This clinical trial investigates heart failure with mildly reduced or preserved ejection fraction (a condition where the heart cannot pump blood effectively despite the heart’s main pumping chamber still being able to squeeze relatively normally) and systemic inflammation (widespread inflammation throughout the body). The study examines the effects of ziltivekimab compared to placebo when added to standard care. Ziltivekimab is administered under the skin once monthly for participants who have heart failure symptoms and elevated markers of inflammation in their blood.
The purpose of this research is to determine if ziltivekimab is better than placebo at improving heart failure symptoms and physical function in people with this specific type of heart failure who also have inflammation. The study focuses on participants with NYHA Class II-III heart failure (a classification system where Class II means mild symptoms during ordinary activities and Class III means marked limitation of activity due to symptoms) and specific levels of inflammation markers in their blood.
During the 12-month study, participants will receive either ziltivekimab or placebo while continuing their standard heart failure treatments. Their heart failure symptoms, quality of life, and physical function will be assessed using questionnaires and a six-minute walk test (a test measuring how far someone can walk in six minutes). Blood tests will also be performed to measure markers of heart failure and inflammation.
1Initial Study Screening
You will be assessed to confirm eligibility for the study. This includes blood tests to check for inflammation levels (hs-CRP of 2 mg/L or higher) and heart failure markers (NT-proBNP of 225 pg/mL or higher, or 375 pg/mL if you have atrial fibrillation).
The medical team will verify your heart failure diagnosis (classified as NYHA Class II-III, which relates to the severity of your symptoms) and confirm that your heart’s ejection fraction is greater than 40% based on an echocardiogram from the past 12 months.
You will need to complete a walking test (6-minute walk test) and be able to walk at least 100 meters during this test.
You will also complete a questionnaire about your heart failure symptoms and how they affect your daily life (KCCQ questionnaire).
2Randomization
If you qualify for the study, you will be randomly assigned to receive either ziltivekimab or a placebo (an injection that contains no active medication).
Neither you nor your doctor will know which treatment you are receiving during the study.
3Treatment Period (12 months)
You will receive monthly injections of either ziltivekimab or placebo for 12 months.
The medication will be given as a subcutaneous injection (under the skin).
You will continue taking your standard heart failure medications throughout the study period.
4Regular Study Visits
You will attend regular study visits throughout the 12-month period.
At these visits, the medical team will assess your heart failure symptoms, perform physical examinations, and collect blood samples to monitor your response to treatment.
You will complete the KCCQ questionnaire multiple times during the study to track changes in your heart failure symptoms and quality of life.
You will perform the 6-minute walk test at various timepoints to measure your physical function and exercise capacity.
Your NYHA Class (heart failure severity classification) will be assessed to monitor if your heart failure symptoms improve or worsen during the study.
5End-of-Treatment Assessment (Month 12)
At the end of the 12-month treatment period, you will have a final comprehensive assessment.
This includes completing the KCCQ questionnaire and 6-minute walk test to compare with your results from the beginning of the study.
Blood tests will measure changes in inflammation markers (hs-CRP), heart failure markers (NT-proBNP), and kidney function (eGFR).
Your heart failure classification (NYHA Class) will be assessed to determine if there has been any improvement or deterioration.
Who Can Join the Study?
You must have heart failure with a preserved or mildly reduced ejection fraction (how well your heart pumps blood) greater than 40%, documented in the last 12 months
You must have systemic inflammation with a high-sensitivity C-reactive protein (hs-CRP) level of 2 mg/L or higher in your blood test
Your NT-proBNP level (a marker of heart stress) must be at least 225 pg/mL, or 375 pg/mL if you have atrial fibrillation (irregular heartbeat)
You must have a diagnosis of heart failure with NYHA Class II-III symptoms (mild to moderate limitations during physical activity)
You must have structural or functional heart disease shown on an echocardiogram (heart ultrasound) in the past 12 months, with at least one specific heart measurement outside normal range
You must not have been hospitalized or had urgent visits for heart failure between screening and randomization
You must be able to perform the 6-minute walk test (6MWT) and walk at least 100 meters
Your KCCQ clinical summary score (a questionnaire measuring heart failure symptoms and limitations) must be less than 80 at screening
Who Cannot Join the Study?
Having a heart ejection fraction (a measure of how well your heart pumps blood) less than 40% or greater than 70%
Having a recent hospitalization for heart failure (within the past 30 days)
Having a planned heart surgery or procedure within the next 12 months
Having had a heart attack, stroke, or other major cardiovascular problem within the past 90 days
Having uncontrolled high blood pressure (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg)
Having severe kidney problems (estimated glomerular filtration rate <30 mL/min/1.73m²)
Having active liver disease or significant abnormal liver function tests
Having an active or recent infection
Having a history of tuberculosis or positive tuberculosis test
Having HIV, hepatitis B, or hepatitis C infection
Having a history of certain cancers within the past 5 years
Having a known hypersensitivity (allergic reaction) to the study drug
Being pregnant, breastfeeding, or planning to become pregnant
Having received certain medications that affect the immune system
Having any condition that, in the opinion of the investigator, would make participation unsafe
Ziltivekimab is a medication given by injection under the skin once a month. It is being studied for its potential benefits in improving heart failure symptoms and physical function in people with certain types of heart failure who also have systemic inflammation (inflammation throughout the body). This medication targets inflammation, which may play a role in heart failure progression.
Placebo is an inactive substance that looks like the real medication but contains no active ingredients. It is used in clinical trials to help determine if the actual medication being studied is effective. In this study, the placebo is given as an injection under the skin once a month, similar to ziltivekimab.
Heart failure with mildly reduced or preserved ejection fraction – A condition where the heart cannot pump enough blood to meet the body’s needs, despite having a mildly reduced (between 41-49%) or preserved (50% or higher) ejection fraction. The ejection fraction measures how much blood the left ventricle pumps out with each contraction. This form of heart failure occurs when the heart muscle becomes stiff and cannot relax properly between beats, making it difficult to fill with blood. As the disease progresses, patients experience symptoms such as shortness of breath, fatigue, and fluid retention. The condition is often accompanied by systemic inflammation, which can worsen heart function and contribute to disease progression.
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