Back to resultsOral Iron Repletion Effects On Oxygen Uptake in Heart Failure (IRONOUT)
Primary Purpose
Chronic Heart Failure
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Polysaccharide Iron Complex 150 mg
Placebo (for Polysaccharide Iron Complex)
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Heart Failure
Eligibility Criteria
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
Sites / Locations
- Emory University School of Medicine
- Johns Hopkins Hospital
- Tufts Medical Center
- Massachusetts General Hospital
- Brigham and Women's Hospital
- Mayo Clinic
- Saint Louis University Hospital
- Washington University School of Medicine
- Duke University Medical Center
- University Hospitals-Case Medical Center
- Metor Health System
- Cleveland Clinic Foundation
- Lancaster General Hospital
- Hospital of the University of Pennsylvania
- Thomas Jefferson University
- University of Utah Hospitals and Clinics
- The University of Vermont - Fletcher Allen Health Care
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Polysaccharide iron complex 150 mg
Placebo (for Polysaccharide Iron Complex 150 mg)
Arm Description
oral Fe polysaccharide 150mg twice daily for 16 weeks
Oral placebo twice a day for 16 weeks
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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
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)
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.
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
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
Full Information
NCT ID
NCT02188784
First Posted
July 10, 2014
Last Updated
June 9, 2017
Sponsor
Adrian Hernandez
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT02188784
Brief Title
Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure
Acronym
IRONOUT
Official Title
Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure
Study Type
Interventional
2. Study Status
Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
September 3, 2014 (Actual)
Primary Completion Date
April 6, 2016 (Actual)
Study Completion Date
April 6, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Adrian Hernandez
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Heart Failure
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
225 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Polysaccharide iron complex 150 mg
Arm Type
Active Comparator
Arm Description
oral Fe polysaccharide 150mg twice daily for 16 weeks
Arm Title
Placebo (for Polysaccharide Iron Complex 150 mg)
Arm Type
Placebo Comparator
Arm Description
Oral placebo twice a day for 16 weeks
Intervention Type
Drug
Intervention Name(s)
Polysaccharide Iron Complex 150 mg
Other Intervention Name(s)
Feramax 150 mg
Intervention Description
Oral Iron
Intervention Type
Drug
Intervention Name(s)
Placebo (for Polysaccharide Iron Complex)
Intervention Description
Sugar capsule designed to mimic Polysaccharide Iron Complex.
Primary Outcome Measure Information:
Title
Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption)
Description
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.
Time Frame
Baseline (BL) and Week 16
Secondary Outcome Measure Information:
Title
Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT)
Description
To determine the impact of oral Fe repletion on Submaximal exercise capacity as measured by 6MWT
Time Frame
Measured at BL, week 8 and week 16
Title
Change in Plasma NT-pro BNP
Description
To determine the impact of oral Fe repletion on Plasma N-terminal pro-B-type natriuretic peptide (NT-pro BNP)
Time Frame
Measured at Baseline and Week 16
Title
Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score
Description
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.
Time Frame
Measured at Baseline, Week 8 and Week 16
Title
Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET
Description
To determine the impact of oral Fe repletion on O2 Uptake Kinetics as measured by CPET
Time Frame
Measured at BL week 16
Title
Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2
Description
Change from baseline in Ventilatory Efficiency defined by Ve/VCO2 (carbon dioxide output) as measured by CPET
Time Frame
Measured at BL week 16
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adrian Hernandez, MD,MHS,FAHA
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University School of Medicine
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Tufts Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Saint Louis University Hospital
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
University Hospitals-Case Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Metor Health System
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44109
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Lancaster General Hospital
City
Lancaster
State/Province
Pennsylvania
ZIP/Postal Code
17603
Country
United States
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
University of Utah Hospitals and Clinics
City
Murray
State/Province
Utah
ZIP/Postal Code
84107
Country
United States
Facility Name
The University of Vermont - Fletcher Allen Health Care
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05401
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
28510680
Citation
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.
Results Reference
derived
PubMed Identifier
27140203
Citation
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.
Results Reference
derived
Learn more about this trial
Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure
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