Effect of Oral sucRosomIal Iron on exerciSE Capacity and Quality of Life in Patients With Heart Failure (RISE-HF)

Effect of Oral sucRosomIal Iron on exerciSE Capacity and Quality of Life in Patients With Heart Failure: a Randomized, Placebo-controlled Trial (RISE-HF)

The goal of this study is to investigate the effect of oral sucrosomial iron on exercise capacity and quality of life in patients with heart failure (HF) and iron deficiency (ID).

The main question the study aims to answer is whether oral sucrosomial iron improved exercise capacity, assessed by six-minute walk test, and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire, compared with placebo.

One group of participants will receive treatment with oral sucrosomial iron and the other group will receive treatment with placebo.

Study Overview

• Status: Not yet recruiting
• Conditions: Iron-deficiency; Chronic Heart Failure; Left Ventricular Systolic Dysfunction
• Intervention / Treatment: Dietary supplement: Sucrosomial iron; Other: Placebo

Detailed Description

Based on clinical trials, treatment with intravenous iron improves symptoms, exercise capacity, and may reduce HF hospitalizations in patients with HF and ID. On the contrary, treatment of ID with oral iron has no effect on exercise capacity. High hepcidin levels prevent oral intestinal absorption and blunt the response to oral iron administration. Sucrosomial iron (SI) consists of a nucleus of ferric pyrophosphate with an envelope of sucrose ester of fatty acids, which promotes intestinal absorption through paracellular and lymphatic routes, independent of hepcidin. In contrast with intravenous iron infusion, administration of oral iron may not promote oxidative stress, since the intestinal iron absorption prevent the formation of labile, non-transferrin bound, plasma iron.

The study will investigate the effect of oral SI supplementation on exercise capacity, assessed by six-minute walk test, and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire, compared with placebo in patients with HF, a left ventricular ejection fraction (LVEF) <50%. Iron deficiency was defined as transferrin saturation (TSAT) <20%.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Gabriele Masini, MD PhD; Phone Number: 0039 050996712; Email: gabriele.masini@unipi.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Chronic HF (New York Heart Association [NYHA] functional class II-IV) patients, on optimal therapy, and clinically stable for at least 4 weeks with no dose changes of HF drugs
2. LVEF <50% at screening visit (historical value can be used if performed within 6 months of screening visit)
3. Either a documented hospitalization for HF in the previous 12 months of enrolment or an elevated NT-proBNP: >300 pg/mL (or BNP >100 pg/mL) for patients in normal sinus rhythm; >1,000 pg/mL (or BNP >400 pg/mL) for patients in atrial fibrillation
4. TSAT <20%
5. Hemoglobin 10.0-15.0 g/dL
6. Rapid iron repletion with intravenous iron is not considered a clinical necessity by physicians after reviewing patient medical record (if anaemia is present, its grade is no more than mild)
7. Age ≥18 years, male and female
8. Willingness to provide informed consent
9. Subjects who decide to use single or dual contraceptive methods to avoid conceiving during the study period

Exclusion Criteria:

1. Neuromuscular, orthopedic or other non-cardiac condition that prevents the patient from exercise testing
2. Exercise training program in the previous 3 months, or planned in the next 3 months
3. Recent (<3 month) acute coronary syndrome, coronary artery bypass surgery, percutaneous coronary interventions, transient ischemic attack, or stroke
4. Severe valvular disease, hypertrophic obstructive cardiomyopathy, restrictive or constrictive cardiomyopathy, acute myocarditis
5. Atrial fibrillation or flutter with a ventricular response rate of >100 beats per minute at rest
6. Temperature >38 °C (oral or equivalent) or active infection as defined by current use of oral or intravenous antimicrobial agents
7. Need for blood transfusion within the last month
8. Hb<10 g/dL or Hb>15 g/dL
9. Rapid iron repletion with intravenous iron is considered a clinical necessity by physicians after reviewing patient medical record
10. Documented active gastrointestinal bleeding
11. Oral iron, i.v. iron or erythropoietin stimulating agent within the last 3 months
12. eGFR ≤15 mL/min or on hemodialysis
13. Chronic liver disease and/or alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range
14. Active cancer
15. Evidence of iron overload (ferritin >400 ng/mL)
16. Hypersensitivity to any of the study products or known severe allergies
17. Participation in another study
18. Low body weight (<35 kg)
19. Known or anticipated pregnancy in the next 4 months
20. Need for forbidden medications
21. Breastfeeding
22. Consumption of iron-rich foods or any food that alter iron absorption (i.e. food rich in vitamin C) due to dietary requirements
23. Any pathological condition or disease associated with a reduction or an impairment of intestinal iron absorption (i.e., prior gastrectomy, atrophic gastritis, bariatric surgery, coeliac disease)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo pills will be identical in shape, form and color of SI pills; they will contain the same components of SiderAL Forte® except for sucrosomial iron and vitamin D. Placebo will be administered orally once a day for 3 months according to the same dose scheme in the intervention arm.
Active Comparator: Sucrosomial iron	Dietary supplement: Sucrosomial iron; Sucrosomial iron with the addition at a fixed dose of vitamin C to promote iron absorption (SiderAL® Forte) will be administered orally once a day for 12 weeks. The dose regimen for all participants will be calculated according to the haemoglobin (Hb) levels at baseline evaluation and to patient's body weight as follows: Hb 14-15 g/dL: 1 tablet once a day, corresponding to 30 mg/daily, for 12 weeks; Hb 10-13.9 g/dL: 2 tablets once a day, corresponding to 60 mg/daily, for 12 weeks; Other Names: SiderAL Forte

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exercise capacity	Difference in six-minute walk test (6MWT) distance, expressed as meters	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life	Difference in Kansan City Cardiomyopathy Questionnaire (KCCQ)-12 overall score	12 weeks
6MWT distance improvement	Proportion of patients with 15 meters improvement in 6MWT distance (responders)	12 weeks
Quality of life improvement	Proportion of patients with 5-point improvement in KCCQ-12 score (responders)	12 weeks
Exercise capacity (peak oxygen consumption)	Difference in exercise capacity, assessed by peak oxygen consumption (pVO2) (in the subgroup of patients subjected to cardio-pulmonary exercise stress test)	12 weeks
F2-isoprostanes	Change in serum F2-isoprostanes	12 weeks
Soluble NOX2-derived peptide (sNOX2-dp)	Change in soluble NOX2-derived peptide (sNOX2-dp)	12 weeks
H2O2	Change in H2O2 production	12 weeks
Phosphate	Change in serum phosphate	12 weeks
Fibroblast growth factor (FGF)-23	Change in GFG-23	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
N-terminal pro-B-type natriuretic peptide (NTproBNP)	Change in N-terminal pro-B-type natriuretic peptide (NTproBNP)	12 weeks
Transferrin saturation (TSAT)	Change in TSAT	12 weeks
Ferritin	Change in ferritin levels	12 weeks
Serum iron	Change in serum iron	12 weeks
Soluble transferrin receptor (sTfR)	Change in sTfR	12 weeks
Hepcidin	Change in Hepcidin	12 weeks
Cardiac structure and function 1	Difference in left ventricular ejection fraction (LVEF)	12 weeks
Cardiac structure and function 2	Difference in left ventricular end-diastolic volume	12 weeks
Cardiac structure and function 3	Difference in left ventricular end-systolic volume (LVESV)	12 weeks
Cardiac structure and function 4	Difference in E/e'	12 weeks
Cardiac structure and function 5	Difference in left atrial volume index (LAVi)	12 weeks
Cardiac structure and function 6	Difference in pulmonary artery systolic pressure (PASP)	12 weeks
Clinical outcome	Time to death or first HF hospitalization	12 weeks

Collaborators and Investigators

• Sponsor: Raffaele De Caterina
• Collaborators: University of Pisa, Italy
• Investigators: Principal Investigator: Gabriele Masini, MD PhD, University of Pisa; Study Director: Raffaele De Caterina, MD PhD, University of Pisa

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: February 10, 2024
• First Submitted That Met QC Criteria: February 19, 2024
• First Posted (Estimated): February 21, 2024

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: heart failure; iron deficiency; sucrosomial iron
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Ventricular Dysfunction; Heart Failure; Anemia, Iron-Deficiency; Ventricular Dysfunction, Left; Iron Deficiencies
• Other Study ID Numbers: 24811

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No