E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute heart failure with iron deficiency |
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E.1.1.1 | Medical condition in easily understood language |
Acute heart failure with iron deficiency |
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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 | 10000803 |
E.1.2 | Term | Acute heart failure |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10007541 |
E.1.2 | Term | Cardiac disorders |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10022970 |
E.1.2 | Term | Iron deficiency |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 |
To evaluate, relative to placebo, the effect of intravenous (IV) FCM on repeated heart failure (HF) hospitalisations and cardiovascular (CV) death. |
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E.2.2 | Secondary objectives of the trial |
To evaluate, relative to placebo, the effect of IV FCM on: HF hospitalizations, CV hospitalizations, CV mortality and all cause mortality Quality of life and New York Heart Association Classification (NYHA) Tolerability and safety. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biomarker Blood Samples It is planned to perform biomarker analyses in blood samples from approximately 60% of randomised subjects. The decision concerning which biomarkers will be analysed will be made by in collaboration with the Study Steering Committee, together with the Sponsor. If the biomarker samples will not be analysed, they will be destroyed. Details concerning the blood samples storage will be provided in an instruction manual. If conducted, the statistical analysis for the biomarker blood samples will be detailed in a separate biomarker SAP and results of these exploratory analyses will be not part of the clinical study report of the main study . |
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E.3 | Principal 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: a. Upon admission for the AHF episode, persistent dyspnoea at rest in a recumbent sitting position (30-45°) or with minimal exertion b. Upon or during the AHF admission, at least two (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) c Natriuretic peptide levels, measured ≤24 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 d AHF episode treated with minimally 40 mg of IV furosemide (or equivalent IV loop diuretic defined as 20 mg of torsemide 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.
*Following section are applicable for the Netherlands only (NL only): The option that legally accepted representatives of subjects can sign the written informed consent is not valid for sites in the Netherlands |
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E.4 | Principal 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/randomization). 3. Clinical evidence of acute coronary syndrome, transient ischemic attack or stroke, within the last 30 days prior randomisation. 4. 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. 5. Subject has a body weight <35 kg at randomisation. 6. Subject at an immediate need of transfusion or with a Hb <8 g/dL* or with a Hb >15 g/dL. 7. 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. 8. Subject has known hypersensitivity to any of the study products to be administered or known serious hypersensitivity to other parenteral iron products. 9. Renal dialysis (previous, current or planned within the next 6 months). 10. Chronic liver disease (including active hepatitis) and/or alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range. 11. Subjects with known hepatitis B surface antigen positivity and/or hepatitis C virus ribonucleic acid positivity. 12. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast feeding. 13. 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. *Following section are applicable for the Netherlands only (NL only): The lower threshold of Hb values is set to 10 g/dL. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The composite of recurrent HF hospitalizations and CV death up to 52 weeks after randomization. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 52 weeks after randomization. |
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E.5.2 | Secondary end point(s) |
Safety Endpoints : • Summary of adverse events (AEs): by system organ class and preferred term (Medical Dictionary for Regulatory Activities (MedDRA) coded term), by severity and relation to study product. • Summary of serious adverse events (SAEs) by study treatment group presented by system organ class and preferred terms (MedDRA coded term). • Summary of clinical laboratory panels and cardiac biomarkers (absolute and change from baseline).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 52 weeks after randomization |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Argentina |
Brazil |
Croatia |
Georgia |
Israel |
Italy |
Lebanon |
Netherlands |
Poland |
Romania |
Singapore |
Spain |
Sweden |
Ukraine |
United Kingdom |
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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
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LVLS - last patient last visit |
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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 | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |