HERMES: Effects of ziltivekimab versus placebo on morbidity and mortality in patients with heart failure with mildly reduced or preserved ejection fraction and systemic inflammation
- Trial ID
- 2022-501939-16-00
- Protocol
- EX6018-4915
- Sponsor
- Novo Nordisk A/S
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to evaluate the efficacy of ziltivekimab administered via subcutaneous injection once monthly compared to a placebo, both in addition to the standard of care, to determine if it reduces the risk of cardiovascular death and heart failure events in patients presenting with heart failure with mildly reduced or preserved ejection fraction and systemic inflammation. 5
Secondary objectives involve comparing the effects of ziltivekimab versus placebo regarding:
- the expanded composite heart failure endpoint, including all-cause mortality,
- overall clinical benefit and heart failure events,
- atrial fibrillation,
- heart failure symptoms and physical limitations,
- chronic kidney disease,
- severe infections,
- biomarkers of inflammation, and
- cardiovascular inflammatory disease.
Participants
This clinical trial involves 3379 participants diagnosed with heart failure with either mildly reduced ejection fraction or preserved ejection fraction accompanied by systemic inflammation. The study population consists of both male and female patients, including vulnerable groups, aged between 18 and 65 years. Selection is based on several clinical parameters, including a diagnosis of NYHA Class II-IV heart failure and a left ventricular ejection fraction greater than 40% documented via echocardiography. Inclusion requires a high-sensitivity C-reactive protein level of ≥2 mg/L and specific NT-proBNP thresholds. Furthermore, participants must exhibit evidence of structural heart disease or functional heart disease through specific left atrial or ventricular measurements.
Plans and Procedures
This Phase IIIa cardiovascular outcomes trial is designed to evaluate the effects of ziltivekimab compared to a placebo in individuals with heart failure characterized by a mildly reduced or preserved ejection fraction and systemic inflammation. The study utilizes a randomized approach to compare the administration of ziltivekimab via subcutaneous injection once monthly against a placebo, both in addition to the standard of care. The research methodology aims to demonstrate superiority in reducing the risk of cardiovascular death and heart failure events. The study protocol begins with a screening visit to assess eligibility through measurements of hs-CRP, NT-proBNP, and echocardiography. Following randomization, participants will undergo the intervention and follow-up procedures until the end of the study. Primary endpoints include the time to the first occurrence of a composite endpoint involving cardiovascular death, heart failure hospitalization, or urgent heart failure visits. Secondary outcomes involve assessing changes in KCCQ clinical summary scores, eGFR, and various mortality and morbidity rates. The trial is estimated to continue through July 2027.
Treatment
The experimental medication is ziltivekimab, provided as a solution for injection. This substance is administered via a subcutaneous route on a once-monthly dosing schedule.
The control group receives a placebo, which is administered in place of the experimental medication. Both the test product and the placebo are administered in addition to standard of care for patients with heart failure with mildly reduced ejection fraction or preserved ejection fraction and systemic inflammation.
Efficacy
The primary efficacy assessment is based on the time to the first occurrence of a composite HF endpoint, which includes cardiovascular death, heart failure hospitalization, or urgent heart failure visit, measured from randomization to the end of the study. Additionally, the total number of cardiovascular deaths, heart failure hospitalizations, and urgent heart failure visits is evaluated.
Secondary endpoints include several expanded composite measures:
- A 4-point expanded composite heart failure endpoint consisting of cardiovascular death, heart failure hospitalization, urgent heart failure visit, non-fatal myocardial infarction, and non-fatal stroke.
- A 4-point expanded composite endpoint consisting of all-cause death, heart failure hospitalization, urgent heart failure visit, non-fatal myocardial infarction, and non-fatal stroke.
- A hierarchical composite evaluated by the win ratio, incorporating time to all-cause death, the number of heart failure hospitalizations or urgent heart failure visits, time to the first heart failure hospitalization or urgent heart failure visit, and a change of at least 5 points in the KCCQ clinical summary score from baseline to 12 months.
- A composite chronic kidney disease endpoint comprising cardiovascular death, onset of persistent eGFR reduction of ≥ 40% compared to baseline, and kidney failure.
Other secondary parameters involve the assessment of atrial fibrillation events and hospitalizations or deaths due to infection. Clinical improvements are measured through changes in the NYHA class and the KCCQ clinical summary score from randomization to 12 months, including the achievement of meaningful within-patient change. Biomarker evaluations include changes in hs-CRP, NT-proBNP, and the cardiovascular inflammatory index from randomization to 12 months. The annual rate of change in eGFR is also monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Serum hs-CRP ≥2 mg/L at screening.
- 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).
- Diagnosis of heart failure (NYHA Class II-IV)
- 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).
- 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.
- No heart failure hospitalisations or urgent heart failure visits between screening and randomisation.
- Age 18 years or above at the time of signing the informed consent.
Exclusion Criteria
- Known or suspected hypersensitivity to study intervention or related products.
- Previous randomisation in this study.
- Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using a highly effective contraceptive method.
- 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.
- Participation in any clinical study of an approved or non-approved device for the treatment of heart failure within 30 days prior to screening.
- Any disorder or circumstance, which in the investigator’s opinion might jeopardise participant’s safety or compliance with the protocol.
- Inadequate standard of care treatment which in the investigator’s opinion makes participation in the study inappropriate.
- Unstable medical therapy for heart failure (including dose of diuretics) within 14 days prior to screening visit (at the discretion of the investigator).
- Absolute neutrophil count <2×10^9/L at screening.
- Platelet count <120×10^9/L at screening.
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × upper limit of normal at screening.
- 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).
- Myocardial infarction, stroke, unstable angina pectoris, transient ischaemic attack, or heart failure hospitalisation within 30 days prior to screening.
- 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).
- 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).
- Planned coronary, carotid or peripheral artery revascularisation known during the screening period. (Note: planned coronary angiogram is not exclusionary).
- Planned cardiac device or atrial flutter/atrial fibrillation ablation procedure known during the screening period.
- 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.
- Left Ventricular Assist Device (LVAD) implantation or heart transplantation
- 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.
- Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD.
- Any other condition judged by the investigator that could account for heart failure symptoms and signs (e.g., CCI, CCI).
- Clinical evidence of, or suspicion of, active infection at the discretion of the investigator.
- 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.
- Diagnosis of human immunodeficiency virus (HIV) and not receiving a stable antiretroviral regimen, at the discretion of the investigator at screening.
- 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.
- eGFR<15 mL/min/1.73 m^2 (CKD-EPI9) at screening or chronic haemodialysis or peritoneal dialysis.
- History of gastrointestinal perforation. (Note: History of perforated appendicitis more than 5 years prior to screening is not exclusionary).
- History of active diverticulitis in the 5 years prior to randomisation.
- History of inflammatory bowel disease that has been clinically active during the 12 months prior to randomisation.
- 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.
- 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.
- 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.
- 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).
- 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).
- Use of anti-IL-6 products at screening or anticipated use of such drugs any time during the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 08 May 2023 | 43 |
 Belgium | Not Recruiting | 08 May 2023 | 50 |
 Bulgaria | Not Recruiting | 08 May 2023 | 145 |
 Croatia | Not Recruiting | 08 May 2023 | 100 |
 Czechia | Not Recruiting | 08 May 2023 | 130 |
 Denmark | Not Recruiting | 08 May 2023 | 60 |
 Estonia | Not Recruiting | 08 May 2023 | 35 |
 Finland | Not Recruiting | 08 May 2023 | 50 |
 France | Not Recruiting | 08 May 2023 | 50 |
 Germany | Not Recruiting | 08 May 2023 | 120 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ziltivekimab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 0 | 48 | PRD8676484 |
Placeboziltivekimab | Placebo | N/A | — | — | — | N/A |
ziltivekimab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 0 | 48 | PRD10000896 |
Placeboziltivekimab | Placebo | N/A | — | — | — | N/A |