HERMES – A research study to look at how ziltivekimab works compared to placebo in people with heart failure and inflammation.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novo Nordisk A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

9 May 2023 → ongoing

Decision date (initial)

2023-05-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novo Nordisk A/S

External identifiers

EU CT number

2022-501939-16-00

WHO UTN

U1111-1280-0810

ClinicalTrials.gov

NCT05636176

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate the superiority of ziltivekimab CCI s.c. once-monthly versus placebo, both added to standard of care, in reducing the risk of CV death and HF events in participants with HFmrEF or HFpEF and systemic inflammation

Secondary objectives 2

1. To demonstrate the superiority of ziltivekimab CCI s.c. once-monthly versus placebo, both added to standard of care, in reducing the risk of expanded composite HF endpoint (including CV death) and death in participants with HFmrEF or HFpEF and systemic inflammation.
2. To compare the effects of ziltivekimab CCI s.c. once-monthly versus placebo, both added to standard of care with regards to: expanded composite HF endpoint (including all-cause death), overall clinical benefit, HF events, atrial fibrillation (AF ) events, HF symptoms, physical limitations, CKD, severe infections, biomarkers of inflammation, HF and CCI, in participants with HFmrEF or HFpEF and systemic inflammation

Conditions and MedDRA coding

Heart failure (HF) with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF) and systemic inflammation.

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002840-PIP02-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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.
2. Serum hs-CRP ≥2 mg/L at screening.
3. At least one of the following: NT-proBNP ≥ 300 pg/mL at screening for patients without ongoing atrial fibrillation/flutter (if ongoing atrial fibrillation/flutter at screening, NTproBNP must be ≥ 600 pg/mL).Note that the screening ECG must be obtained the same day as sampling for NT-proBNP. Or HF hospitalisation or urgent/unplanned visit with a primary diagnosis of decompensated heart failure which required intravenous loop diuretic treatment, within the last 9 months prior to screening in combination with NT-proBNP ≥ 200 pg/mL at screening for patients without ongoing atrial fibrillation/flutter (if ongoing atrial fibrillation/flutter at screening, NTproBNP must be ≥ 600 pg/mL).
4. Diagnosis of heart failure (NYHA Class II-IV)
5. LVEF > 40% documented by echocardiography within 12 months prior to or at screening. The LVEF must be documented in medical records and the most recent measurement must be used to determine eligibility with no interim event signalling potential deterioration in ejection fraction (e.g., MI or HF hospitalisation).
6. Structural heart disease and/or functional heart disease documented by echocardiography within 12 months prior to or at screening showing at least one of the following: LA volume index > 34 mL/m^2, LA diameter ≥ 3.8 cm, LA length ≥ 5.0 cm, LA area ≥ 20 cm^2, LA volume ≥ 55 mL, Intraventricular septal thickness ≥1.1 cm, Posterior wall thickness ≥1.1 cm, LV mass index ≥115 g⁄m^2 in men or ≥ 95 g⁄m^2 in women, E/e’ (mean septal and lateral) ≥ 10, e’ (mean septal and lateral) < 9 cm/s.
7. No heart failure hospitalisations or urgent heart failure visits between screening and randomisation.
8. Age 18 years or above at the time of signing the informed consent.

Exclusion criteria 36

1. Known or suspected hypersensitivity to study intervention or related products.
2. Previous randomisation in this study.
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using a highly effective contraceptive method.
4. Participation (i.e., signed informed consent) in any other interventional clinical study of an approved or non-approved investigational medicinal product within 30 days prior to screening.
5. Participation in any clinical study of an approved or non-approved device for the treatment of heart failure within 30 days prior to screening.
6. Any disorder or circumstance, which in the investigator’s opinion might jeopardise participant’s safety or compliance with the protocol.
7. Inadequate standard of care treatment which in the investigator’s opinion makes participation in the study inappropriate.
8. Unstable medical therapy for heart failure (including dose of diuretics) within 14 days prior to screening visit (at the discretion of the investigator).
9. Absolute neutrophil count <2×10^9/L at screening.
10. Platelet count <120×10^9/L at screening.
11. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × upper limit of normal at screening.
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. (Note: Participants with positive anti-HBc and undetectable HBV DNA can be enrolled).
13. Myocardial infarction, stroke, unstable angina pectoris, transient ischaemic attack, or heart failure hospitalisation within 30 days prior to screening.
14. Systolic blood pressure ≥180 mmHg at screening. If the systolic blood pressure is 160-179 mmHg, the patient should be receiving ≥3 antihypertensive drugs. (Note: Potential participants may be retested for this criterion within the visit window and without rescreening, at the discretion of the investigator).
15. Heart rate above 110 or below 40 beats per minute as evaluated on the ECG performed at screening. (Note: Potential participants may be retested for this criterion within the visit window and without rescreening, at the discretion of the investigator).
16. Planned coronary, carotid or peripheral artery revascularisation known during the screening period. (Note: planned coronary angiogram is not exclusionary).
17. Planned cardiac device or atrial flutter/atrial fibrillation ablation procedure known during the screening period.
18. Major cardiac surgical, non-cardiac surgical, or major endoscopic procedure (thoracoscopic or laparoscopic) within the past 60 days prior to randomisation or any major surgical procedure planned at the time of randomisation.
19. Left Ventricular Assist Device (LVAD) implantation or heart transplantation
20. Heart failure due to infiltrative cardiomyopathy (e.g., sarcoid, amyloid), arrhythmogenic right ventricular cardiomyopathy, Takutsubo cardiomyopathy, genetic hypertrophic cardiomyopathy or obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac tamponade, uncorrected more than moderate primary valve disease.
21. Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD.
22. Any other condition judged by the investigator that could account for heart failure symptoms and signs (e.g., CCI, CCI).
23. Clinical evidence of, or suspicion of, active infection at the discretion of the investigator.
24. History of recurrent serious infections (infections leading to hospitalisation or use of i.v. antibiotics) in the 12 months prior to randomisation, at the discretion of the investigator.
25. Diagnosis of human immunodeficiency virus (HIV) and not receiving a stable antiretroviral regimen, at the discretion of the investigator at screening.
26. 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 screening and TB treatment initiated less than 28 days prior to randomisation.
27. eGFR<15 mL/min/1.73 m^2 (CKD-EPI9) at screening or chronic haemodialysis or peritoneal dialysis.
28. History of gastrointestinal perforation. (Note: History of perforated appendicitis more than 5 years prior to screening is not exclusionary).
29. History of active diverticulitis in the 5 years prior to randomisation.
30. History of inflammatory bowel disease that has been clinically active during the 12 months prior to randomisation.
31. 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 screening.
32. History of bone marrow or solid organ transplant or anticipated to receive an organ transplant during the study. Note: Patients no longer receiving immune suppressant therapy and who are in full remission following bone marrow transplant can be included in the study.
33. Received a live or attenuated-live vaccine product within 4 weeks of study intervention administration 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.
34. Use of preventive systemic antibiotics, systemic antivirals, or systemic antifungals at screening. (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).
35. Use of systemic immunosuppressive drugs (both small molecules and biologics) or disease modifying anti-rheumatic drugs (DMARDs including both biologic DMARDs like anti-TNF-alpha and conventional DMARDs like methotrexate) at screening 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).
36. Use of anti-IL-6 products at screening or anticipated use of such drugs any time during the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Time to first occurrence of a composite HF endpoint consisting of CV death, HF hospitalisation or urgent HF visit from randomisation to end of study.
2. Number of CV deaths, HF hospitalisations or urgent HF visits (first and recurrent) from randomisation to end of study.

Secondary endpoints 19

1. Time to first occurrence of 4-point expanded composite HF endpoint, a composite endpoint consisting of CV death, HF hospitalisation or urgent HF visit, Non-fatal MI and Non-fatal stroke. Measued from randomisation to end of study
2. Time to first occurrence of 4-point expanded composite HF endpoint, a composite endpoint consisting of all-cause death, HF hospitalisation or urgent HF visit, Non-fatal MI and Non-fatal stroke. Measued from randomisation to end of study
3. Time to occurrence of CV death from randomisation to end of study
4. Time to occurrence of all-cause death from randomisation to end of study
5. Hierarchical composite of Time to all-cause death, number of HF hospitalisation or urgent HF visits, time to first HF hospitalisation or urgent HF visit (measured from randomisation to end of study) and difference of at least 5 in KCCQ clinical summary score change from baseline to 12 months (assessed by the win ratio)
6. Time to first occurrence of HF hospitalisation or urgent HF visit from randomisation to end of study
7. Number of events of atrial fibrillation from randomisation to end of study
8. Change in KCCQ clinical summary score from randomisation to 12 months
9. Improvement of 5 points or more in KCCQ clinical summary score (yes/no) ) from randomisation to 12 months
10. Improvement of 10 points or more in KCCQ clinical summary score (yes/no) from randomisation to 12 months
11. Improvement in NYHA Class (yes/no) from randomisation to 12 months
12. Time to first occurrence of a composite CKD endpoint consisting of CV death, onset of persistent ≥ 40% reduction in eGFR (CKD-EPI) compared with baseline and kidney failure (defined as death from kidney failure, onset of persistent eGFR< 15 mL/min/1.73 m^2 (CKD-EPI), initiation of chronic kidney replacement therapy (maintenance dialysis or kidney transplantation). Measured from randomisation to end of study
13. Change in eGFR (CKD-EPI) from randomisation to 12 months
14. Annual rate of change in eGFR (CKD-EPI) (total eGFR slope) from randomisation to end of study
15. Number of hospitalisations with infection as primary cause or death due to infection. Measured from randomisation to end of study
16. Change in hs-CRP from randomisation to 12 months
17. Change in NT-proBNP from randomisation to 12 months
18. Change in CCI from randomisation to 12 months
19. Participants achieving threshold of meaningful within-patient change (MWPC) in KCCQ-CSS (yes/no) from randomisation to 12 months

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novo Nordisk A/S

Sponsor organisation

Novo Nordisk A/S

Address

Novo Alle 1

City

Bagsvaerd

Postcode

2880

Country

Denmark

Scientific contact point

Organisation

Novo Nordisk A/S

Contact name

EU Submission Hub

Public contact point

Organisation

Novo Nordisk A/S

Contact name

EU Submission Hub

Third parties 13

Locations

24 EU/EEA countries · 305 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 4 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 405 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

54 submissions — initial application plus substantial / non-substantial modifications