This study involves people with heart failure who have either mildly reduced or preserved ejection fraction, which means their heart is not pumping blood as well as it should but has not severely weakened. Ejection fraction is a measurement that shows how much blood the heart pumps out with each beat. The study also focuses on people who have inflammation in their body, which is a condition where the body’s immune system is more active than normal and can be measured by certain blood tests. The treatment being tested is called ziltivekimab, which is given as an injection under the skin once a month. Some people in the study will receive ziltivekimab while others will receive placebo, and both groups will continue taking their regular heart failure medications.
The purpose of this study is to find out if ziltivekimab works better than placebo in reducing the risk of death from heart and blood vessel problems and preventing heart failure events such as hospital stays or urgent visits for worsening heart failure. The study will also look at other health outcomes including the combined risk of death from heart problems, heart attacks, and strokes, as well as how the treatment affects kidney function, quality of life, and inflammation levels in the body. Quality of life will be measured using questionnaires that ask about symptoms and daily activities.
During the study, participants will receive monthly injections for up to 48 months. The study will track various health events including hospitalizations for heart failure, deaths, heart attacks, strokes, and changes in heart and kidney function. Blood tests will be done to measure inflammation markers like hs-CRP and heart stress markers like NT-proBNP. Heart function will be checked using echocardiography, which is an ultrasound test that creates pictures of the heart. The study will continue until enough information has been collected to determine whether ziltivekimab is effective in helping people with this type of heart failure and inflammation.
1Initial screening and enrollment
Your blood will be tested to measure high-sensitivity C-reactive protein, which is a marker of inflammation in your body. The level must be at least 2 milligrams per liter.
Your blood will also be tested for NT-proBNP, a substance that indicates how well your heart is working. The required level depends on whether you have an irregular heart rhythm called atrial fibrillation or flutter.
An electrocardiogram, a test that records the electrical activity of your heart, will be performed on the same day as the NT-proBNP blood test.
An echocardiography, which is an ultrasound of your heart, will be reviewed or performed. This test shows the structure and function of your heart, including measurements of heart chambers, wall thickness, and how well your heart muscle moves.
Your left ventricular ejection fraction, which measures how much blood your heart pumps out with each beat, must be greater than 40 percent.
Your heart failure symptoms will be assessed using the New York Heart Association classification, which ranges from Class II to Class IV based on how much your symptoms limit your daily activities.
2Randomization
After screening is complete and you have not had any heart failure hospitalizations or urgent visits requiring immediate care, you will be randomly assigned to receive either ziltivekimab or placebo.
A placebo looks identical to the actual medication but contains no active ingredient.
Neither you nor your doctor will know which treatment you are receiving.
3Treatment phase
You will receive injections of either ziltivekimab or placebo under your skin, which is called subcutaneous administration.
The injections will be given once every month throughout the study.
You will continue taking your regular heart failure medications as prescribed by your doctor. The study medication is added to your standard treatment.
The treatment will continue until the end of the study, which is estimated to occur in July 2027.
4Follow-up visit at 12 months
At 12 months after starting treatment, you will have blood tests to measure high-sensitivity C-reactive protein, NT-proBNP, and a substance called CCI.
Your kidney function will be assessed by measuring estimated glomerular filtration rate, which shows how well your kidneys are filtering waste from your blood.
You will complete a questionnaire called the Kansas City Cardiomyopathy Questionnaire, which asks about your heart failure symptoms and how they affect your quality of life.
Your heart failure symptoms will be assessed again using the New York Heart Association classification.
5Ongoing monitoring throughout the study
Throughout the study, information will be collected about any hospitalizations related to heart failure or urgent visits where you needed immediate treatment for worsening heart failure symptoms.
Any heart-related events will be recorded, including heart attacks, strokes, or death related to heart or blood vessel problems.
Any episodes of irregular heart rhythm called atrial fibrillation will be documented.
Changes in your kidney function will be monitored regularly by measuring estimated glomerular filtration rate.
Any hospitalizations or deaths related to infections will be recorded.
Information about whether you needed to start kidney replacement therapy, such as dialysis or kidney transplantation, will be collected.
6End of study
The study is expected to end in July 2027.
Final assessments will be performed to evaluate the effects of the treatment on your heart failure, kidney function, and overall health.
All information collected throughout the study will be analyzed to determine whether ziltivekimab is effective in reducing heart failure events and death compared to placebo.
Who Can Join the Study?
Requirements to participate in this study:
You must sign a consent form before any study activities begin. Study activities are any procedures done to check if you are suitable for the study or as part of the study itself.
Your blood test must show a level of hs-CRP (a marker of inflammation in your body) of 2 mg/L or higher.
You must meet at least one of these conditions: Your blood test shows NT-proBNP (a substance that indicates heart strain) of 300 pg/mL or higher if you do not have atrial fibrillation or flutter (irregular heart rhythm). If you have irregular heart rhythm, your NT-proBNP must be 600 pg/mL or higher. The heart tracing test called ECG must be done on the same day as the NT-proBNP blood test. OR you were hospitalized or had an urgent unplanned visit for worsening heart failure requiring intravenous water pills in the last 9 months, and your NT-proBNP is 200 pg/mL or higher without irregular heart rhythm, or 600 pg/mL or higher with irregular heart rhythm.
You must have a diagnosis of heart failure with symptoms classified as NYHA Class II to IV (a scale that measures how much heart failure limits your physical activity, from mild to severe limitations).
Your LVEF (left ventricular ejection fraction, which measures how well your heart pumps blood) must be greater than 40 percent, confirmed by echocardiography (an ultrasound test of your heart) within the last 12 months. This measurement must be in your medical records, and there should be no events since then that could have worsened your heart function, such as a heart attack or hospitalization for heart failure.
You must have structural or functional heart disease shown by echocardiography within the last 12 months, with at least one of the following findings: LA volume index (size of your left atrium adjusted for body size) greater than 34 mL/m², LA diameter 3.8 cm or larger, LA length 5.0 cm or larger, LA area 20 cm² or larger, LA volume 55 mL or larger, intraventricular septal thickness (thickness of the wall between heart chambers) 1.1 cm or thicker, posterior wall thickness (thickness of the back wall of your heart) 1.1 cm or thicker, LV mass index (weight of your left ventricle adjusted for body size) 115 g/m² or higher in men or 95 g/m² or higher in women, E/e’ ratio (a measure of heart stiffness) 10 or higher, or e’ velocity (speed of heart muscle relaxation) less than 9 cm/s.
You must not have any hospitalizations or urgent visits for heart failure between your initial screening visit and when you officially join the study.
You must be 18 years of age or older when you sign the consent form.
Who Cannot Join the Study?
The source data does not provide specific exclusion criteria, which are reasons why a patient cannot participate in the study
Without detailed exclusion criteria information, it is not possible to list the specific conditions, medications, or situations that would prevent participation in this clinical trial
Exclusion criteria typically include things like certain other medical conditions, specific medications you are taking, recent surgeries, or laboratory test results that fall outside acceptable ranges
To learn about the specific reasons that might prevent you from joining this study, you would need to review the complete study documentation
Ziltivekimab is an investigational medicine being tested to see if it can help reduce heart-related deaths and heart failure complications in people with certain types of heart failure and inflammation. It is given as an injection under the skin once a month, in addition to the patient’s regular heart failure medications.
Placebo is an inactive substance that looks like the real medicine but contains no active ingredient. It is used in this study to compare against ziltivekimab to determine if the real medicine is effective.
Heart Failure with Mildly Reduced Ejection Fraction – This is a type of heart failure where the heart’s left ventricle does not pump blood as effectively as it should, with the ejection fraction measuring between 41% and 49%. The heart muscle is weakened but not as severely as in other forms of heart failure. Patients experience symptoms such as shortness of breath, fatigue, and swelling in the legs and ankles. The condition occurs when the heart cannot pump enough blood to meet the body’s needs for oxygen and nutrients. Over time, the heart may become further weakened if the underlying causes are not addressed. This form of heart failure often develops gradually and may worsen without proper management.
Heart Failure with Preserved Ejection Fraction – This is a form of heart failure where the heart’s left ventricle pumps normally with an ejection fraction of 50% or higher, but the heart muscle becomes stiff and does not relax properly between beats. The stiffness prevents the heart from filling completely with blood during the relaxation phase. Patients experience symptoms similar to other types of heart failure, including difficulty breathing, especially during physical activity, tiredness, and fluid retention. The condition is often associated with high blood pressure, diabetes, and aging. As the disease progresses, the heart’s ability to fill with blood becomes increasingly impaired. This type of heart failure is particularly common in older adults and people with multiple health conditions.
Systemic Inflammation – This is a condition where inflammation occurs throughout the entire body rather than being limited to a specific area or organ. The immune system becomes activated and releases inflammatory substances into the bloodstream that affect multiple body systems. Common signs include elevated levels of inflammatory markers in the blood, such as C-reactive protein. This widespread inflammation can contribute to the development and worsening of various chronic diseases, including heart conditions. The inflammation may be triggered by various factors including chronic infections, autoimmune responses, or metabolic disorders. Over time, persistent systemic inflammation can damage blood vessels and organs throughout the body.
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