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

• ClinicalTrials.gov Identifier: NCT05021835
• Recruitment Status: Recruiting
• First Posted: August 26, 2021
• Last Update Posted: April 30, 2024
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Tracking Information

• First Submitted Date: August 19, 2021
• First Posted Date: August 26, 2021
• Last Update Posted Date: April 30, 2024
• Actual Study Start Date: August 30, 2021
• Estimated Primary Completion Date: September 24, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 1, 2024)

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 [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]

Months

Original Primary Outcome Measures (submitted: August 19, 2021)

• 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
• 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
• 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

Current Secondary Outcome Measures (submitted: April 1, 2024)

• 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 [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]
  Months
• Number of heart failure hospitalisations or urgent heart failure visits or CV deaths [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]
  Count
• Time to first occurrence of a composite kidney endpoint consisting of: CV death, onset of persistent atleast 40 percent (%) reduction in eGFR (CKD-epidemiology collaboration [CKD-EPI]) compared with baseline, kidney failure [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]
  Months
• Time to occurrence of all-cause mortality [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months) ]
  Months
• Time to first occurrence of each of the individual components of the expanded MACE endpoint and the kidney composite endpoint. [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Months
• Time to first occurrence of MI (fatal and non-fatal). [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Months
• Time to first occurrence of stroke (fatal and non-fatal). [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Months
• Time to first occurrence of a composite MACE endpoint consisting of: all-cause mortality, non-fatal MI and non-fatal stroke [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Months
• Time to first occurrence of a 4-component kidney endpoint consisting of: onset of persistent at least 40% reduction in eGFR (CKD-EPI) compared with baseline, kidney failure [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Months
• Time to first occurrence of coronary revascularisation [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Months
• Change in Urinary Abumin-to-Ceatinine ratio (UACR). [ Time Frame: From randomisation (month 0) to 2 years (24 months). ]
  Percentage
• Change in eGFR (CKD-EPI)) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
  mL/min/1.73 m^2
• 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). ]
  mL/min/1.73 m^2/ year
• Change in high-sensitivity C-reactive protein (hs-CRP) [ Time Frame: From randomisation (month 0) to 2 years (24 months ]
  Percentage
• Change in N-terminal-pro-brain natriuretic peptide ( NT-pro-BNP) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
  Percentage
• Change in left ventricular ejection fraction (LVEF) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
  Percentage
• Number of events of atrial fibrillation [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Count
• Change in haemoglobin [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
  Grams per deciliter (g/dL)
• Number of hospitalisations with infection as primary cause or death due to infection. [ Time Frame: From randomisation (month 0) to end-of-study (up to 48 months). ]
  Count
• 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

Original Secondary Outcome Measures (submitted: August 19, 2021)

• 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
• 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
• 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
• 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
• 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
• 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
• 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)
• 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)
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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)
• 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)
• 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)
• 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
• 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
• Relative change in UACR (urinary albumin-to-creatinine ratio ) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
  Percentage
• 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
• 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
• Change in high-sensitivity C-reactive protein (hs-CRP) [ Time Frame: From randomisation (month 0) to 2 years (24 months ]
  Percentage
• Change in N-terminal-pro-brain natriuretic peptide ( NT-pro-BNP) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
  pg/mL
• Change in left ventricular ejection fraction (LVEF) [ Time Frame: From randomisation (month 0) to 2 years (24 months) ]
  Percentage
• Number of events of atrial fibrillation (MedDRA search) [ 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
• 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
• 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ZEUS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease, Chronic Kidney Disease and Inflammation
• Official Title: ZEUS - Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Participants With Established Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease and Systemic Inflammation

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Cardiovascular Risk
• Chronic Kidney Disease
• Inflammation

Intervention

• Drug: Ziltivekimab B
  Administered subcutaneously (s.c., under skin) once-monthly using single-use pre-filled DV3430-C1 manual syringe and added to standard of care.
• Drug: Ziltivekimab C
  Administered subcutaneously (s.c., under skin) once-monthly using single-dose DV3430-C3 pen-injector and added to standard of care.
• Drug: Placebo (Ziltivekimab B)
  Administered subcutaneously (s.c., under skin) once-monthly using single-use pre-filled DV3430-C1 manual syringe and added to standard of care.
• Drug: Placebo (Ziltivekimab C)
  Administered subcutaneously (s.c., under skin) once-monthly using single-dose DV3430-C3 pen-injector and added to standard of care.

Study Arms

• Experimental: Ziltivekimab
  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.
  Interventions:

  • Drug: Ziltivekimab B
  • Drug: Ziltivekimab C
• Placebo Comparator: Placebo
  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.
  Interventions:

  • Drug: Placebo (Ziltivekimab B)
  • Drug: Placebo (Ziltivekimab C)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 19, 2021): 6200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 29, 2026
• Estimated Primary Completion Date: September 24, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Chronic kidney disease defined by one of the below:

  1. 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)
  2. 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Croatia, Czechia, Denmark, Germany, Greece, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT05021835
• Other Study ID Numbers: EX6018-4758; U1111-1259-3422 ( Other Identifier: World Health Organization (WHO) ); 2023-506926-35 ( Other Identifier: European Medical Agency (EMA) ); jRCT2021210033 ( Registry Identifier: JAPIC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

• Current Responsible Party: Novo Nordisk A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Novo Nordisk A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Transparency (dept. 2834); Novo Nordisk A/S

• PRS Account: Novo Nordisk A/S
• Verification Date: April 2024