Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency
Condition: Iron Deficiency; Heart Failure
MeSH terms: Heart Failure; Anemia, Iron-Deficiency; Iron Deficiencies
Intervention: ferric carboxymaltose; Normal saline 0.9%
Intervention description: FCM will be administered as an undiluted bolus injection. The study treatment dose (mL) to be administered will be determined by the patient's body weight and haemoglobin (Hb) value at the respective visits where study treatment will be administered; Normal saline will be administered as a bolus injection.
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 1132.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Heart Failure; Iron Deficiency

Summary:

      Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and
      Iron Deficiency (Affirm-AHF)
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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:

               1. Upon admission for the AHF episode, persistent dyspnoea at rest in a recumbent
                  sitting position (30-45°) or with minimal exertion

               2. 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)

               3. 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

               4. 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)

          2. Subject is iron deficient defined as serum ferritin <100 ng/mL or 100 ng/mL ≤ serum
             ferritin ≤299 ng/mL if TSAT <20%.

          3. Left ventricular ejection fraction <50% (assessed and documented within 12 months
             prior to randomisation).

          4. Male or female aged ≥18 years old.

          5. 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:

          1. 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).

          2. 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).

          3. 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).

          4. Clinical evidence of acute coronary syndrome, transient ischemic attack or stroke,
             within the last 30 days prior randomisation.

          5. Severe valvular or left ventricular outflow obstruction disease needing intervention.

          6. 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.

          7. Subject has a body weight <35 kg at randomisation.

          8. Subject at an immediate need of transfusion or with a Hb <8 g/dL* or with a Hb >15
             g/dL.

          9. 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.

         10. 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.

         11. Subject has known hypersensitivity to any of the study products to be administered or
             known serious hypersensitivity to other parenteral iron products.

         12. 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).

         13. History of erythropoietin stimulating agent, IV iron therapy, and/or blood transfusion
             in previous 3 months prior to randomisation.

         14. 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.

         15. Currently receiving systemic chemotherapy and/or radiotherapy.

         16. Renal dialysis (previous, current or planned within the next 6 months).

         17. 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.

         18. Terminal illness other than HF with expected survival <12 months.

         19. Chronic liver disease (including active hepatitis) and/or alanine transaminase or
             aspartate transaminase above 3 times the upper limit of the normal range.

         20. Subjects with known hepatitis B surface antigen positivity and/or hepatitis C virus
             ribonucleic acid positivity.

         21. 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.

         22. 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).

         23. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast
             feeding.

         24. 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.

         25. Subject has a history of drug or alcohol abuse within 2 years prior to screening.

         26. 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.'