consisting of: initiation of chronic kidney replacement therapy (maintenance dialysis or kidney transplantation (Based on EAC-confirmed events) [ Time Frame: 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) ]
    Months

  11. 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 [ Time Frame: 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-months follow-up period;) ]
    Months

  12. Time to first occurrence of MIs (acute MI only) (fatal and non-fatal) (Based on EAC-confirmed events) [ Time Frame: 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-months follow-up period;) ]
    Months

  13. Time to first occurrence of stroke (including ischaemic, haemorrhagic and undetermined stroke) (fatal and non-fatal)(Based on EAC-confirmed events) [ Time Frame: 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-months follow-up period;) ]
    Months

  14. Time to first occurrence of a composite MACE endpoint consisting of:all-cause mortality (Based on EAC-confirmed events) [ Time Frame: 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-months follow-up period;) ]
    Months

  15. Time to first occurrence of a composite MACE endpoint consisting of:non-fatal MI (Based on EAC-confirmed events; acute MI only) [ Time Frame: 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-months follow-up period;) ]
    Months

  16. Time to first occurrence of a composite MACE endpoint consisting of:non-fatal stroke (Based on EAC-confirmed events,including ischaemic, haemorrhagic and undetermined stroke) [ Time Frame: 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-months follow-up period;) ]
    Months

  17. Time to first occurrence of an expanded composite kidney endpoint consisting of:CV death (Based on EAC-confirmed events; including undetermined cause of death) [ Time Frame: 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-months follow-up period;) ]
    Months

  18. Time to first occurrence of an expanded composite kidney endpoint consisting of:onset of persistent greater than or equal to 40% reduction in eGFR (CKD-EPI) compared with baseline [ Time Frame: 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-months follow-up period;) ]
    Months ("Persistent" is defined as 2 consecutive samples meeting the criteria. The 2 samples must be at least 4 weeks apart)

  19. Time to first occurrence of an expanded composite kidney endpoint consisting of:kidney failure defined as:death from kidney failure [ Time Frame: 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-months follow-up period;) ]
    Months (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)

  20. Time to first occurrence of an expanded composite kidney endpoint consisting of:kidney failure defined as onset of persistent eGFR below 15 mL/min/1.73 m^2 (CKD-EPI) [ Time Frame: 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-months follow-up period;) ]
    Months ("Persistent" is defined as 2 consecutive samples meeting the criteria. The 2 samples must be at least 4 weeks apart)

  21. Time to first occurrence of an expanded composite kidney endpoint consisting of:kidney failure defined as:initiation of chronic kidney replacement therapy (maintenance dialysis or kidney transplantation) (Based on EAC-confirmed events) [ Time Frame: 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-months follow-up period;) ]
    Months

  22. Time to first occurrence of coronary revascularisation [ Time Frame: 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-months follow-up period;) ]
    Months

  23. Change in UACR (urinary albumin-to-creatinine ratio ) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
    Percentage

  24. Change in eGFR (estimated glomerular filtration rate) (chronic kidney disease - epidemiology collaboration (CKD-EPI)) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
    mL/min/1.73 m^2

  25. Annual rate of change in eGFR (CKD-EPI) (total eGFR slope) [ Time Frame: 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-months follow-up period;) ]
    mL/min/1.73 m^2/ year

  26. Change in high-sensitivity C-reactive protein (hs-CRP) [ Time Frame: From randomisation (month 0) to 2 years (24 months ]
    Percentage

  27. Change in N-terminal-pro-brain natriuretic peptide ( NT-pro-BNP) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
    Percentage

  28. Change in left ventricular ejection fraction (LVEF) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
    Percentage

  29. Number of events of atrial fibrillation [ Time Frame: 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-months follow-up period;) ]
    Count

  30. Number of hospitalisations with infection as primary cause (Based on EAC-confirmed events) or death due to infection (Based on EAC-confirmed events) [ Time Frame: 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-months follow-up period;) ]
    Count

  31. Change in Short Form 36 (SF-36) Physical Component Score (PCS) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
    Score on scale



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Estimated glomerular filtration rate (eGFR) 15 and below 60 mL/min/1.73 m^2 (using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation)
  • Serum high-sensitivity C-reactive protein (hs-CRP) greater than or equal to 2 mg/L at screening (visit 1)
  • Evidence of atherosclerotic cardiovascular disease (ASCVD) by one or more of the following within the last 5 years from screening:

    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 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05021835


Contacts
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Contact: Novo Nordisk (+1) 866-867-7178 clinicaltrials@novonordisk.com

Locations
Show Show 336 study locations
Sponsors and Collaborators
Novo Nordisk A/S
Investigators
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Study Director: Clinical Transparency (dept. 1452) Novo Nordisk A/S
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Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT05021835    
Other Study ID Numbers: EX6018-4758
U1111-1259-3422 ( Other Identifier: World Health Organization (WHO) )
2020-004853-59 ( EudraCT Number )
jRCT2021210033 ( Registry Identifier: JAPIC )
First Posted: August 26, 2021    Key Record Dates
Last Update Posted: December 2, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com
URL: http://novonordisk-trials.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Cardiovascular Diseases
Inflammation
Chronic Disease
Pathologic Processes
Urologic Diseases
Renal Insufficiency
Disease Attributes