Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency

This is a randomised, double-blind, placebo-controlled Trial (RCT). The 52 weeks observation period following randomisation is considered appropriate to investigate the primary endpoint of recurrent HF hospitalisations and CV death. To evaluate the effect of intravenous ferric carboxymaltose (IV FCM) in iron deficient subjects with AHF, subjects will be enrolled during a hospital stay (Index hospitalisation) after the acute care treatment of the index event has been stabilised. All subjects will continue to receive their established standard therapy for HF and medical emergencies will be treated according to local routine.

Inclusion criteria

• Currently hospitalised for an episode of acute heart failure (AHF) where AHF was the primary reason for hospitalisation. All of the following (i.e., items a to d) must apply:

• Upon admission for the AHF episode, persistent dyspnoea at rest in a recumbent sitting position (30-45°) or with minimal exertion
• Upon or during the AHF admission, at least 2 of the following clinical findings were present: i. Congestion on chest X-ray ii. Rales on chest auscultation iii. Oedema ≥1+ on a 0-3+ scale, indicating indentation of skin with mild digital pressure that requires 10 or more seconds to resolve in any dependent area including extremities or sacral region iv. Elevated jugular venous pressure (≥8 cm H2O)
• Natriuretic peptide levels, measured ≤72 hours of the AHF admission must have been: i. Brain natriuretic peptide (BNP) ≥400 pg/mL or N-terminal-pro-brain natriuretic peptide (NT-proBNP) ≥1,600 pg/mL or ii. BNP ≥600 pg/mL or NT-proBNP ≥2,400 pg/mL for subjects presenting with atrial fibrillation when the blood sample was taken iii. For subjects treated with an angiotensin receptor neprilysin inhibitor (ARNI) in the previous 4 weeks prior to randomisation only NT-proBNP values should be considered
• AHF episode treated with minimally 40 mg of IV furosemide (or equivalent IV loop diuretic defined as 20 mg of torasemide or 1 mg of bumetanide)
• Subject is iron deficient defined as serum ferritin <100 ng/mL or 100 ng/mL ≤ serum ferritin ≤299 ng/mL if TSAT <20%.
• Left ventricular ejection fraction <50% (assessed and documented within 12 months prior to randomisation).
• Male or female aged ≥18 years old.
• Subject (or legally acceptable representative)* has provided the appropriate written informed consent. Subject must provide written informed consent before any study-specific procedures are performed.

Exclusion criteria

• Dyspnoea due to non-cardiac causes such as acute or chronic respiratory disorders or infections (i.e., severe chronic obstructive pulmonary disease, acute bronchitis, pneumonia, primary pulmonary hypertension).
• Temperature >38°C (oral or equivalent), active infective endocarditis, sepsis, systemic inflammatory response syndrome, or any other active infection requiring anti-microbial treatment at any time during an Index hospitalisation. (Note that it does NOT include short-term prophylactic administration of antibiotics or short-term temperature elevation at admission which is no longer present at the time point of discharge/randomisation).
• Documented restricted amyloid myocardiopathy, or acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. (Note that it does NOT include restrictive mitral filling patterns seen on Doppler echocardiographic assessments of diastolic function).
• Clinical evidence of acute coronary syndrome, transient ischemic attack or stroke, within the last 30 days prior randomisation.
• Severe valvular or left ventricular outflow obstruction disease needing intervention.
• Coronary-artery bypass graft, cardiac resynchronisation therapy device implantation, percutaneous intervention (e.g., cardiac, cerebrovascular, aortic, diagnostic catheters are allowed) or major surgery that led to significant blood loss, including thoracic and cardiac surgery, within the last 3 months prior to randomisation.
• Subject has a body weight <35 kg at randomisation.
• Subject at an immediate need of transfusion or with a Hb <8 g/dL* or with a Hb >15 g/dL.
• Subjects on treatment for Vitamin B12 and/or serum folate deficiency. Note: Use of Vitamin B12 and folic acid as supplement therapy (not for deficiency treatment) is permitted.
• Subject with a known anaemia not attributed to ID (e.g., other microcytic anaemia) or with an evidence of iron overload (e.g., haemochromatosis) or disturbances in the utilisation of iron.
• Subject has known hypersensitivity to any of the study products to be administered or known serious hypersensitivity to other parenteral iron products.
• Subject with known severe allergies including drug allergies, history of severe asthma, eczema or other atopic allergy and in subjects with immune or inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis).
• History of erythropoietin stimulating agent, IV iron therapy, and/or blood transfusion in previous 3 months prior to randomisation.
• Oral iron therapy at doses >100 mg/day in previous 4 weeks prior to randomisation. Note: Ongoing use of multivitamins containing iron <75 mg/day are permitted.
• Currently receiving systemic chemotherapy and/or radiotherapy.
• Renal dialysis (previous, current or planned within the next 6 months).
• Subject has known active malignancy of any organ system, i.e., clinical evidence of current malignancy or not in stable remission for at least 3 years since completion of last treatment with exception of non-invasive basal cell carcinoma, squamous cell carcinoma of the skin or cervical intra-epithelial neoplasia.
• Terminal illness other than HF with expected survival <12 months.
• Chronic liver disease (including active hepatitis) and/or alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range.
• Subjects with known hepatitis B surface antigen positivity and/or hepatitis C virus ribonucleic acid positivity.
• Subject previously randomised into this study. Note: Subjects may be rescreened but when rescreened, all tests must fall inside the maximum specified screening windows for each criterion.
• Subject is currently enrolled in or has completed any other investigational device or drug study <30 days prior to screening, or is receiving other investigational agent(s).
• Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast feeding.
• If of childbearing potential, subject is not using adequate contraceptive precautions. Subject must agree to use adequate contraception during the study and for 1 month after the last dose of study treatment. A highly effective method of birth control must be used.
• Subject has a history of drug or alcohol abuse within 2 years prior to screening.
• Subject has a significant medical condition(s), anticipated need for major surgery during the study, or any other kind of disorder that may be associated with increased risk to the subject, or may interfere with study assessments, outcomes, or the ability to provide written informed consent or comply with study procedures, in the Investigator's opinion.

• Following section in italics is applicable for The Netherlands, Spain and Singapore only (NL, ES and SG only): 'The lower threshold of Hb values is set to 10 g/dL.'