Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure

Phase 3

Completed

• Conditions: Chronic Heart Failure
• Interventions: Drug: Polysaccharide Iron Complex 150 mg; Drug: Placebo (for Polysaccharide Iron Complex)

• Registration Number: NCT02188784
• Lead Sponsor: Adrian Hernandez

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2014-07-10
• Study First Submitted QC: 2014-07-11
• Study First Posted: 2014-07-14
• Study Start: 2014-09-03
• Primary Completion: 2016-04-06
• Study Completion: 2016-04-06
• Results First Submitted: 2016-12-30
• Results First Submitted QC: 2017-04-05
• Results First Posted: 2017-05-15
• Status Verified: 2017-06
• Last Update Submitted: 2017-06-09
• Last Update Posted: 2017-07-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 225

Inclusion Criteria

1. Age >18 years

2. 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).

3. Serum ferritin between 15-100 ng/ml or serum ferritin between 100-299 ng/ml with transferrin saturation <20%

4. Hemoglobin 9.0-13.5 g/dL (males), 9-13.5 (females) at time of enrollment

5. 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

6. Willingness to provide informed consent

Exclusion Criteria

1. 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
2. Severe renal dysfunction (eGFR< 20 ml/min/1.73m2)
3. Severe liver disease (ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x normal)
4. Gastrointestinal conditions known to impair Fe absorption (i.e. inflammatory bowel disease)
5. Known active infection as defined by current use of oral or intravenous antimicrobial agents
6. Documented active gastrointestinal bleeding
7. Active malignancy other than non-melanoma skin cancers
8. Anemia with known cause other than Fe deficiency or chronic disease
9. Fe overload disorders (i.e. hemochromatosis or hemosiderosis)
10. History of erythropoietin, IV or oral Fe therapy, or blood transfusion in previous 3 months.
11. Current ventricular assist device
12. Anticipated cardiac transplantation within the next 4 months
13. Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade
14. Previous adverse reaction to study drug or other oral Fe preparation
15. Known or anticipated pregnancy in the next 4 months

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Polysaccharide iron complex 150 mg	Polysaccharide Iron Complex 150 mg	oral Fe polysaccharide 150mg twice daily for 16 weeks
Placebo (for Polysaccharide Iron Complex 150 mg)	Placebo (for Polysaccharide Iron Complex)	Oral placebo twice a day for 16 weeks

Primary Outcome Measures

Name	Time	Method
Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption)	Baseline (BL) and Week 16	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT)	Measured at BL, week 8 and week 16	To determine the impact of oral Fe repletion on Submaximal exercise capacity as measured by 6MWT
Change in Plasma NT-pro BNP	Measured at Baseline and Week 16	To determine the impact of oral Fe repletion on Plasma N-terminal pro-B-type natriuretic peptide (NT-pro BNP)
Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score	Measured at Baseline, Week 8 and Week 16	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.
Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET	Measured at BL week 16	To determine the impact of oral Fe repletion on O2 Uptake Kinetics as measured by CPET
Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2	Measured at BL week 16	Change from baseline in Ventilatory Efficiency defined by Ve/VCO2 (carbon dioxide output) as measured by CPET

Trial Locations

Locations (17)

Emory University School of Medicine; 🇺🇸 Atlanta, Georgia, United States

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Saint Louis University Hospital; 🇺🇸 Saint Louis, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

University Hospitals-Case Medical Center; 🇺🇸 Cleveland, Ohio, United States

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