This study will investigate whether intravenous (IV) iron improves symptoms, exercise capacity, and quality of life in patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency.

Iron deficiency is common in heart failure and is associated with worse symptoms, reduced physical activity, poorer quality of life, and increased hospitalisation risk. Intravenous iron therapy has demonstrated clinical benefit in patients with heart failure with reduced ejection fraction (HFrEF), but evidence in HFpEF remains limited.

ISLE-HFpEF is a prospective, randomised, double-blind, placebo-controlled trial enrolling 150 adults with symptomatic HFpEF and iron deficiency. Participants will be randomised in a 1:1 ratio to receive either intravenous ferric derisomaltose (Monofer) or placebo (0.9% sodium chloride). Participants will undergo baseline assessment, treatment infusion, and 12-week follow-up.

The primary outcome is change in 6-minute walk distance at 12 weeks. Secondary outcomes include change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score, physical activity measured using wearable accelerometers, transferrin saturation, NT-proBNP, and New York Heart Association (NYHA) functional class.

The study will also evaluate the feasibility and utility of continuous digital monitoring using wearable technologies, including a thigh-worn SENS Motion accelerometer and the Oura Ring, to assess real-world physical activity and cardiovascular physiology throughout the study period.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and is associated with substantial morbidity, reduced exercise capacity, impaired quality of life, and frequent hospitalisation. Iron deficiency is highly prevalent in patients with heart failure and may be even more common in HFpEF than in heart failure with reduced ejection fraction (HFrEF). In heart failure populations, iron deficiency has been associated with impaired functional capacity, reduced quality of life, and adverse cardiovascular outcomes.

Intravenous (IV) iron therapy has demonstrated symptomatic and functional benefits in multiple randomised trials in patients with HFrEF and iron deficiency, leading to incorporation into contemporary heart failure guidelines. However, evidence supporting IV iron therapy in HFpEF remains limited. The FAIR-HFpEF trial suggested potential improvements in exercise capacity following IV iron therapy, but recruitment challenges resulted in early termination and limited statistical power. Additional adequately powered studies are therefore required to evaluate the efficacy of IV iron in HFpEF.

Iron plays a central role in mitochondrial oxidative phosphorylation and cellular energy production. Impaired myocardial energetics have been demonstrated in iron-deficient heart failure patients and may be particularly relevant in HFpEF, where diastolic relaxation is an energy-dependent process. Restoration of iron stores may therefore improve exercise tolerance, symptoms, and functional status in patients with HFpEF.

ISLE-HFpEF is a prospective, randomised, double-blind, placebo-controlled, parallel-group trial evaluating the effects of intravenous ferric derisomaltose (Monofer) in adults with symptomatic HFpEF and iron deficiency. A total of 150 participants will be randomised in a 1:1 ratio to receive either a single infusion of ferric derisomaltose (up to 20 mg/kg) or placebo (0.9% sodium chloride). Participants will undergo baseline assessment, randomisation and infusion after a two-week run-in period, and follow-up assessment 12 weeks after treatment.

The primary objective is to determine whether IV iron improves exercise capacity, assessed by change in 6-minute walk distance at 12 weeks. Secondary objectives include assessment of quality of life, symptom burden, biochemical markers, and functional status.

The study will also investigate the use of wearable technologies as digital endpoints in cardiovascular clinical trials. Participants will wear a SENS Motion thigh-worn accelerometer continuously for 12 weeks to measure habitual physical activity, including daily step count, physical activity intensity, and sedentary behaviour. Participants will additionally use the Oura Ring Generation 4 to collect exploratory physiological metrics including heart rate variability, resting heart rate, respiratory rate, activity patterns, and estimated cardiorespiratory fitness. These devices are intended to provide objective measures of real-world functional status and behavioural change that may complement traditional clinic-based assessments.

Safety assessments will include monitoring for adverse events and infusion-related hypersensitivity reactions throughout the study period.

Inclusion Criteria:

• Age ≥18 years.
• Willing and able to provide written informed consent.
• Clinical diagnosis of heart failure with preserved ejection fraction (HFpEF).
• New York Heart Association (NYHA) class II or III symptoms at the time of randomisation.
• Ambulatory for at least 7 days prior to randomisation.
• Iron deficiency defined as transferrin saturation (TSAT) <20%.
• Haemoglobin ≤15.0 g/dL.
• Baseline 6-minute walk distance <450 metres.

Exclusion Criteria:

• Unable or unwilling to provide informed consent.
• Prior documented left ventricular ejection fraction (LVEF) <40%.
• Clinical signs or symptoms of active infection, including fever >38°C.
• Intravenous iron therapy, erythropoietin therapy, or blood transfusion within the previous 3 months.
• Concurrent immunosuppressive therapy.
• Known iron overload syndrome or haemochromatosis, or first-degree relative with haemochromatosis.
• Known hypersensitivity to ferric derisomaltose (Monofer) or other intravenous iron preparations.
• Known bleeding anaemia or haemolytic anaemia.
• Any condition precluding exercise testing, including decompensated heart failure, unstable angina, obstructive cardiomyopathy, severe uncorrected valvular disease, significant musculoskeletal disease, or uncontrolled bradyarrhythmias or tachyarrhythmias.
• Probable alternative explanation for symptoms in the opinion of the investigator, including severe obesity, primary pulmonary hypertension, or chronic obstructive pulmonary disease (COPD).
• Severe COPD defined as FEV1 <50%, requirement for home oxygen therapy, or chronic oral steroid therapy.
• Renal replacement therapy or estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m².
• Uncontrolled atrial fibrillation with resting heart rate >110 beats/minute.
• Uncontrolled hypertension with blood pressure >180/110 mmHg.
• Concurrent therapy with an erythropoiesis-stimulating agent.
• Known active malignancy.
• Known HIV infection or active hepatitis infection.
• Pregnancy.
• Decompensated liver disease.

This study will be conducted in a double-blind fashion. Ferric derisomaltose and placebo infusions will be prepared and administered by non-study clinical staff not otherwise involved in trial assessments. Infusion bags and tubing will be concealed to maintain blinding, and participants will be offered an eye mask during infusion procedures. Randomisation records will be retained separately for emergency unblinding if required.