E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart Failure with Iron Deficiency |
|
E.1.1.1 | Medical condition in easily understood language |
Heart Failure with Iron Deficiency |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022974 |
E.1.2 | Term | Iron deficiency anemia |
E.1.2 | System Organ Class | 100000004851 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effect of IV FCM, relative to placebo, on the functional capacity of patients in heart failure with reduced ejection fraction and with iron deficiency. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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 elevated 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 |
|
E.4 | Principal 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 (expect 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. Current COVID-19 infection. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Hierarchical composite of 1) death, 2) hospitalization for heart
failure (defined in section 10.2), or 3) change in 6MWT. (Death and hospitalizations for heart failure will be evaluated at one year,
Change in 6MWT will be evaluated at 6 months) and tested using the nonparametric Wilcoxon-type test. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Time to first event of the composite of cardiovascular death or heart failure hospitalization. The composite endpoint will be
composed of adjudicated occurrence of one of the following:
a. Cardiovascular Death
i. Death due to Heart Failure
ii. Death due to Acute Myocardial Infarction
iii. Sudden Cardiac Death
iv. Death due to Stroke
v. Death due to other Cardiovascular Causes
b. Hospitalization for Worsening Heart Failure
2. Mean change in 6MWT from baseline to 12 months
3. Time to first event of the composite of cardiovascular death or intervention for worsening heart failure (hospitalization or urgent heart failure visits)
4. Time to first event of the composite of cardiovascular death and cardiovascular hospitalizations
5. Time to cardiovascular death
Additional events to be adjudicated for analysis of the secondary endpoints include:
a) Non-cardiovascular death
b) Hospitalization for myocardial infarction
c) Hospitalization for stroke
d) Other cardiovascular hospitalizations
e) Urgent heart failure visits |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Georgia |
New Zealand |
Ukraine |
United States |
Hungary |
Poland |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |