Heart Failure, Iron Deficiency
Conditions
Keywords
Acute Heart Failure, Iron Deficiency
Brief summary
Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency (Affirm-AHF)
Detailed description
This is a randomised, double-blind, placebo-controlled Trial (RCT). The 52 weeks observation period following randomisation is considered appropriate to investigate the primary endpoint of recurrent HF hospitalisations and CV death. To evaluate the effect of intravenous ferric carboxymaltose (IV FCM) in iron deficient subjects with AHF, subjects will be enrolled during a hospital stay (Index hospitalisation) after the acute care treatment of the index event has been stabilised. All subjects will continue to receive their established standard therapy for HF and medical emergencies will be treated according to local routine.
Interventions
DRUGferric carboxymaltose
FCM will be administered as an undiluted bolus injection. The study treatment dose (mL) to be administered will be determined by the patient's body weight and haemoglobin (Hb) value at the respective visits where study treatment will be administered
OTHERNormal saline 0.9%
Normal saline will be administered as a bolus injection.
Sponsors
Worldwide Clinical Trials
Cytel Inc.
Vifor (International) Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Currently hospitalised for an episode of acute heart failure (AHF) where AHF was the primary reason for hospitalisation. All of the following (i.e., items a to d) must apply: 1. Upon admission for the AHF episode, persistent dyspnoea at rest in a recumbent sitting position (30-45°) or with minimal exertion 2. Upon or during the AHF admission, at least 2 of the following clinical findings were present: i. Congestion on chest X-ray ii. Rales on chest auscultation iii. Oedema ≥1+ on a 0-3+ scale, indicating indentation of skin with mild digital pressure that requires 10 or more seconds to resolve in any dependent area including extremities or sacral region iv. Elevated jugular venous pressure (≥8 cm H2O) 3. Natriuretic peptide levels, measured ≤72 hours of the AHF admission must have been: i. Brain natriuretic peptide (BNP) ≥400 pg/mL or N-terminal-pro-brain natriuretic peptide (NT-proBNP) ≥1,600 pg/mL or ii. BNP ≥600 pg/mL or NT-proBNP ≥2,400 pg/mL for subjects presenting with atrial fibrillation when the blood sample was taken iii. For subjects treated with an angiotensin receptor neprilysin inhibitor (ARNI) in the previous 4 weeks prior to randomisation only NT-proBNP values should be considered 4. AHF episode treated with minimally 40 mg of IV furosemide (or equivalent IV loop diuretic defined as 20 mg of torasemide or 1 mg of bumetanide) 2. Subject is iron deficient defined as serum ferritin \<100 ng/mL or 100 ng/mL ≤ serum ferritin ≤299 ng/mL if TSAT \<20%. 3. Left ventricular ejection fraction \<50% (assessed and documented within 12 months prior to randomisation). 4. Male or female aged ≥18 years old. 5. Subject (or legally acceptable representative)\* has provided the appropriate written informed consent. Subject must provide written informed consent before any study-specific procedures are performed.
Exclusion criteria
1. Dyspnoea due to non-cardiac causes such as acute or chronic respiratory disorders or infections (i.e., severe chronic obstructive pulmonary disease, acute bronchitis, pneumonia, primary pulmonary hypertension). 2. Temperature \>38°C (oral or equivalent), active infective endocarditis, sepsis, systemic inflammatory response syndrome, or any other active infection requiring anti-microbial treatment at any time during an Index hospitalisation. (Note that it does NOT include short-term prophylactic administration of antibiotics or short-term temperature elevation at admission which is no longer present at the time point of discharge/randomisation). 3. Documented restricted amyloid myocardiopathy, or acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. (Note that it does NOT include restrictive mitral filling patterns seen on Doppler echocardiographic assessments of diastolic function). 4. Clinical evidence of acute coronary syndrome, transient ischemic attack or stroke, within the last 30 days prior randomisation. 5. Severe valvular or left ventricular outflow obstruction disease needing intervention. 6. Coronary-artery bypass graft, cardiac resynchronisation therapy device implantation, percutaneous intervention (e.g., cardiac, cerebrovascular, aortic, diagnostic catheters are allowed) or major surgery that led to significant blood loss, including thoracic and cardiac surgery, within the last 3 months prior to randomisation. 7. Subject has a body weight \<35 kg at randomisation. 8. Subject at an immediate need of transfusion or with a Hb \<8 g/dL\* or with a Hb \>15 g/dL. 9. Subjects on treatment for Vitamin B12 and/or serum folate deficiency. Note: Use of Vitamin B12 and folic acid as supplement therapy (not for deficiency treatment) is permitted. 10. Subject with a known anaemia not attributed to ID (e.g., other microcytic anaemia) or with an evidence of iron overload (e.g., haemochromatosis) or disturbances in the utilisation of iron. 11. Subject has known hypersensitivity to any of the study products to be administered or known serious hypersensitivity to other parenteral iron products. 12. Subject with known severe allergies including drug allergies, history of severe asthma, eczema or other atopic allergy and in subjects with immune or inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis). 13. History of erythropoietin stimulating agent, IV iron therapy, and/or blood transfusion in previous 3 months prior to randomisation. 14. Oral iron therapy at doses \>100 mg/day in previous 4 weeks prior to randomisation. Note: Ongoing use of multivitamins containing iron \<75 mg/day are permitted. 15. Currently receiving systemic chemotherapy and/or radiotherapy. 16. Renal dialysis (previous, current or planned within the next 6 months). 17. Subject has known active malignancy of any organ system, i.e., clinical evidence of current malignancy or not in stable remission for at least 3 years since completion of last treatment with exception of non-invasive basal cell carcinoma, squamous cell carcinoma of the skin or cervical intra-epithelial neoplasia. 18. Terminal illness other than HF with expected survival \<12 months. 19. Chronic liver disease (including active hepatitis) and/or alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range. 20. Subjects with known hepatitis B surface antigen positivity and/or hepatitis C virus ribonucleic acid positivity. 21. Subject previously randomised into this study. Note: Subjects may be rescreened but when rescreened, all tests must fall inside the maximum specified screening windows for each criterion. 22. Subject is currently enrolled in or has completed any other investigational device or drug study \<30 days prior to screening, or is receiving other investigational agent(s). 23. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast feeding. 24. If of childbearing potential, subject is not using adequate contraceptive precautions. Subject must agree to use adequate contraception during the study and for 1 month after the last dose of study treatment. A highly effective method of birth control must be used. 25. Subject has a history of drug or alcohol abuse within 2 years prior to screening. 26. Subject has a significant medical condition(s), anticipated need for major surgery during the study, or any other kind of disorder that may be associated with increased risk to the subject, or may interfere with study assessments, outcomes, or the ability to provide written informed consent or comply with study procedures, in the Investigator's opinion. * Following section in italics is applicable for The Netherlands, Spain and Singapore only (NL, ES and SG only): 'The lower threshold of Hb values is set to 10 g/dL.'
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HF Hospitalizations and CV Death | up to 52 weeks after randomization | HF = Heart Failure, CV = Cardiovascular. The composite of recurrent HF hospitalizations and CV death up to 52 weeks after randomization Total hospitalisations included first and recurrent events. If a participant was hospitalised for heart failure and died within 24 h from any cardiovascular event, this was counted as one event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrent CV Hospitalisations and CV Death | up to 52 weeks after randomization | CV = Cardiovascular The composite of recurrent CV hospitalisations and CV death at 52 weeks after randomisation Total hospitalisations included first and recurrent events. If a participant was hospitalised for a cardiovascular reason and died within 24 h of admission from any cardiovascular event, this was counted as one event. |
| HF Hospitalisations | up to 52 weeks after randomisation | HF = Heart Failure HF hospitalisations up to 52 weeks after randomisation analysed as recurrent event. |
| CV Mortality | at 52 weeks after randomisation. | CV = Cardiovascular CV mortality analysed as time to first event at 52 weeks after randomisation. |
| Composite of HF Hospitalisations or CV Death | at 52 weeks after randomisation | HF = Heart Failure, CV = Cardiovascular Analysed as time to first event at 52 weeks after randomisation. The number of participants with at least one HF Hospitalisation or CV Death is presented below. |
| Days Lost Due to HF Hospitalisation or CV Death | at 52 weeks after randomisation | HF = Heart Failure, CV = Cardiovascular Number of days lost due to heart failure hospitalisations or cardiovascular death corresponds to the total number of days in hospital for heart failure from randomisation to last known date. Days lost due to cardiovascular death are added to the number of days lost due to heart failure hospitalisation. |
Other
| Measure | Time frame | Description |
|---|---|---|
| HF Hospitalisations | up to 52 weeks after randomisation | HF = Heart Failure Number of participants with at least one HF Hospitalisation up to 52 weeks after randomisation |
| CV Hospitalisations | up to 52 weeks after randomisation | CV = Cardiovascular Number of participants with at least one CV Hospitalisation up to 52 weeks after randomisation |
| All-cause Mortality | up to 52 weeks after randomisation | Number of participants who died up to 52 weeks after randomisation |
| Change From Baseline in NYHA Functional Class | at 6, 12, 24 and 52 weeks after randomisation | NYHA = New York Heart Association NYHA functional class was assessed as Class I, II, III, IV or V: Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest. Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. If a participant was hospitalised at any point during any post-baseline visit and did not have any NYHA assessment for this visit, then Class IV was to be imputed for the visit. Class V - Imputed for participants who died. Lower response categories are better for score NYHA. |
| Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | at 6, 24 and 52 weeks after randomisation | EQ-5D-5L: European Quality of Life-5 Dimensions-5 Levels The EQ 5D questionnaire consists of a health descriptive system for participants to self-classify and rate their health status on the day of administration. The descriptive system includes 5 items/dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, which are coded from 1 (best state) to 5 (worst state). |
| KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | up to 52 weeks after randomisation | KCCQ = Kansas City Cardiomyopathy Questionnaire The KCCQ 12 is a health-related quality of life questionnaire for Heart Failure. It is a 12 item questionnaire that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge and Quality of life. Scores are generated for each domain and scaled from 0 to 100, with 0 denoting the lowest reportable health status and 100 the highest reportable health status. |
Countries
Argentina, Brazil, Croatia, Georgia, Israel, Italy, Lebanon, Netherlands, Poland, Romania, Singapore, Spain, Sweden, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FCM (Ferric Carboxymaltose) Ferric carboxymaltose (FCM), administered by bolus intravenous (IV) injection at a dose of 10 ml or 20 ml of undiluted solution (containing 500 mg or 1,000 mg of iron respectively) depending on the participant's body weight and haemoglobin (Hb) level.
From a single dose given at Visit 2 (Week 0) up to 4 doses given over 24 weeks (at Visit 2 (Week 0), Visit 3 (Week 6), Visit 4 (Week 12) and Visit 5 (Week 24), depending on the participant's Hb levels measured prior to planned dosing dates. | 559 |
| Placebo (Normal Saline (NaCl 0.9%)) Normal saline (NaCl 0.9%), administered by bolus intravenous (IV) injection at a volume corresponding to the FCM dose determined by the participant's body weight and haemoglobin (Hb) level (i.e., 10 ml or 20 ml per administration).
From a single dose given at Visit 2 (Week 0) up to 4 doses given over 24 weeks (at Visit 2 (Week 0), Visit 3 (Week 6), Visit 4 (Week 12) and Visit 5 (Week 24)), depending on the participant's Hb levels measured prior to planned dosing dates. | 551 |
| Total | 1,110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 98 | 95 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other | 8 | 5 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 6 | 10 |
| Overall Study | Withdrawal by Subject | 27 | 15 |
Baseline characteristics
| Characteristic | Placebo (Normal Saline (NaCl 0.9%)) | FCM (Ferric Carboxymaltose) | Total |
|---|---|---|---|
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized ≥ 85 years | 39 Participants | 51 Participants | 90 Participants |
| Age, Customized Between 18 and 64 years | 142 Participants | 139 Participants | 281 Participants |
| Age, Customized Between 65 and 84 years | 370 Participants | 369 Participants | 739 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 50 Participants | 51 Participants | 101 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 489 Participants | 498 Participants | 987 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants | 10 Participants | 22 Participants |
| Region of Enrollment Argentina | 24 Participants | 24 Participants | 48 Participants |
| Region of Enrollment Brazil | 14 Participants | 14 Participants | 28 Participants |
| Region of Enrollment Croatia | 43 Participants | 39 Participants | 82 Participants |
| Region of Enrollment Georgia | 95 Participants | 98 Participants | 193 Participants |
| Region of Enrollment Israel | 38 Participants | 41 Participants | 79 Participants |
| Region of Enrollment Italy | 58 Participants | 55 Participants | 113 Participants |
| Region of Enrollment Lebanon | 16 Participants | 16 Participants | 32 Participants |
| Region of Enrollment Netherlands | 31 Participants | 38 Participants | 69 Participants |
| Region of Enrollment Poland | 90 Participants | 90 Participants | 180 Participants |
| Region of Enrollment Romania | 78 Participants | 76 Participants | 154 Participants |
| Region of Enrollment Singapore | 22 Participants | 23 Participants | 45 Participants |
| Region of Enrollment Spain | 12 Participants | 12 Participants | 24 Participants |
| Region of Enrollment Sweden | 1 Participants | 4 Participants | 5 Participants |
| Region of Enrollment Ukraine | 23 Participants | 23 Participants | 46 Participants |
| Region of Enrollment United Kingdom | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 250 Participants | 244 Participants | 494 Participants |
| Sex: Female, Male Male | 301 Participants | 315 Participants | 616 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 99 / 559 | 96 / 551 |
| other Total, other adverse events | 51 / 559 | 45 / 551 |
| serious Total, serious adverse events | 250 / 559 | 282 / 551 |
Outcome results
Primary
HF Hospitalizations and CV Death
HF = Heart Failure, CV = Cardiovascular. The composite of recurrent HF hospitalizations and CV death up to 52 weeks after randomization Total hospitalisations included first and recurrent events. If a participant was hospitalised for heart failure and died within 24 h from any cardiovascular event, this was counted as one event.
Time frame: up to 52 weeks after randomization
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.~The management and follow-up of patients was affected by the COVID-19 pandemic. Participants were censored in each country on the date when the first patient with COVID-19 was reported in the respective country.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FCM (Ferric Carboxymaltose) | HF Hospitalizations and CV Death | Full Analysis Set (FAS) | 293 Events |
| FCM (Ferric Carboxymaltose) | HF Hospitalizations and CV Death | Covid-19 Sensitivity Analysis | 274 Events |
| Placebo (Normal Saline (NaCl 0.9%)) | HF Hospitalizations and CV Death | Full Analysis Set (FAS) | 372 Events |
| Placebo (Normal Saline (NaCl 0.9%)) | HF Hospitalizations and CV Death | Covid-19 Sensitivity Analysis | 363 Events |
Comparison: Full Analysis Set (FAS)p-value: 0.05995% CI: [0.62, 1.01]Negative binomial model
Comparison: Covid-19 Sensitivity Analysisp-value: 0.02495% CI: [0.59, 0.96]Negative binomial model
Secondary
Composite of HF Hospitalisations or CV Death
HF = Heart Failure, CV = Cardiovascular Analysed as time to first event at 52 weeks after randomisation. The number of participants with at least one HF Hospitalisation or CV Death is presented below.
Time frame: at 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.~The management and follow-up of patients was affected by the COVID-19 pandemic. Participants were censored in each country on the date when the first patient with COVID-19 was reported in the respective country.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FCM (Ferric Carboxymaltose) | Composite of HF Hospitalisations or CV Death | Full Analysis Set (FAS) | 181 Participants |
| FCM (Ferric Carboxymaltose) | Composite of HF Hospitalisations or CV Death | COVID-19 sensitivity analyses | 175 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Composite of HF Hospitalisations or CV Death | Full Analysis Set (FAS) | 209 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Composite of HF Hospitalisations or CV Death | COVID-19 sensitivity analyses | 205 Participants |
Comparison: Full Analysis Set (FAS)p-value: 0.0395% CI: [0.66, 0.98]Regression, Cox
Comparison: Covid-19 Sensitivity Analysisp-value: 0.02395% CI: [0.65, 0.97]Regression, Cox
Secondary
CV Mortality
CV = Cardiovascular CV mortality analysed as time to first event at 52 weeks after randomisation.
Time frame: at 52 weeks after randomisation.
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.~The management and follow-up of patients was affected by the COVID-19 pandemic. Participants were censored in each country on the date when the first patient with COVID-19 was reported in the respective country.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FCM (Ferric Carboxymaltose) | CV Mortality | Full Analysis Set (FAS) | 77 Participants |
| FCM (Ferric Carboxymaltose) | CV Mortality | COVID-19 sensitivity analyses | 73 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | CV Mortality | Full Analysis Set (FAS) | 78 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | CV Mortality | COVID-19 sensitivity analyses | 76 Participants |
Comparison: Full Analysis Set (FAS)p-value: 0.80995% CI: [0.7, 1.32]Regression, Cox
Comparison: Covid-19 Sensitivity Analysisp-value: 0.68795% CI: [0.68, 1.29]Regression, Cox
Secondary
Days Lost Due to HF Hospitalisation or CV Death
HF = Heart Failure, CV = Cardiovascular Number of days lost due to heart failure hospitalisations or cardiovascular death corresponds to the total number of days in hospital for heart failure from randomisation to last known date. Days lost due to cardiovascular death are added to the number of days lost due to heart failure hospitalisation.
Time frame: at 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.~The management and follow-up of patients was affected by the COVID-19 pandemic. Participants were censored in each country on the date when the first patient with COVID-19 was reported in the respective country.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FCM (Ferric Carboxymaltose) | Days Lost Due to HF Hospitalisation or CV Death | Full Analysis Set (FAS) | 3.8 days | Standard Deviation 9.06 |
| FCM (Ferric Carboxymaltose) | Days Lost Due to HF Hospitalisation or CV Death | COVID-19 sensitivity analyses | 3.5 days | Standard Deviation 8.18 |
| Placebo (Normal Saline (NaCl 0.9%)) | Days Lost Due to HF Hospitalisation or CV Death | Full Analysis Set (FAS) | 6.2 days | Standard Deviation 14.48 |
| Placebo (Normal Saline (NaCl 0.9%)) | Days Lost Due to HF Hospitalisation or CV Death | COVID-19 sensitivity analyses | 6.1 days | Standard Deviation 14.42 |
Comparison: Full Analysis Set (FAS)p-value: 0.03595% CI: [0.47, 0.97]Negative binomial model
Comparison: Covid-19 Sensitivity Analysisp-value: 0.00995% CI: [0.42, 0.88]Negative binomial model
Secondary
HF Hospitalisations
HF = Heart Failure HF hospitalisations up to 52 weeks after randomisation analysed as recurrent event.
Time frame: up to 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.~The management and follow-up of patients was affected by the COVID-19 pandemic. Participants were censored in each country on the date when the first patient with COVID-19 was reported in the respective country.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FCM (Ferric Carboxymaltose) | HF Hospitalisations | Full Analysis Set (FAS) | 217 Events |
| FCM (Ferric Carboxymaltose) | HF Hospitalisations | COVID-19 sensitivity analyses | 202 Events |
| Placebo (Normal Saline (NaCl 0.9%)) | HF Hospitalisations | Full Analysis Set (FAS) | 294 Events |
| Placebo (Normal Saline (NaCl 0.9%)) | HF Hospitalisations | COVID-19 sensitivity analyses | 287 Events |
Comparison: Full Analysis Set (FAS)p-value: 0.01395% CI: [0.58, 0.94]Negative binomial model
Comparison: COVID-19 sensitivity analysesp-value: 0.00595% CI: [0.55, 0.9]Negative binomial model
Secondary
Recurrent CV Hospitalisations and CV Death
CV = Cardiovascular The composite of recurrent CV hospitalisations and CV death at 52 weeks after randomisation Total hospitalisations included first and recurrent events. If a participant was hospitalised for a cardiovascular reason and died within 24 h of admission from any cardiovascular event, this was counted as one event.
Time frame: up to 52 weeks after randomization
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.~The management and follow-up of patients was affected by the COVID-19 pandemic. Participants were censored in each country on the date when the first patient with COVID-19 was reported in the respective country.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FCM (Ferric Carboxymaltose) | Recurrent CV Hospitalisations and CV Death | Full Analysis Set (FAS) | 370 Events |
| FCM (Ferric Carboxymaltose) | Recurrent CV Hospitalisations and CV Death | COVID-19 sensitivity analyses | 350 Events |
| Placebo (Normal Saline (NaCl 0.9%)) | Recurrent CV Hospitalisations and CV Death | Full Analysis Set (FAS) | 451 Events |
| Placebo (Normal Saline (NaCl 0.9%)) | Recurrent CV Hospitalisations and CV Death | COVID-19 sensitivity analyses | 440 Events |
Comparison: Full Analysis Set (FAS)p-value: 0.0595% CI: [0.64, 1]Negative binomial model
Comparison: COVID-19 sensitivity analysesp-value: 0.02495% CI: [0.62, 0.97]Negative binomial model
Other Pre-specified
All-cause Mortality
Number of participants who died up to 52 weeks after randomisation
Time frame: up to 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FCM (Ferric Carboxymaltose) | All-cause Mortality | 98 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | All-cause Mortality | 96 Participants |
Comparison: Full Analysis Set (FAS)p-value: 0.94495% CI: [0.75, 1.31]Regression, Cox
Other Pre-specified
Change From Baseline in NYHA Functional Class
NYHA = New York Heart Association NYHA functional class was assessed as Class I, II, III, IV or V: Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest. Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. If a participant was hospitalised at any point during any post-baseline visit and did not have any NYHA assessment for this visit, then Class IV was to be imputed for the visit. Class V - Imputed for participants who died. Lower response categories are better for score NYHA.
Time frame: at 6, 12, 24 and 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 6 | Class IV | 13 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 12 | Class IV | 14 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 6 | Class V | 18 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 12 | Class V | 36 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Baseline | Class III | 272 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 24 | Class I | 47 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 12 | Class I | 39 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 24 | Class II | 288 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 12 | Class II | 296 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 24 | Class III | 88 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 6 | Class II | 296 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 24 | Class IV | 13 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Baseline | Class I | 14 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 24 | Class V | 56 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Baseline | Class IV | 16 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 52 | Class I | 48 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Baseline | Class II | 255 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 52 | Class II | 234 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Baseline | Class V | 0 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 52 | Class III | 61 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 6 | Class III | 151 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 52 | Class IV | 7 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 6 | Class I | 38 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 52 | Class V | 99 Participants |
| FCM (Ferric Carboxymaltose) | Change From Baseline in NYHA Functional Class | Week 12 | Class III | 107 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 52 | Class V | 95 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Baseline | Class III | 277 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Baseline | Class IV | 22 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Baseline | Class V | 0 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 6 | Class I | 38 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 6 | Class II | 271 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 6 | Class III | 151 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 6 | Class V | 23 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 12 | Class II | 267 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Baseline | Class I | 8 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 6 | Class IV | 31 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 12 | Class I | 40 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 12 | Class III | 131 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 12 | Class IV | 18 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 12 | Class V | 32 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 24 | Class I | 47 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 24 | Class II | 265 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 24 | Class III | 100 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 24 | Class IV | 20 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 24 | Class V | 63 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 52 | Class I | 53 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 52 | Class II | 223 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 52 | Class III | 75 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Week 52 | Class IV | 17 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in NYHA Functional Class | Baseline | Class II | 240 Participants |
Comparison: Full Analysis Set (FAS)p-value: 0.19695% CI: [0.93, 1.39]Generalised Estimating Equations (GEE)
Other Pre-specified
Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value
EQ-5D-5L: European Quality of Life-5 Dimensions-5 Levels The EQ 5D questionnaire consists of a health descriptive system for participants to self-classify and rate their health status on the day of administration. The descriptive system includes 5 items/dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, which are coded from 1 (best state) to 5 (worst state).
Time frame: at 6, 24 and 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FCM (Ferric Carboxymaltose) | Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | Week 6 | 0.05 Change from baseline in EQ-5D-5L | Standard Error 0.01 |
| FCM (Ferric Carboxymaltose) | Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | Week 24 | 0.06 Change from baseline in EQ-5D-5L | Standard Error 0.01 |
| FCM (Ferric Carboxymaltose) | Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | Week 52 | 0.06 Change from baseline in EQ-5D-5L | Standard Error 0.01 |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | Week 6 | 0.03 Change from baseline in EQ-5D-5L | Standard Error 0.01 |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | Week 24 | 0.05 Change from baseline in EQ-5D-5L | Standard Error 0.01 |
| Placebo (Normal Saline (NaCl 0.9%)) | Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | Week 52 | 0.06 Change from baseline in EQ-5D-5L | Standard Error 0.01 |
Comparison: Week 6p-value: 0.208Mixed-effect model of repeated measures
Comparison: Week 24p-value: 0.408Mixed-effect model of repeated measures
Comparison: Week 52p-value: 0.999Mixed-effect model of repeated measures
Other Pre-specified
CV Hospitalisations
CV = Cardiovascular Number of participants with at least one CV Hospitalisation up to 52 weeks after randomisation
Time frame: up to 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FCM (Ferric Carboxymaltose) | CV Hospitalisations | 181 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | CV Hospitalisations | 220 Participants |
Comparison: Full Analysis Set (FAS)p-value: 0.00995% CI: [0.63, 0.94]Regression, Cox
Other Pre-specified
HF Hospitalisations
HF = Heart Failure Number of participants with at least one HF Hospitalisation up to 52 weeks after randomisation
Time frame: up to 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FCM (Ferric Carboxymaltose) | HF Hospitalisations | 142 Participants |
| Placebo (Normal Saline (NaCl 0.9%)) | HF Hospitalisations | 178 Participants |
Comparison: Full Analysis Set (FAS)p-value: 0.00695% CI: [0.59, 0.92]Regression, Cox
Other Pre-specified
KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference
KCCQ = Kansas City Cardiomyopathy Questionnaire The KCCQ 12 is a health-related quality of life questionnaire for Heart Failure. It is a 12 item questionnaire that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge and Quality of life. Scores are generated for each domain and scaled from 0 to 100, with 0 denoting the lowest reportable health status and 100 the highest reportable health status.
Time frame: up to 52 weeks after randomisation
Population: Full Analysis Set (FAS): All randomised participants for whom administration of study treatment was started and who had at least one post-baseline visit (including calls), death or hospitalisation or who withdrew from the study after but not on the randomisation date.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FCM (Ferric Carboxymaltose) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 12 | 25.57 KCCQ-12 score | Standard Error 1.24 |
| FCM (Ferric Carboxymaltose) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 24 | 26.30 KCCQ-12 score | Standard Error 1.26 |
| FCM (Ferric Carboxymaltose) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 36 | 25.78 KCCQ-12 score | Standard Error 1.28 |
| FCM (Ferric Carboxymaltose) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 52 | 25.75 KCCQ-12 score | Standard Error 1.33 |
| FCM (Ferric Carboxymaltose) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 2 | 18.53 KCCQ-12 score | Standard Error 1.16 |
| FCM (Ferric Carboxymaltose) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 4 | 21.26 KCCQ-12 score | Standard Error 1.18 |
| FCM (Ferric Carboxymaltose) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 6 | 23.49 KCCQ-12 score | Standard Error 1.2 |
| Placebo (Normal Saline (NaCl 0.9%)) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 12 | 21.88 KCCQ-12 score | Standard Error 1.26 |
| Placebo (Normal Saline (NaCl 0.9%)) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 2 | 17.24 KCCQ-12 score | Standard Error 1.19 |
| Placebo (Normal Saline (NaCl 0.9%)) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 24 | 23.32 KCCQ-12 score | Standard Error 1.27 |
| Placebo (Normal Saline (NaCl 0.9%)) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 6 | 19.88 KCCQ-12 score | Standard Error 1.23 |
| Placebo (Normal Saline (NaCl 0.9%)) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 36 | 23.70 KCCQ-12 score | Standard Error 1.3 |
| Placebo (Normal Saline (NaCl 0.9%)) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 4 | 18.36 KCCQ-12 score | Standard Error 1.21 |
| Placebo (Normal Saline (NaCl 0.9%)) | KCCQ-12 Repeated-Measures Model for Analysis of Treatment Difference | Week 52 | 24.31 KCCQ-12 score | Standard Error 1.34 |
Comparison: Week 2p-value: 0.227Mixed-effect model of repeated measures
Comparison: Week 4p-value: 0.018Mixed-effect model of repeated measures
Comparison: Week 6p-value: 0.005Mixed-effect model of repeated measures
Comparison: Week 12p-value: 0.006Mixed-effect model of repeated measures
Comparison: Week 24p-value: 0.028Mixed-effect model of repeated measures
Comparison: Week 36p-value: 0.136Mixed-effect model of repeated measures
Comparison: Week 52p-value: 0.329Mixed-effect model of repeated measures