Changes in Myocardial Iron After Iron Administration

Study Overview
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Brief Summary
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Recent studies have shown that treatment with intravenous iron in patients with iron deficiency (ID) and heart failure with reduced ejection fraction (HFrEF) improves symptomatology, functional capacity, quality of life, and decreases hospitalizations regardless of anemia. In addition, a decrease in myocardial iron content has been observed in patients with chronic HFrEF. This preliminary evidence has led to postulate that myocardial iron deficiency could play a direct role in the pathogenesis and progression of the disease. The investigators hypothesize that the repletion of myocardial iron would explain part of the benefit of this treatment. Thus, the investigators postulate that cardiac magnetic resonance (CMR) (T2* and T1-mapping sequences) will be sensible enough to detect changes in myocardial iron content as a result of intravenous iron administration, and that such changes will correlate with simultaneous changes in parameters of heart failure severity. In this double-blind 1:1 randomized study controlled by placebo the investigators aim to determine the changes in myocardial iron content after treatment with intravenous ferric carboxymaltose (FCM) by CMR at 7 and 30 days in patients with stable HFrEF and ID.

Official Title
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Changes in Myocardial Iron Content Following Administration of Intravenous Iron (Myocardial-IRON)

Conditions
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Heart Failure, Iron-deficiency

Intervention / Treatment
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* Drug: Ferric carboymaltose
* Drug: Placebo (Normal saline)
* Diagnostic Test: Cardiac magnetic resonance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with ambulatory chronic heart failure Older than 18 years Patients in NYHA class II-III on optimal background therapy (as determined by the investigator) for at least 4 weeks with no dose changes of HF drugs during the last 2 weeks (with the exception of diuretics) Elevated natriuretic peptides levels (NT-proBNP >400 pg/ml) at the screening visit Left ventricle ejection fraction <50% documented in the last 12 months Iron deficiency defined as: serum ferritin level <100 μg/L or ferritin level 100-299 μg/L when TSAT is less than 20%, and hemoglobin <15 g/dL (all at screening) Participant is willing and able to give informed consent for participation in the study Exclusion Criteria: Known sensitivity to any of the products to be administered per protocol. History of acquired iron overload. Severe valve disease, or being scheduled for cardiac surgery within the next 30 days. Acute myocardial infarction or acute coronary syndrome, transient ischemic attack, or stroke within the last 3 months prior to randomization. Coronary artery bypass graft, percutaneous intervention (e.g. cardiac, cerebrovascular, and aortic; diagnostic catheters are allowed), or major surgery, including thoracic and cardiac surgery, within the last 3 months prior to randomization. Ischemic heart disease scheduled for revascularization procedures within the next 30 days. HF scheduled for cardiac resynchronization therapy within the next 30 days. Patients with active bleeding in the last 30 days. Known active infection or active malignancy. Subject at an immediate need of transfusion or hemoglobin ≥15 g/dL. Anemia due to reasons other than iron deficiency Immunosuppressive therapy or renal dialysis History of erythropoietin, intravenous iron therapy, and blood transfusion in the previous 12 weeks. Oral iron therapy at doses >100 mg/day in previous 1 week prior to randomization. Subjects with an immediate need for transfusion. Pregnant or breastfeeding women. Subject of childbearing potential who is not willing to use adequate contraceptive precautions during the study and for up to 5 days after the last scheduled dose of study medication. Subject currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study, or subject is receiving other investigational agent(s). Any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: After providing informed consent, patients will be randomly assigned, with a remote, web-based computer-generated block randomization procedure in an allocation 1:1 ratio, to either receive intravenous ferric carboxymaltose (FCM) or placebo. Intramyocardial iron will be evaluated at 3 time points: before administration of CMF/placebo, and at 7 and 30 days. At 30 days, patients assigned to placebo will receive intravenous CMF if iron deficiency persists.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intravenous ferric carboxymaltose<br>Ferric Carboxymaltose solution [Ferinject® (FCM), Vifor Pharma (Glattbrugg, Switzerland)] will be given as a perfusion of 20 mL (which is the amount of FCM that is equivalent to 1000 mg of iron) diluted in a sterile saline solution (0.9% weight/volume (w/v) NaCl) administered over at least 15 min. | Drug: Ferric carboymaltose<br>* Ferric Carboxymaltose solution [Ferinject® (FCM), Vifor Pharma (Glattbrugg, Switzerland)]<br>* Other names: Ferinject, intravenous iron;Diagnostic Test: Cardiac magnetic resonance<br>* Cardiac magnetic resonance including T2* and T1-mapping sequences<br>|
| Placebo Comparator: Normal saline<br>Normal saline (0.9% weight/volume (w/v) NaCl) administered as per the instructions for active therapy. | Drug: Placebo (Normal saline)<br>* Normal saline (0.9% weight/volume (w/v) NaCl)<br>Diagnostic Test: Cardiac magnetic resonance<br>* Cardiac magnetic resonance including T2* and T1-mapping sequences<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in myocardial iron content assessed by CMR T2* |  | 7 and 30 days | 
| Changes in myocardial iron content assessed by CMR T1-mapping |  | 7 and 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in left ventricular systolic function evaluated with cardiac magnetic resonance | Changes in left ventricular systolic function evaluated with cardiac magnetic resonance | 7 and 30 days | 
| 6-minute walking test | Changes in functional capacity assessed by distance walked in 6 minutes (6-minute walking test) | 7 and 30 days | 
| New York Heart Association (NYHA) class. | Changes in functional capacity assessed by New York Heart Association (NYHA) class. | 7 and 30 days | 
| The Kansas City quality of life questionnaire (KCCQ) | Quality of life assessed by The Kansas City quality of life questionnaire (KCCQ). KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. | 7 and 30 days | 
| Antigen carbohydrate 125 (CA125) | Laboratory tests, biomarkers: antigen carbohydrate 125 (CA125) | 30 days | 
| Amino-terminal pro-brain natriuretic peptide (NT-proBNP) | Laboratory tests, biomarkers: amino-terminal pro-brain natriuretic peptide (NT-proBNP) | 30 days | 
| Galectin-3 | Laboratory tests, biomarkers: galectin-3 | 30 days | 
| ST-2 | Laboratory tests, biomarkers: ST-2 | 30 days | 
| High-sensitivity troponin (hsTnT) | Laboratory tests, biomarkers: high-sensitivity troponin (hsTnT) | 30 days | 
| Cystatin C | Laboratory tests, biomarkers: cystatin C | 30 days | 
| Neutrophil gelatinase-associated lipocalin (NGAL) | Laboratory tests, biomarkers: neutrophil gelatinase-associated lipocalin (NGAL) | 30 days | 
| Serum creatinine | Laboratory tests: serum creatinine | 30 days | 
| Urea | Laboratory tests: urea | 30 days | 
| Estimated glomerular filtration rate (eGFR) | Laboratory tests: estimated glomerular filtration rate (eGFR) | 30 days | 
| Hemoglobin | Laboratory tests: hemoglobin | 30 days | 
| Ferritin | Laboratory tests: ferritin | 30 days | 
| Transferrin saturation (TSAT) | Laboratory tests: transferrin saturation (TSAT) | 30 days | 
| soluble transferrin receptor (sTfR) | Laboratory tests: soluble transferrin receptor (sTfR) | 30 days | 
| Hepcidin | Laboratory tests: hepcidin. | 30 days | 
| Clinical events: all-cause hospitalizations | All-cause hospitalizations | 30 days | 
| Clinical events: cardiovascular hospitalizations. | Cardiovascular hospitalizations | 30 days | 
| Clinical events: heart failure hospitalizations. | Heart failure hospitalizations | 30 days | 
| Clinical events: time to first hospitalization for any reason. | Time to first hospitalization for any reason. | 30 days | 
| Clinical events: time to first hospitalization for any cardiovascular reason. | Time to first hospitalization for any cardiovascular reason. | 30 days | 
| Clinical events: time to first hospitalization due to worsening heart failure. | Time to first hospitalization due to worsening heart failure. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, Iron deficiency, Cardiac magnetic resonance, Ferric carboxymaltose, Myocardial iron