Chronic Heart Failure
Conditions
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.
Interventions
DRUGPolysaccharide Iron Complex 150 mg
Oral Iron
DRUGPlacebo (for Polysaccharide Iron Complex)
Sugar capsule designed to mimic Polysaccharide Iron Complex.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Adrian Hernandez
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Polysaccharide Iron Complex 150 mg oral Fe polysaccharide 150mg twice daily for 16 weeks
Polysaccharide Iron Complex 150 mg: Oral Iron | 111 |
| Placebo (for Polysaccharide Iron Complex 150 mg) Oral placebo twice a day for 16 weeks
Placebo (for Polysaccharide Iron Complex): Sugar capsule designed to mimic Polysaccharide Iron Complex. | 114 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 9 |
Baseline characteristics
| Characteristic | Polysaccharide Iron Complex 150 mg | Total | Placebo (for Polysaccharide Iron Complex 150 mg) |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 13.4 | 61.7 years STANDARD_DEVIATION 12.9 | 51.6 years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 215 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 57 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 79 Participants | 164 Participants | 85 Participants |
| Region of Enrollment United States | 111 Participants | 225 Participants | 114 Participants |
| Sex: Female, Male Female | 44 Participants | 80 Participants | 36 Participants |
| Sex: Female, Male Male | 67 Participants | 145 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 111 | 24 / 114 |
| serious Total, serious adverse events | 11 / 111 | 9 / 114 |
Outcome results
Primary
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.
Time frame: Baseline (BL) and Week 16
Population: All randomized patients with available change data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Polysaccharide Iron Complex 150 mg | Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption) | 28.04 mL/min | Standard Deviation 212.75 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change in Peak VO2 (ml/Min) (VO2 =Oxygen Consumption) | 3.90 mL/min | Standard Deviation 190.24 |
p-value: 0.45795% CI: [-34.38, 76.43]Regression, Linear
Secondary
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
Time frame: Measured at BL week 16
Population: All randomized patients with available change data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Polysaccharide Iron Complex 150 mg | Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET | 2.63 seconds | Standard Deviation 13.31 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change From Baseline in O2 Uptake Kinetics as Assessed by Mean Response Time From CPET | -0.95 seconds | Standard Deviation 13.29 |
p-value: 0.064395% CI: [-0.21, 7.33]Regression, Linear
Secondary
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
Time frame: Measured at BL, week 8 and week 16
Population: All randomized patients with available change data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Polysaccharide Iron Complex 150 mg | Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT) | 8 weeks | 12.65 meters | Standard Deviation 95.89 |
| Polysaccharide Iron Complex 150 mg | Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT) | 16 weeks | 10.76 meters | Standard Deviation 62.29 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT) | 8 weeks | 16.63 meters | Standard Deviation 83.2 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change From Baseline in Sub-maximal Exercise Capacity as Assessed by the 6 Minute Walk Test (6MWT) | 16 weeks | 30.94 meters | Standard Deviation 77.33 |
Comparison: Change from Baseline to Week 8p-value: 0.948795% CI: [-24.12, 22.59]Regression, Linear
Comparison: Change from Baseline to Week 16p-value: 0.192195% CI: [-31.71, 6.37]Regression, Linear
Secondary
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
Time frame: Measured at BL week 16
Population: All randomized patients with available change data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Polysaccharide Iron Complex 150 mg | Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2 | -0.48 VE/VCO2 Slope | Standard Deviation 5.85 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change From Baseline in Ventilatory Efficiency Defined by Ve/VCO2 | -1.31 VE/VCO2 Slope | Standard Deviation 8.85 |
p-value: 0.400695% CI: [-1.04, 2.58]Regression, Linear
Secondary
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.
Time frame: Measured at Baseline, Week 8 and Week 16
Population: All randomized patients with available change data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Polysaccharide Iron Complex 150 mg | Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score | Week 8 | 3.25 units on a scale | Standard Deviation 16.91 |
| Polysaccharide Iron Complex 150 mg | Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score | Week 16 | 3.42 units on a scale | Standard Deviation 16.05 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score | Week 8 | 0.58 units on a scale | Standard Deviation 13.63 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change in Health Status: Kansas City Cardiomyopathy Questionnaire (KCCQ) - Clinical Summary Score | Week 16 | 4.11 units on a scale | Standard Deviation 11.8 |
Comparison: Change from baseline to week 8p-value: 0.072295% CI: [-0.33, 7.52]Regression, Linear
Comparison: Change from baseline to week 16p-value: 0.692795% CI: [-2.83, 4.24]Regression, Linear
Secondary
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)
Time frame: Measured at Baseline and Week 16
Population: All randomized patients with available change data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Polysaccharide Iron Complex 150 mg | Change in Plasma NT-pro BNP | 119.36 pg/ml | Standard Deviation 1937.58 |
| Placebo (for Polysaccharide Iron Complex 150 mg) | Change in Plasma NT-pro BNP | -70.88 pg/ml | Standard Deviation 1256.49 |
p-value: 0.429695% CI: [-272.14, 637]Regression, Linear