ZEUS - Effects of ziltivekimab for heart diseases and long-term kidney diseases
Scientific Title of Study
ZEUS - Effects of ziltivekimab versus placebo on cardiovascular outcomes in
participants with established atherosclerotic cardiovascular disease, chronic
kidney disease and systemic inflammation
Novo Nordisk India Private Limited, Nxt Tower - 2, Floor 1 & 2, Embassy Manyata Business Park, Nagavara Village, Kasaba Hobli, Bangalore - 560045. India
Novo Nordisk India Private Limited, Nxt Tower - 2, Floor 1 & 2, Embassy Manyata Business Park, Nagavara Village, Kasaba Hobli, Bangalore - 560045. India
Novo Nordisk India Private Limited, Nxt Tower - 2, Floor 1 & 2 Embassy Manyata Business Park,Nagavara Village, Kasaba Hobli,Bangalore - 560045. India
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India Argentina Australia Belgium Brazil Bulgaria Canada China Denmark Germany Greece Israel Italy Japan Lithuania Malaysia Mexico Netherlands Poland Portugal Republic of Korea Russian Federation Serbia Slovakia South Africa Spain Sweden Taiwan Turkey United Kingdom United States of America Ukraine
Interventional cardiology, Chairman and Dean Academics and Research at Batra Hospital & Medical Research Centre, 1, Mehrauli - Badarpur Rd, Tughlakabad Institutional Area, Vayusenabad, New Delhi, Delhi 110062 New Delhi DELHI
9811150518
upendra.kaul@batrahospitaldelhi.org
Dr Sameer Dani
Apollo CVHF heart institute
Pakwan Cross Road, Sarkhej Gandhinagar Hwy, Next to l.O.C petrol pump, Opposite GNFC Infotower - n Code Solutions, Bodakdev, Ahmedabad, Gujarat 380059 Ahmadabad GUJARAT
9825038855
drsameerdani@gmail.com
Dr Abraham Oomman
Apollo Hospitals Educational and Research Foundation (AHERF)
Flat No 16/1 and 17/1, 2nd Floor, Krishnadeep Chambers (Apollo Annexe),
No.1, Wallace Garden, Thousand Lights,
Chennai - 600006, Tamil Nadu Chennai TAMIL NADU
9841174518
drabrahamoomman@gmail.com
Dr A Sreenivas Kumar
Apollo Research and Innovations (ARI)
1st Floor, Auditorium Building, Apollo Health City,
Jubilee Hills, Hyderabad, Telangana -500033 Hyderabad TELANGANA
9848046785
arramraj@yahoo.com
Dr Jaspal Singh Arneja
Arneja heart and multi-speciality hospital
Arneja heart and multi-speciality hospital,123, Ramdaspeth, Nagpur Maharashtra-440010 Nagpur MAHARASHTRA
9823056562
jaspalarneja_200@yahoo.com
Dr Parshottam G Koradia
BAPS Pramukh Swami Hospital
Shri Pramukh Swami Maharaj Marg, Adajan Cross road, Surat Surat GUJARAT
9825312027
purushottam_koradia@yahoo.co.in
Dr Manoj Chopada
Chopda Medicare & Research Centre Pvt. Ltd
Magnum Heart Institute, 3/5, Patil Lane No. 1,Laxmi nagar, Near K.B.H. Vidyalaya, Canada Corner, Nashik, Maharashtra-422005, India Nashik MAHARASHTRA
9823021613
drchopdamanoj@gmail.com
Dr Gurpreet Singh Wander
Dayanand Medical College & Hospital
Unit Hero DMC Heart Institute, Tagore Nagar,
Ludhiana (141001), Punjab, India Ludhiana PUNJAB
9815545316
drgswander@yahoo.com
Dr Jayakumar
Department of Nephrology, Super Speciality building Government Medical College
Department of Nephrology, Super Speciality building Government Medical College, Kozhikode-673008, Kerala Kozhikode KERALA
9447232900
jayakumarek@gmail.com
Dr J B Gupta
Eternal Heart Care Centre and Research Institute Private Limited
3 A Jagatpura Road,
Near Jawahar Circle Jaipur RAJASTHAN
9829414680
drjbgupta@gmail.com
Dr Ashok Seth
Fortis Escort Heart Institute
Okhla road, Sukhdev Vihar Metro Station, New Delhi, Delhi 110025, India New Delhi DELHI
9810025814
ashok.seth@fortishealthcare.com
Dr Vimal Mehta
G.B. Pant Institute of Postgraduate Medical Education & Research
1,
Jawaharlal Nehru Marg,, 64 Khamba, Raj Ghat,
New Delhi, 110002, India
New Delhi DELHI
9718599105
drvimalmehta@yahoo.co.in
Dr Sunil Washimkar
Government Medical College and Super Specialty Hospital
Govt. Medical College and Super Speciality Hospital, Tukdoji Square, Nagpur-440009, Maharashtra, India Nagpur MAHARASHTRA
9823065380
sunil_wash@rediffmail.com
Dr Ragi Krishnan
Government Medical College, Trivandrum
Department of Nephrology, Super Speciality block, Government Medical College, Trivandrum -695011 Thiruvananthapuram KERALA
8921713262
ragikrishnangmc@gmail.com
Dr Johann Christopher
Guru Nanak- CARE Hospitals
Guru Nanak- CARE Hospitals - 1-4-908/7/1, Musheerabad Main Rd, near Raja Deluxe Theatre, Musheerabad, Bakaram, Kavadiguda, Hyderabad, Telangana 500020 Hyderabad TELANGANA
9701445011
johann1403@gmail.com
Dr Ajit Bhagwat
Kamalnayan Bajaj Hospital
Gut No 43, Satara Parisar, Beed Bypass Road, Aurangabad-431005, Maharashtra, India Aurangabad MAHARASHTRA
9822050817
drajitbhagwat@gmail.com
Dr Tom Devasia
Kasturba medical college and hospital, Manipal Academy of higHer education
Kasturba medical college and hospital, Manipal Academy of higHer education, Madhavanagar ,manipal -576104 Karnataka Udupi KARNATAKA
9448158508
tomdevasia@hotmail.com
Dr Charan Lanjewar
King Edward Memorial VII Hospital & Seth Gordhandas Sunderdas Medical College
Department of Cardiology ,4th Floor CVTC Building ,King Edward Memorial VII Hospital & Seth Gordhandas Sunderdas Medical College,Acharya Donde Marg, Parel,Mumbai, Maharashtra 400012 Mumbai MAHARASHTRA
9769133740
drlanjewar_cr@kem.edu
Dr Prasad MR
KLES Dr. Prabhakar Kore Hospital & Medical Research Centre
KLES Dr. Prabhakar Kore Hospital & Medical Research Centre, Belagavi Belgaum KARNATAKA
9243245777
drprasadmr@gmail.com
Dr Jayagopal
Lakshmi Hospital
Kunnathurmedu, Chittur Rd, Palakkad, Kerala 678013 Palakkad KERALA
9847023777
jaigopallakshmi@gmail.com
Dr P V Raghava Sarma
Lalitha Super Specialities Hospitals Pvt Ltd
Lalitha Super Specialities Hospitals pvt Ltd Kothapet Guntur ANDHRA PRADESH
9440800355
drpvr.lssh@gmail.com
Dr Rishi Sethi
Lari Cardiology Centre, King Georges Medical University
Lari Cardiology Centre, King Georges Medical University, Shah Mina Rd, Jawahar Nagar, Chowk, Lucknow, Uttar Pradesh 226003 Lucknow UTTAR PRADESH
9415085717
drrishisethi1@gmail.com
Dr L Sreenivasa Murthy
Life Care Hospital and Research centre
8th Main Rd, next to UNION BANK OF INDIA, D Block, Sahakarnagar Bengaluru, Karnataka 560092 Bangalore KARNATAKA
9448051046
drlsm@lcrc.in
Dr Jabir Abdullakutty
Lisie Hospital
Department of Cardiology, PO. Box No. 3053, Kochi-682018 Ernakulam KERALA
9447-0117733
drjabi@yahoo.co.in
Dr Sunita Aggarwal
Lok Nayak Hospital
Lok Nayak Hospital, Maulana Azad Medical
College, Delhi New Delhi DELHI
9968604281
drsunita.mamc@gmail.com
Dr Ranjan SK
Manipal Hospital
98, HAL Old Airport Rd, Kodihalli, Bengaluru, Karnataka 560017 Bangalore KARNATAKA
9243350978
ranjan.shetty@gmail.com
Dr Dinesh Khullar
Max Super Speciality Hospital
Max Super Speciality Hospital
1, Press Enclave Road, Saket, New Delhi - 110 017 New Delhi DELHI
Nephrology Research room, Department of Nephrology, Sir Gangaram Hospital, Sir Gangaram Hospital
Room No. 1297, Nephrology Research room, Department of Nephrology, Sir Gangaram Hospital, Sir Gangaram Hospital Marg, Old Rajinder Nagar, New Delhi-110060, New Delhi DELHI
9811047377
bhallaak@yahoo.com
Dr D Sree Bhushan Raju
NIZAMS INSTITUTE OF MEDICAL SCIENCES
Department of Nephrology NIMS Hospital Punjagutta Rd Panjagutta 500082
Hyderabad TELANGANA
Osmania General hospital, Quliqutubshah building, Department of Cardiology, 15-5-104, Second Floor, Begum Bazar, Afzal Gunj, Hyderabad, Telangana 500012, India Hyderabad TELANGANA
9848015098
drkmkreddyp@yahoo.com
Dr Manisha Sahay
Osmania Medical College and Osmania General Hospital
Osmania Medical College and Osmania General Hospital, 5-1-876, Turrebaz Khan Rd, Troop Bazaar, Koti, Hyderabad, Telangana 500095 Hyderabad TELANGANA
9849097507
drmanishasahay@gmail.com
Dr Atul Abhayankar
Shri Bachubhai Dahyabhai Mehta Mahavir Heart Institute
Shri Bachubhai Dahyabhai Mehta Mahavir Heart Institute,Shri Mahavir Health Campus,Athwagate,Gujarat, India
Surat GUJARAT
9824145738
heartfirst.surat@gmail.com
Dr Mahesh Fulwani
Shrikrishna Hrudayalaya and Critical Care Center
Shrikrishna Hrudayalaya and Critical Care Center,Congress Nagar Square, Tikekar Road, Dhantoli, Nagpur, Maharashtra-440012 Nagpur MAHARASHTRA
7122444434
drmaheshfulwani@gmail.com
Dr Madhukara H M
Sri Jayadeva Institute of Cardiovascular Sciences and Research
Bannerghatta Main Rd, Phase 3, Jayanagar 9th Block, Jayanagar, Bengaluru, Karnataka 560069, India Bangalore KARNATAKA
9040593969
makhm564@gmail.com
Dr Sai Krishna M V
Sunrise Hospitals
Sunrise Hospitals, Eluru Rd, near Swathi press, Seetharampuram, Suryaraopeta, Vijayawada, Andhra Pradesh 520002, India Krishna ANDHRA PRADESH
91-9949105936
drsaikrishnamaddi@gmail.com
Dr Devang Desai
Unicare Heart Institute and Research Centre
1st floor OPD ,Unicare Heart Institute and Research Centre ,52,Canal Road ,Ambanagar,Surat ,Gujrat,395001
Surat GUJARAT
9825117900
hridayamheartcare@gmail.com
Dr Sandeep Bansal
Vardhaman Mahavir Medical College & Safdarjunj Hospital
Vardhaman Mahavir Medical College & Safdarjunj Hospital,Specialty block, 7th floor,Ansari Nagar East, Near to AIIMS Metro Station,New Delhi, Delhi 110029 New Delhi DELHI
9810543368
drsbansal2000@yahoo.com
Dr Chinta Ramakrishna
Vedanta Hospital
15-11-154 Near Best Price Mangalagiri, Road, Guntur, Andhra Pradesh 522001 Guntur ANDHRA PRADESH
9701504777
rknephro@gmail.com
Dr Vinod Vijan
Vijan Cardiac & Critical Care Centre
Vijan Cardiac & Critical Care Centre,
College Rd, Nashik, Maharashtra- 422005 Nashik MAHARASHTRA
Institutional Ethics Committee New UG/PG Hospital, 20 Storey Hostel building, Ground Floor,K.E.M.Hospitalcampus,Near main boys hostel, Dr S.S.Rao’s Marg, Parel,Mumbai 400012
Approved
Institutional Ethics Committee, Academics and Research Department, Room 23-A 2nd floor, Residential tower, Fortis Escorts Heart Institute, Okhla road, new Delhi - 110025
Approved
Institutional Ethics Committee, GMC, NagpurGovernment Medical College and Hospital, Medical Square, Hanuman Nagar,Nagpur- 440003, Maharashtra, India.Â
Approved
Institutional Ethics Committee, Government Medical College Kozhikode ,4 th Floor, Golden Jubilee Annex Institute of Maternal and Child Health, Medical College. PO,Calicut-673008
Life Care Hospital Institutional Review Board 2748-2152, M.L.N Enclave, 16th E CrossRoad, 8th Main, D-Block Next to Corportion Bank, Sahakarnagar Bangalore Bengaluru (Bangalore) Urban Karnataka - 560092 India
NIMS Institutional Ethics Committee Nizams Institute of Medical Sciences Punjagutta Hyderabad Hyderabad Hyderabad Telangana - 500082 India
Approved
Omega Ethical Committee
Approved
Scientific Research and Ethical Review Committee, Department of Laboratory Medicine, Batra Hospital and Medical Research Centre, 1 Tughlakabad Institutional Area Mehrauli-Badarpur Road, New Delhi-110062
Approved
Sri Jayadeva Institute Ethics Committee, Bannerghatta road, Jayanagar 9th Block, Bangalore 560069
Approved
Vedanta Hospital Institutional Ethics Committee
Approved
Virtuous Institutional Medical Research Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
No Objection Certificate
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: I52||Other heart disorders in diseasesclassified elsewhere,
Ziltivekimab B 15 mg/mL
Dosage form: Solution for injection
Route of administration: Subcutaneous injection
Dose: 15 mg
Dosing instructions: Once-monthly
Duration of therapy: Approximately 63 months including a 3 month follow up period
Ziltivekimab C 30 mg/mL,
Dosage Form: Solution for injection,
Route of administration:
Subcutaneous, Dose: 15mg,
Dosing instructions: Once monthly,
Duration of Therapy: Approximately 63 months including 3 month follow up period.
Comparator Agent
Ziltivekimab placebo
Ziltivekimab placebo 0 mg (volume equivalent to
15 mg/mL ziltivekimab)
Frequency: once monthly
Route of Administration: subcutaneous injection
Duration: Approximately 63 months including a 3 month follow up period.
Ziltivekimab placebo 0 mg (volume equivalent to 30 mg/mL ziltivekimab)
Frequency: once monthly
Route of Administration: subcutaneous
Injection Duration: Approximately 63 months including a 3 month follow up period
1. Informed consent obtained before any study-related activities. Study-related activities are any
procedures that are carried out as part of the study, including activities to determine suitability
for the study, except for protocol described pre-screening activities which require a separate
informed consent.
2. Age above or equal to 18 years at the time of signing informed consent.
3. Chronic kidney disease defined by one of the below:
eGFR ≥ 15 and < 60 mL/min/1.73 m2 (using the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) creatinine equation)a
UACR ≥ 200 mg/g and eGFR ≥ 60 mL/min/1.73 m2 (using the CKD-EPI creatinine
equation).a
4. Serum hs-CRP ≥ 2 mg/L.a
5. Evidence of ASCVD by one or more of the following:
a) Coronary heart disease defined as at least one of the following:
1. Documented history of MI.
2. Prior coronary revascularisation procedure.
3. ≥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:
1. Prior stroke of atherosclerotic origin.
2. Prior carotid artery revascularisation procedure.
3. ≥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:
1. Intermittent claudication with an ankle-brachial index (ABI) ≤ 0.90 at rest.
2. Intermittent claudication with a ≥50% stenosis in peripheral artery (excluding
carotid) documented by X-ray angiography, MR angiography, CT angiography
or Doppler ultrasound.
3. Prior peripheral artery (excluding carotid) revascularisation procedure.
4. Lower extremity amputation at or above ankle due to atherosclerotic disease
(excluding e.g., trauma or osteomyelitis).
a Laboratory results of eGFR3-5, UACR and hs-CRP for inclusion can be based on:
measurements no more than 90 days old at screening, documented in medical records or
measurements obtained at the optional pre-screening visit (see Section 8.1), documented in
medical records or
central laboratory measurement of eGFR, UACR or hs-CRP obtained at the screening visit
(visit 1) or
measurements from the prevalence study (NN6018-7527, FPFV expected Sep-2023) if nomore than 90 days old at screening.
ExclusionCriteria
Details
1. Known or suspected hypersensitivity to study intervention (s) or related products.
2. Previous participation in this study. Participation is defined as randomisation.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing
potential and not using an adequate and highly effective contraceptive method (adequate
contraceptive measures as required by local regulation or practice).
4. Participation (i.e., signed informed consent) in any interventional clinical study of an approved
or non-approved investigational medicinal product within 30 days prior to screening (visit 1).
5. Any disorder, which in the investigator’s opinion might jeopardise participant’s safety or
compliance with the protocol.
6. Inadequate standard of care treatment which in the investigator’s opinion makes the
participant’s participation in the study inappropriate.
Laboratory values
7. Absolute neutrophil count <2×109/L at screening (visit 1).
8. Platelet count <120×109/L at screening (visit 1).
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × upper limit of
normal at screening (visit 1).
10. HbA1c ≥ 10% (≥ 86 mmol/mol)a
Medical conditions
11. Diagnosis of human immunodeficiency virus (HIV) and not receiving a stable antiretroviral
regimen, at the discretion of the investigator at screening (visit 1). (Note: for Argentina, see
country specific requirements (Appendix 8, Section 10.8)).
12. Active hepatitis C (positive anti-HCV and detectable HCV RNA) or hepatitis B (positive
HBsAg and/or positive anti-HBc with detectable HBV DNA) at screening (visit 1). (Note:
participants with positive anti-HBc and undetectable HBV DNA can be enrolled, see
Section 8.3.7 for details).
13. Current (or within 90 days of visit 1) chronic or intermittent haemodialysis or peritoneal
dialysis.
14. Clinical evidence of, or suspicion of, active infection at the discretion of the investigator.
15. History of recurrent serious infections (infections leading to hospitalisation or use of i.v.
antibiotics, i.v. antiviral or i.v. antifungal treatment) in the 12 months prior to randomisation, at
the discretion of the investigator.
16. History or evidence of untreated latent tuberculosis (TB) such as (but not limited to):
History of a positive TB test or chest X-ray compatible with latent TB; and TB treatment
initiated less than 28 days prior to randomisation.
Confirmed positive for latent TB at optional pre-screening visit or screening (visit 1) (see
details in Section 8.3.6) and TB treatment initiated less than 28 days prior to randomisation.
17. History of gastrointestinal perforation. (Note: History of perforated appendicitis more than
5 years prior to screening (visit 1) is not exclusionary).
18. History of active diverticulitis in the 5 years prior to randomisation (visit 2).
19. History of inflammatory bowel disease that has been clinically active during the 12 months prior to randomisation (visit 2).
20. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris, or transient ischaemic attack within 60 days prior to randomisation (visit 2).
21. Uncontrolled hypertension (defined as an average systolic blood pressure >180 mmHg or an
average diastolic blood pressure >110 mmHg) at screening (visit 1). (Note: Potential
participants may be retested for this criterion within the visit window and without rescreening,
1. at the discretion of the investigator).
22. Planned coronary, carotid or peripheral artery revascularisation known on the day of
randomisation (visit 2).
23. 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).
24. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at
screening (visit 1).
25. Presence or history of malignant neoplasms or in situ carcinomas (other than basal or squamous
cell skin cancer, low risk prostate cancer, or in-situ carcinomas of the cervix, or carcinoma in
situ/high grade prostatic intraepithelial neoplasia (PIN)) within 5 years prior to the day of
screening (visit 1).
26. History of bone marrow or solid organ transplant or anticipated to receive an organ transplant
during the study (not including patients who have been in full remission following transplant at
least 5 years and who are not receiving any immunosuppressive therapy). Prior or current medication
27. Received a live or attenuated-live vaccine product within 4 weeks of study intervention
administration (visit 2) or expected to receive a live or attenuated-live vaccine product during
the treatment period. (Note: Not-live and not attenuated-live vaccines are not exclusionary. For
guidance refer to Appendix 10, Section 10.10).
28. Use of preventive systemic antibiotics, systemic antivirals, or systemic antifungals at screening
(visit 1). (Note: “Systemic†is defined as oral or i.v. administered drugs that are absorbed into
the circulation. Antibiotics used to treat latent TB are exempted).
29. Use of systemic immunosuppressive drugs (both small molecules and biologics) or disease
modifying anti-rheumatic drugs (DMARDs including both biologic DMARDs like anti-TNFalpha and conventional DMARDs like methotrexate) at screening (visit 1) or anticipated chronic use of such drugs any time during the study. (Note: Use of otic, ophthalmic, inhaled, and topical corticosteroids or local corticosteroid injections are not exclusionary.)
30. Use of anti-IL-6 products at screening (visit 1) or anticipated use of such drugs any time during
the study.
a Laboratory results of HbA1c for inclusion can be based on:
measurements no more than 90 days old at screening, documented in medical records or
measurements from the optional pre-screening visit (see Section 8.1), documented in
medical records or central laboratory measurement obtained at the screening visit (visit 1).
The subject must have been/be in usual health condition at the time of sample collection used for inclusion as evaluated by the investigator.
Time to first occurrence of expanded MACE, a composite
endpoint consisting of:
• CV deatha
• non-fatal MI
• non-fatal stroke
• hospitalisation for unstable angina pectoris requiring
urgent coronary revascularisation
From randomisation (month 0) to
end-of-study (up to 63 months)
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
ZEUS is a study 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.
This is an interventional, randomised, parallel-group, double-blind, placebo-controlled, multicentre, multi-national CVOT designed to evaluate the effects of 15 mg ziltivekimab versus placebo (randomised 1:1), both administered s.c. once-monthly and added to standard of care, on CV outcomes in participants with established ASCVD, CKD and systemic inflammation