Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure (IRONOUT)

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.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure
• Intervention / Treatment: Drug: Polysaccharide Iron Complex 150 mg; Drug: Placebo (for Polysaccharide Iron Complex)

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 Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • University Hospitals-Case Medical Center
    • Cleveland, Ohio, United States, 44109
      • Metor Health System
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17603
      • Lancaster General Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Utah
    • Murray, Utah, United States, 84107
      • University of Utah Hospitals and Clinics
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont - Fletcher Allen Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Adrian Hernandez
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Adrian Hernandez, MD,MHS,FAHA, Duke University

Publications and helpful links

General Publications

• Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, Tang WHW, LaRue SJ, Redfield MM, Semigran MJ, Givertz MM, Van Buren P, Whellan D, Anstrom KJ, Shah MR, Desvigne-Nickens P, Butler J, Braunwald E; NHLBI Heart Failure Clinical Research Network. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017 May 16;317(19):1958-1966. doi: 10.1001/jama.2017.5427. Erratum In: JAMA. 2017 Jun 20;317(23 ):2453.
• Lewis GD, Semigran MJ, Givertz MM, Malhotra R, Anstrom KJ, Hernandez AF, Shah MR, Braunwald E. Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure. Circ Heart Fail. 2016 May;9(5):e000345. doi: 10.1161/CIRCHEARTFAILURE.115.000345.

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2014
• Primary Completion (Actual): April 6, 2016
• Study Completion (Actual): April 6, 2016

Study Registration Dates

• First Submitted: July 10, 2014
• First Submitted That Met QC Criteria: July 11, 2014
• First Posted (Estimate): July 14, 2014

Study Record Updates

• Last Update Posted (Actual): July 11, 2017
• Last Update Submitted That Met QC Criteria: June 9, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Trace Elements; Micronutrients; Iron
• Other Study ID Numbers: Pro00054061; 2U10HL084904 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After the study results have been published, site-specific participant data will be shared with sites upon request. Sites are expected to follow their specific institutional policies regarding sharing results with their participants.