Evaluation of Ziltivekimab Versus Placebo on Heart Failure Symptoms and Physical Function in Patients with HFmrEF or HFpEF and Systemic Inflammation
- Trial ID
- 2023-506988-34-00
- Protocol
- NN6018-4914
- Sponsor
- Novo Nordisk A/S
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **superiority** of ziltivekimab administered subcutaneously once monthly compared to placebo, both in addition to standard care, in improving heart failure symptoms and physical function in participants with heart failure with mildly reduced or preserved ejection fraction (HFmrEF or HFpEF) and systemic inflammation. This is clinically relevant as it addresses the need for effective treatments in managing heart failure symptoms and enhancing physical capabilities in this patient population.
Secondary objectives include comparing the effects of ziltivekimab versus placebo on biomarkers of inflammation, heart failure symptoms, progression of chronic kidney disease (CKD), and physical limitations in the same participant group. These objectives aim to provide a comprehensive understanding of the potential benefits of ziltivekimab beyond symptom management, including its impact on inflammation and disease progression.
Participants
The clinical trial involves a total of **362 participants** diagnosed with **heart failure** with mildly reduced or preserved ejection fraction and systemic inflammation. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as having a serum hs-CRP level of at least 2 mg/L and an NT-proBNP level of 225 pg/mL or higher at screening. Additionally, participants must have a diagnosis of heart failure classified as NYHA Class II-III and a left ventricular ejection fraction greater than 40%, documented by echocardiography. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to perform a 6-minute walk test with a minimum distance of 100 meters, indicating a certain level of physical function. The trial aims to assess the effects of ziltivekimab administered subcutaneously once monthly, compared to a placebo, on heart failure symptoms and physical function.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **ziltivekimab** compared to a placebo in patients with heart failure with mildly reduced or preserved ejection fraction and systemic inflammation. This is a randomized, double-blind, placebo-controlled trial, with participants receiving either ziltivekimab or placebo in addition to standard care. The trial is expected to last for 12 months, with the estimated recruitment start date in April 2024 and an estimated end date in January 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as serum hs-CRP levels, NT-proBNP levels, and echocardiographic documentation of heart failure. The inclusion visit will also confirm the ability to perform a six-minute walk test (6MWT) with a minimum distance of 100 meters. Following randomization, participants will receive monthly subcutaneous injections of either ziltivekimab or placebo for the duration of the study.
Throughout the trial, follow-up visits will be conducted to monitor changes in key endpoints, including the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, six-minute walk distance, and biomarkers such as hs-CRP and NT-proBNP. The primary endpoint is the change in KCCQ clinical summary score from randomization to the end of treatment. Secondary endpoints include changes in six-minute walk distance, hs-CRP, and NT-proBNP, as well as improvements in NYHA class and other quality of life measures.
The end-of-study visit will occur at the conclusion of the 12-month treatment period, where final assessments will be made to evaluate the overall impact of the treatment. Participant involvement is expected to last for the entire 12-month period unless early termination is warranted due to adverse events, withdrawal of consent, or failure to adhere to study protocols. The trial aims to provide valuable insights into the potential benefits of ziltivekimab in managing heart failure symptoms and improving physical function in the target population.
Treatment
The clinical trial involves the administration of **ziltivekimab**, an experimental medication, which is a **solution for injection**. Ziltivekimab is a protein-based therapeutic agent developed by Novo Nordisk A/S. The medication is administered via the **subcutaneous** route. Participants receive a once-monthly dose as part of the study protocol. The maximum treatment period for ziltivekimab is 12 months. The trial aims to evaluate the effects of ziltivekimab on heart failure symptoms and physical function in patients with heart failure with mildly reduced or preserved ejection fraction and systemic inflammation. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen.
In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo is designed to mimic the administration of ziltivekimab but does not contain any active substance. It serves as a control to assess the efficacy and safety of the experimental medication. The placebo is administered under the same conditions as ziltivekimab, ensuring that participants and investigators remain blinded to the treatment allocation. Both ziltivekimab and placebo are administered alongside standard-of-care therapy, which is provided to all participants as part of their routine medical management for heart failure.
Efficacy
The efficacy of ziltivekimab in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) from randomization (month 0) to the end of treatment (month 12). This score ranges from 0 to 100 and evaluates heart failure symptoms and physical function.
Secondary endpoints include both confirmatory and supportive measures. The confirmatory secondary endpoint is the change in six-minute walk distance (6MWD) from randomization to the end of treatment, measured in meters. Supportive secondary endpoints encompass various parameters such as changes in high-sensitivity C-reactive protein (hs-CRP), NT-proBNP levels, and estimated glomerular filtration rate (eGFR) using the CKD-EPI formula, all assessed from baseline to the end of treatment. Additionally, the trial will evaluate the number of participants experiencing improvement in New York Heart Association (NYHA) Class, achieving meaningful changes in KCCQ-CSS and 6MWD, and changes in KCCQ overall summary score, total symptom score, physical limitations score, social limitations score, and health-related quality of life score.
These efficacy parameters will be measured and collected at specified time points, with the primary and secondary endpoints assessed from randomization to the end of the 12-month treatment period. The tools and instruments involved in these assessments include validated scales such as the KCCQ and standardized tests like the 6MWD. The analysis will focus on the comparison of ziltivekimab versus placebo, both added to standard care, in patients with heart failure with mildly reduced or preserved ejection fraction and systemic inflammation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Serum hs-CRP 2 mg/L at screening (visit 1).
- NT-proBNP ≥ 225 pg/mL (375 pg/mL for patients with atrial fibrillation/flutter) at screening.
- Diagnosis of heart failure (NYHA Class II-III).
- LVEF > 40% documented by echocardiography within 12 months prior to or at screening (visit 1). 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 (visit 1) showing at least one of the following: a) LA volume index > 34mL/m2 b) LA diameter ≥ 3.8cm c) LA length ≥ 5.0cm d) LA area ≥ 20cm2 e) LA volume ≥ 55mL f) Intraventricular septal thickness ≥ 1.1cm g) Posterior wall thickness ≥ 1.1cm h) LV mass index ≥ 115g∕m2 in men or ≥ 95 g∕m2 in women i) E/e’ (mean septal and lateral) ≥ 10 j) e’ (mean septal and lateral) < 9cm/s
- No heart failure hospitalisations or urgent heart failure visits between screening and randomisation.
- Able to perform the 6MWT at screening with a minimum distance of 100 metres. (NOTE: Patients are not eligible if any disease or condition, rather than HF, constitutes the main reason for limiting the ability to exercise/reduces exercise capacity).
- KCCQ clinical summary score < 80 at screening
Exclusion Criteria
- Myocardial infarction, stroke, unstable angina pectoris, transient ischaemic attack, or heart failure hospitalisation within 30 days prior to screening (visit 1).
- Systolic blood pressure ≥180 mmHg at screening (visit 1). 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 (visit 1). (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 (visit 1). (NOTE: Planned coronary angiogram is not exclusionary).
- Planned cardiac device or atrial flutter/atrial fibrillation ablation procedure known during the screening period (visit 1).
- 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).
- 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., anaemia, hypothyroidism).
- Clinical evidence of, or suspicion of, active infection at the discretion of the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 01 Apr 2024 | 65 |
 Czechia | Not Recruiting | 01 Apr 2024 | 35 |
 France | Not Recruiting | 01 Apr 2024 | 20 |
 Germany | Not Recruiting | 01 Apr 2024 | 13 |
 Greece | Not Recruiting | 01 Apr 2024 | 55 |
 Poland | Not Recruiting | 01 Apr 2024 | 75 |
 Spain | Not Recruiting | 01 Apr 2024 | 55 |
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 | 12 | PRD10000896 |
Placeboziltivekimab C | Placebo | N/A | — | — | — | N/A |