Clinical trial NCT02188784: Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure
Official title: Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Heart Failure
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-07-14
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption)
timeFrame: Baseline (BL) and Week 16
Secondary outcomes:
measure: Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT)
timeFrame: Measured at BL, week 8 and week 16
measure: Change in Plasma NT-pro BNP
timeFrame: Measured at Baseline and Week 16
measure: Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score
timeFrame: Measured at Baseline, Week 8 and Week 16
measure: Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET
timeFrame: Measured at BL week 16
measure: Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2
timeFrame: Measured at BL week 16
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals-Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Metor Health System
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Murray
country: United States
facility: University of Utah Hospitals and Clinics
state: Utah
city: Burlington
country: United States
facility: The University of Vermont - Fletcher Allen Health Care
state: Vermont
Study officials:
affiliation: Duke University
name: Adrian Hernandez, MD,MHS,FAHA
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.