Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure

Study Overview
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Brief Summary
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The purpose of this study is to determine if oral iron (Fe) polysaccharide is superior to oral placebo in improving functional capacity as measured by change in peak VO2 (oxygen uptake) by CPET (Cardiopulmonary Exercise Testing) , of a broad population of patients with HFrEF (Heart Failure with Reduced Ejection Fraction) and Fe deficiency at 16 weeks. Hypothesis: In a broad population of HFrEF patients with Fe deficiency, compared to oral placebo, therapy with oral Fe polysaccharide will be associated with improvement in functional capacity at 16 weeks as assessed by CPET.

Detailed Description
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Therapeutic options to further improve functional capacity and symptoms in HF beyond neurohormonal antagonism are limited. Studies have demonstrated impaired oxidative capacity of skeletal muscle among HF patients, which may contribute to symptoms of breathlessness and persistent fatigue. In addition to its role in erythropoiesis, iron (Fe) plays a critical role in skeletal muscle's oxygen (O2)-storage capacity (myoglobin) and systemic aerobic energy production. As Fe deficiency is common in patients with symptomatic HF, repletion of iron stores may improve submaximal exercise capacity among these patients beyond the effects on erythropoiesis. While intravenous Fe repletion in HF patients with mild Fe-deficiency (i.e. Ferritin <100 or Ferritin 100-299 with transferrin saturation <20%) with or without anemia global well-being and functional status, oral Fe repletion has not been studied. Furthermore, the efficacy of oral Fe to replete iron stores in a similar population and its impact on functional capacity, measured objectively by peak VO2, remains unknown.

Official Title
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Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Drug: Polysaccharide Iron Complex 150 mg
* Drug: Placebo (for Polysaccharide Iron Complex)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Previous clinical diagnosis of heart failure with current New York Heart Association (NYHA) Class II-IV symptoms LVEF≤0.40 within 2 years prior to consent, and ≥3 months after a major change in cardiac status (i.e. CABG or CRT). Serum ferritin between 15-100 ng/ml or serum ferritin between 100-299 ng/ml with transferrin saturation <20% Hemoglobin 9.0-13.5 g/dL (males), 9-13.5 (females) at time of enrollment Stable evidence-based medical therapy for HF (including beta-blocker and ACE-inhibitor/ARB unless previously deemed intolerant, and diuretics as necessary) with </= 100% change in dose for 30 days prior to randomization a. Changes in diuretic dose guided by a patient-directed flexible dosing program are considered stable medical therapy Willingness to provide informed consent Exclusion Criteria: Presence of a neuromuscular, orthopedic or other non-cardiac condition that prevents the patient from exercise testing on a bicycle/treadmill ergometer and/or inability to achieve an RER ≥ 1.0 on screening/baseline CPET Severe renal dysfunction (eGFR< 20 ml/min/1.73m2) Severe liver disease (ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x normal) Gastrointestinal conditions known to impair Fe absorption (i.e. inflammatory bowel disease) Known active infection as defined by current use of oral or intravenous antimicrobial agents Documented active gastrointestinal bleeding Active malignancy other than non-melanoma skin cancers Anemia with known cause other than Fe deficiency or chronic disease Fe overload disorders (i.e. hemochromatosis or hemosiderosis) History of erythropoietin, IV or oral Fe therapy, or blood transfusion in previous 3 months. Current ventricular assist device Anticipated cardiac transplantation within the next 4 months Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade Previous adverse reaction to study drug or other oral Fe preparation Known or anticipated pregnancy in the next 4 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Polysaccharide iron complex 150 mg<br>oral Fe polysaccharide 150mg twice daily for 16 weeks | Drug: Polysaccharide Iron Complex 150 mg<br>* Oral Iron<br>* Other names: Feramax 150 mg;|
| Placebo Comparator: Placebo (for Polysaccharide Iron Complex 150 mg)<br>Oral placebo twice a day for 16 weeks | Drug: Placebo (for Polysaccharide Iron Complex)<br>* Sugar capsule designed to mimic Polysaccharide Iron Complex.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption) | To determine if oral Fe (Iron) polysaccharide is superior to oral placebo in improving functional capacity as measured by change in peak VO2 by CPET (Cardiopulmonary Exercise Testing) , of a broad population of patients with HFrEF (Heart Failure with Reduced Ejection Fraction) and Fe deficiency at 16 weeks. | Baseline (BL) and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT) | To determine the impact of oral Fe repletion on Submaximal exercise capacity as measured by 6MWT | Measured at BL, week 8 and week 16 | 
| Change in Plasma NT-pro BNP | To determine the impact of oral Fe repletion on Plasma N-terminal pro-B-type natriuretic peptide (NT-pro BNP) | Measured at Baseline and Week 16 | 
| Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score | To determine the impact of oral Fe repletion on Health Status: KCCQ. KCCQ is a 23-item, self administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life for patients with congestive heart failure. It is a predictive tool that tracks how patients are doing if they have weakened heart muscle due to prior heart attacks, heart valve problems, viral infections, or other causes. The KCCQs questions are used to calculate scores in ten domains. Physical Limitation, Symptom Stability, Frequency, Burden and Total Symptom. Social Limitation, Self-Efficacy, Quality of Life, and Clinical Summary. Overall summary: a combined measure of all the above. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. | Measured at Baseline, Week 8 and Week 16 | 
| Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET | To determine the impact of oral Fe repletion on O2 Uptake Kinetics as measured by CPET | Measured at BL week 16 | 
| Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2 | Change from baseline in Ventilatory Efficiency defined by Ve/VCO2 (carbon dioxide output) as measured by CPET | Measured at BL week 16 |