Effects of Iron Therapy in Heart Failure With Preserved Ejection Fraction and Iron Deficiency (PREFER-HF)

Prior treatment

• History of erythropoietin-stimulating agent, i.v. iron therapy, and/or blood transfusion in previous 6 weeks prior torandomization.
• Oral iron therapy at doses \>100 mg/day in previous 1 week prior to randomization. Note: ongoing use of multivitamins containing iron \<75 mg/day is permitted.
• Exercise training programme(s) in the 3 months prior to screening or planned in the next 6 months.
• Currently receiving systemic chemotherapy and/or radiotherapy.
• Renal dialysis (previous, current, or planned within the next 6 months).
• 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.
• Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(ies), or subject is receiving other investigational agent(s).

Other illness

• History of acquired iron overload.
• Known active bacterial infection.
• Subjects with known hepatitis B surface antigen positivity and/or hepatitis C virus ribonucleic acid positivity.
• Clinical evidence of current malignancy with exception of basal cell or squamous cell carcinoma of the skin, and cervical intraepithelial neoplasia.
• Unstable angina pectoris as judged by the investigator; severe valvular or left ventricular outflow obstruction disease needing intervention; atrial fibrillation/flutter with a mean ventricular response rate at rest \>100 beats per minute.
• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.

Lab values

• Chronic liver disease (including active hepatitis) and/or screening alanine transaminase or aspartate transaminase above three times the upper limit of the normal range.
• Vitamin B12 and/or serum folate deficiency. If deficiency-corrected subject may be rescreened for inclusion.

Other

• Subject has known sensitivity to any of the products to be administered during dosing.
• Subjects with known seropositivity to human immunodeficiency virus.
• Subject of childbearing potential who is pregnant (e.g. positive human chorionic gonadotropin test) or is breastfeeding.
• Subject will not be available for all protocol-specified assessments.

• Subjects with stable chronic HF (NYHA II/IV functional class) on optimal background therapy (as determined by the investigator) for at least 4 weeks with no dose changes of heart failure drugs during the last 2 weeks (with the exception of diuretics). In general, optimal pharmacological treatment should include an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and a beta blocker unless contraindicated or not tolerated and diuretic if indicated.
• Left ventricular ejection fraction \>45% (value within 3 months of planned date of randomization).
• BNP \>100 pg/mL and/or N-terminal-pro-BNP \>400 pg/mL at the screening visit.
• Subject must be capable of completing the 6 minute walking test
• Screening serum ferritin \<100 ng/mL or 100-300 ng/mL with transferrin saturation \<20%.
• At least 18 years of age.
• Before any study-specific procedure, the appropriate written informed consent must be obtained.