Heart Failure, Iron-deficiency
Conditions
Brief summary
The primary objective of this study is to determine the efficacy and safety of iron therapy using intravenous (IV) ferric carboxymaltose (FCM), relative to placebo in the treatment of participants in heart failure with a reduced ejection fraction and with iron deficiency
Detailed description
This is a double-blind, multicenter, prospective, randomized, placebo-controlled study to assess the effects of IV FCM compared to placebo on the 12-month rate of death, hospitalization for worsening heart failure, and the 6-month change in 6 minute walk test (6MWT) distance for patients in heart failure with iron deficiency. After an initial screening period of up to 28 days, eligible participants will be stratified by region and randomized in a 1:1 ratio to FCM or placebo for treatment. Study drug administration will occur on Day 0 and Day 7 (±2) as an undiluted slow IV push, with additional study visits planned at 3 month intervals, and additional dosing administered every 6 months as applicable. In a subset of sites, a sub-study will be conducted to characterize serum phosphate levels over time in participants with heart failure and iron deficiency after dosing with FCM. For all participants, hematology, ferritin, and transferrin saturation (TSAT), with appropriate safety evaluations, to determine additional treatment, will occur at 6 month intervals.
Interventions
DRUGFerric Carboxymaltose
Intravenous Iron
DRUGPlacebo
Normal Saline Solution
Sponsors
Duke Clinical Research Institute
American Regent, Inc.
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. Adult (≥18 years of age) able to provide signed, written informed consent. 2. Stable heart failure (NYHA II-IV) on maximally-tolerated background therapy (as determined by the site Principle Investigator) for at least 2 weeks prior to randomization. 3. Able and willing to perform a six-minute walk test (6MWT) at the time of randomization. 4. Reduced left ventricular ejection fraction. Assessment must be performed at least 12 weeks after major cardiac surgical intervention including coronary artery bypass graft (CABG), valvular repair/replacement, or cardiac resynchronization therapy (CRT) device implantation. a. Left ventricular ejection fraction ≤ 40% obtained during the screening visit OR either of the following i. Historical value of ejection fraction ≤ 40% within 24 months of screening visit ii. Historical value of ejection fraction ≤ 30% within 36 months of screening visit 5. Hemoglobin \>9.0 g/dL and \< 13.5 g/dL (females) or \<15.0 g/dL (males) within 28 days of randomization. 6. Serum ferritin \<100 ng/mL or 100 to 300 ng/mL with TSAT \<20%.Patients with screening ferritin \<15 ng/mL must have documentation of an appropriate evaluation, as determined by the Principle Investigator, within 3 months of screening and prior to randomization. 7. Either documented hospitalization for heart failure within 12 months of enrollment or elavated N-terminal-pro-brain natriuretic peptide (NT-proBNP) within 90 days of randomization. a. For patients in normal sinus rhythm: N-terminal-pro-brain natriuretic peptide (NT- proBNP) \> 600 pg/mL (or BNP \>200 pg/mL) . b . For patients in atrial fibrillation: NT-proBNP \>1000 pg/mL (or BNP \>400 pg/mL) .
Exclusion criteria
1. Known hypersensitivity reaction to any component of FCM. 2. History of acquired iron overload, or the recent receipt (within 3 months) of erythropoietin stimulating agent, IV iron therapy, or blood transfusion. 3. Acute myocardial infarction, acute coronary syndrome, transient ischemic attack, or stroke within 30 days of enrollment. 4. Uncorrected severe aortic stenosis, severe valvular regurgitation (except mitral regurgitation due to left ventricular dilatation without planned intervention), or left ventricular outflow obstruction requiring intervention. 5. Current atrial fibrillation or atrial flutter with a mean ventricular response rate \>100 per minute (at rest). 6. Current or planned mechanical circulatory support or heart transplantation. 7. Hemodialysis or peritoneal dialysis (current or planned within the next 6 months). 8. Documented liver disease, or active hepatitis (i.e. alanine transaminase or aspartate transaminase \>3 times the upper limit of normal range). 9. Current or recent (within 3 years) malignancy with exception of basal cell carcinoma or squamous cell carcinoma of the skin, or cervical intraepithelial neoplasia. 10. Active gastrointestinal bleeding. 11. Female participant of child-bearing potential who is pregnant, lactating, or not willing to use adequate contraceptive precautions during the study and for up to 5 days after the last scheduled dose of study medication. 12. Inability to return for follow up visits within the necessary windows 13. Concurrently in a study with investigational product. 14. No participants with Current Coronavirus Disease-19 (COVID-19) Infection into the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Deaths | 1 year | The number of participants who died out of the total treated group. |
| Number of Hospitalizations for Heart Failure | 1 year | The number of participants who were hospitalized for heart failure out of the total treated group. |
| Change in 6MWT (Six Minute Walk Test) Distance | 6 months | The change in meters walked at baseline compared to 6 months later. |
Countries
Australia, Bulgaria, Canada, Czechia, Georgia, Hungary, Latvia, Lithuania, New Zealand, Poland, Russia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ferric Carboxymaltose Ferric Carboxymaltose 2 doses intravenously of 15mg/kg to a maximum individual dose of 750mg 7 days apart and a maximum combined dose of 1500mg - repeated every 6 months as indicated by the results of iron indices.
Ferric Carboxymaltose: Intravenous Iron | 1,532 |
| Placebo Normal saline 15ml - 2 doses 7 days apart repeated every 6 months.
Placebo: Normal Saline Solution | 1,533 |
| Total | 3,065 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 354 | 367 |
| Overall Study | Lost to Follow-up | 7 | 4 |
| Overall Study | Withdrawal by Subject | 48 | 41 |
Baseline characteristics
| Characteristic | Ferric Carboxymaltose | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1024 Participants | 2032 Participants | 1008 Participants |
| Age, Categorical Between 18 and 65 years | 508 Participants | 1033 Participants | 525 Participants |
| Age, Continuous | 68.57 years STANDARD_DEVIATION 10.94 | 68.57 years STANDARD_DEVIATION 11.07 | 68.57 years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 85 Participants | 185 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1440 Participants | 2864 Participants | 1424 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 16 Participants | 9 Participants |
| Intent-to-treat Analysis Population | 1123 Participants | 2244 Participants | 1121 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 40 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 162 Participants | 322 Participants | 160 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 27 Participants | 14 Participants |
| Race (NIH/OMB) White | 1324 Participants | 2649 Participants | 1325 Participants |
| Region of Enrollment Australia | 59 participants | 110 participants | 51 participants |
| Region of Enrollment Bulgaria | 195 participants | 392 participants | 197 participants |
| Region of Enrollment Canada | 109 participants | 229 participants | 120 participants |
| Region of Enrollment Czechia | 14 participants | 33 participants | 19 participants |
| Region of Enrollment Estonia | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Georgia | 88 participants | 180 participants | 92 participants |
| Region of Enrollment Hungary | 11 participants | 28 participants | 17 participants |
| Region of Enrollment Latvia | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Lithuania | 13 participants | 22 participants | 9 participants |
| Region of Enrollment New Zealand | 46 participants | 100 participants | 54 participants |
| Region of Enrollment Poland | 83 participants | 170 participants | 87 participants |
| Region of Enrollment Russia | 58 participants | 123 participants | 65 participants |
| Region of Enrollment Ukraine | 243 participants | 460 participants | 217 participants |
| Region of Enrollment United States | 612 participants | 1213 participants | 601 participants |
| Sex: Female, Male Female | 506 Participants | 1037 Participants | 531 Participants |
| Sex: Female, Male Male | 1026 Participants | 2028 Participants | 1002 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 354 / 1,532 | 367 / 1,533 |
| other Total, other adverse events | 424 / 1,532 | 412 / 1,533 |
| serious Total, serious adverse events | 413 / 1,532 | 401 / 1,533 |
Outcome results
Primary
Change in 6MWT (Six Minute Walk Test) Distance
The change in meters walked at baseline compared to 6 months later.
Time frame: 6 months
Population: Number of participants within the ITT population which contributed to the 6MWT data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ferric Carboxymaltose | Change in 6MWT (Six Minute Walk Test) Distance | 8.179 unit of measure in meters | Standard Deviation 59.963 |
| Placebo | Change in 6MWT (Six Minute Walk Test) Distance | 3.979 unit of measure in meters | Standard Deviation 58.896 |
Primary
Number of Deaths
The number of participants who died out of the total treated group.
Time frame: 1 year
Population: Intent-to-treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ferric Carboxymaltose | Number of Deaths | 131 Participants |
| Placebo | Number of Deaths | 158 Participants |
Primary
Number of Hospitalizations for Heart Failure
The number of participants who were hospitalized for heart failure out of the total treated group.
Time frame: 1 year
Population: Intent-to-treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ferric Carboxymaltose | Number of Hospitalizations for Heart Failure | 297 Participants |
| Placebo | Number of Hospitalizations for Heart Failure | 332 Participants |