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

Prior treatment

• 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).
• 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.
• Previous randomisation in this study.
• 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.
• 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.
• 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 anti-IL-6 products at screening or anticipated use of such drugs any time during the study.
• 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.
• Unstable medical therapy for heart failure (including dose of diuretics) within 14 days prior to screening visit (at the discretion of the investigator).

Other illness

• Known or suspected hypersensitivity to study intervention or related products.
• 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).
• 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 cardiac device or atrial flutter/atrial fibrillation ablation procedure known during the screening period.
• 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.
• 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.
• 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).
• Any disorder or circumstance, which in the investigator’s opinion might jeopardise participant’s safety or compliance with the protocol.

Lab values

• Platelet count <120×10^9/L at screening.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × upper limit of normal at screening.
• eGFR<15 mL/min/1.73 m^2 (CKD-EPI9) at screening or chronic haemodialysis or peritoneal dialysis.
• Absolute neutrophil count <2×10^9/L at screening.

Other

• Planned coronary, carotid or peripheral artery revascularisation known during the screening period. (Note: planned coronary angiogram is not exclusionary).
• Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using a highly effective contraceptive method.
• Inadequate standard of care treatment which in the investigator’s opinion makes participation in the study inappropriate.

• 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.