Rationale and design of the RISE-HF trial: sucrosomial iron in heart failure.

Aims: Compared with intravenous iron, oral iron is less expensive, avoids healthcare complexities, and reduces the risk of iron overload. However, conventional oral formulations have not improved clinical outcomes in heart failure (HF) and iron deficiency (ID), largely due to poor absorption. Sucrosomial iron (SI) partially bypasses hepcidin-controlled absorption and showed favorable effects in a small case-control study, warranting further evaluation in a randomized trial. Methods: The Effect of Oral sucRosomIal Iron on exerciSE Capacity and Quality of Life in Patients With Heart Failure (RISE-HF; NCT06270498) is a randomized, placebo-controlled, double-blind study enrolling 60 patients with HF with left ventricular ejection fraction <50%, ID (transferrin saturation (TSAT) < 20%), ferritin <400 μg/L and hemoglobin (Hb) 10-16 g/dL. Participants are randomized 1:1 to receive SI (Sideral Forte®: sucrosomial iron 30 mg + 70 mg vitamin C) or placebo for 24 weeks, with daily dose tailored to Hb (2 capsules for Hb 10-13.9 g/dL; 1 capsule for Hb 14-16 g/dL). Co-primary endpoints are changes from baseline to week 12 in exercise capacity, assessed by the 6-min walk test (6MWT) distance, and in quality of life, assessed by the Kansas City Cardiomyopathy Questionnaire-12. Secondary endpoints include changes in individual co-primary endpoints at week 24, effects on iron status and oxidative stress biomarkers, N-terminal pro type-B natriuretic peptide and echocardiographic indices of cardiac function, and gastrointestinal tolerability. Conclusions: RISE-HF will determine whether SI can safely improve exercise capacity, quality of life, and iron status in patients with HF and TSAT-defined ID, justifying a larger multicenter trial.