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    Summary
    EudraCT Number:2019-003461-17
    Sponsor's Protocol Code Number:71272
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-10-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2019-003461-17
    A.3Full title of the trial
    Pathophysiological relevance of IRON deficiency and related mitochondrial dysfunction in Heart Failure with Preserved Ejection Fraction (IRON-HFpEF)
    De pathofysiologische relevantie van ijzer deficiëntie en gerelateerde mitochondriële dysfunctie in hartfalen met behouden ejectiefractie (IRON-HFpEF)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pathophysiological relevance of IRON deficiency and related mitochondrial dysfunction in Heart Failure with Preserved Ejection Fraction (IRON-HFpEF)
    De pathofysiologische relevantie van ijzer deficiëntie en gerelateerde mitochondriële dysfunctie in hartfalen met behouden ejectiefractie (IRON-HFpEF)
    A.3.2Name or abbreviated title of the trial where available
    IRON-HFpEF
    IRON-HFpEF
    A.4.1Sponsor's protocol code number71272
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmsterdam UMC, location VUmc
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportVifor (International) AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmsterdam UMC, location VUmc
    B.5.2Functional name of contact pointdr. M.L. Handoko, cardiologist
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081 HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31204440123
    B.5.6E-mailml.handoko@amsterdamumc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ferric Carboxymaltose (Ferinject®)
    D.2.1.1.2Name of the Marketing Authorisation holderVifor Pharma Nederland BV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFerric carboxymaltose (Ferinject)
    D.3.2Product code RVG 33865
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heart failure with preserved ejection fraction
    Hartfalen met behouden ejectie fractie
    E.1.1.1Medical condition in easily understood language
    Diastolic heart failure
    Diastolisch hartfalen
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Asses whether, in patients with heart failure with preserved ejection fraction and iron deficiency, ferric carboxymaltose improves left ventricular diastolic function and skeletal muscle function by improving energy metabolism
    Evalueren of, in patienten met hartfalen met behouden ejectie fractie en ijzer deficientie, ferric carboxymaltose verbetering geeft van linker ventrikel diastologie en skelet spier functie, door verbetering van energie metabolisme/
    E.2.2Secondary objectives of the trial
    Whether ferric carboxymaltose corrects iron tissue in end-organs (heart and skeletal muscle)
    Evalueren of ferric carboxy maltose correctie geeft van de ijzer voorraad in eind organen (hart en skeletspier)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of HFpEF:
    Signs/and or symptoms of heart failure, NYHA II or higher (and ambulant); AND LVEF ≥ 50% (by any modality); AND evidence of LV diastolic dysfunction:
    • PCWP at rest ≥ 15mmHg and/or PCWP during passive leg-lifting ≥ 19 mmHg and/or PCWP during exercise ≥ 25mmHg;

    if no clinical right heart catheterization was performed, diagnose could be made using:
    • LV diastolic dysfunction grade II or higher on echocardiogram* with a NT-proBNP level >125 pg/mL). OR
    • H2FpEF score ≥ 6
    2. No other significant cardiac (e.g., significant valvular disease) or extra-cardiac condition (e.g., severe COPD) that explains symptoms.
    3. Optimal medical treatment (euvolemic, preferable on SGLT2i and mineralocorticoid receptor antagonist) and remaining symptomatic after offering of a cardiac rehabilitation program.
    4. Clinically stable (no change in diuretic for >1 month), co-morbidities managed (e.g. hypertension, atrial fibrillation), cardiac rehabilitation program finished (or offered but refused).
    5. ID (ferritin <100pg/L, or ferritin 100-300pg/L and transferrin saturation (TSAT) <20%).
    6. Haemoglobin 9.0–15.2 g/dL (5.6–9.5 mmol/L) at screening, and possible chronic (gastro-intestinal) blood loss was reasonably excluded.
    *In case of atrial fibrillation during echocardiogram diastolic dysfunction cannot be graded using the standard ASE/EACVI-algorithm. If atrial fibrillation is present, diastolic dysfunction is diagnosed if most of the following criteria was present (measurements were based on at least 5 consecutive beats):
    1. peak tricuspid regurgitation velocity (TRV) >2.8 m/s
    2. mitral valve early inflow (E) velocity (≥1.9 m/s)
    3. Isovolumic relaxation time (IVRT) (≤65 ms)
    4. Deceleration time of pulmonary venous diastolic velocity (≤220 ms)
    5. E/mitral flow propagation velocity (Vp) (≥1.4)
    E/e′ ratio (≥11)
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. Unable or unwilling to sign informed consent
    2. Contraindication for FCM
    • Known allergic reaction to FCM
    • Clinical signs and/or symptoms of an acute infection
    • Conditions with high risk of an allergic reaction: severe asthma or eczema, systemic lupus erhytematosus, rheumatoid arthritis or concurrent use of significant immunosuppressive therapy (with an exception of patients who previously have received intravenous iron without allergic response).
    • Pregnancy
    • Unexplained, bleeding or hemolytic anaemia
    • Liver dysfunction (defined as AST or ALT > 3x upper limit of normal)
    3. History of (previous 2 months) or planned use of intravenous/oral iron, erythropoietin or blood transfusion
    4. Indication for iron supplementation*
    5. Hypertrophic cardiomyopathy, cardiac amyloidosis or other infiltrative cardiomyopathy, cardiac storage disease, significant congenital and other structural heart disease
    6. Acute coronary syndrome, TIA/CVA, PCI/CABG/valve replacement or any major surgery within 3 months prior
    7. Current, planned or recent (previous 6 months) dialysis
    8. Known HIV, hepatitis infection or active malignancy (with exception of low-risk prostate cancer (biopsy Gleason score of ≤ 6 and clinical stage T1c or T2a)
    9. Unable to undergo the complete study protocol (i.e. RHC, 6MWD)
    10. Under 18 years of age
    11. Subject currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study.
    *Based on current Dutch general practitioner guideline
    E.5 End points
    E.5.1Primary end point(s)
    Exercise PCWP measured by right heart catheterisation (gold standard for evaluation of left ventricular diastology)
    PCWP bij inspanning gemeten met rechter hartkatheterisatie
    E.5.1.1Timepoint(s) of evaluation of this end point
    4 months
    4 maanden
    E.5.2Secondary end point(s)
    1. Myocardial and calf muscle PCr/ATP-ratio at rest measured by 31P-MRS.
    2. PCr/ATP ratio in calf muscle during exercise . And PCr recovery after exercise
    3. Change in mitochondrial function
    4. Correction of iron storage in plasma (ao ferritin and TSAT) and organs (MRI of heart / skeletal muscle)
    5 Safety endpoints (SAE's)
    6. Change in symptoms (NYHA, fatigue-score and quality of life questionairres (KCCQ and EQ-5D)
    7. Change in exercise tolerance (6 minute walk test; bicycle ergometry)
    8. Change in NTproBNP
    9. Change in microvascular function (substudy)
    1. Myocardiale en skelet spier PCr/ATP ratio in rust gemeten mbv 31-fosfor MRI.
    2. PCr/ATP ratio van de skelet spier bij inspanning + PCr recovery na inspanning
    3. Verandering in systemische mitochondriele functie (bv verandering plasma acetylcarnitines)
    4. Correctie van ijzer voorraden in plasma (oa ferritine en TSAT) en organen (MRI hart en skeletspier)
    5. Veiligheid beoordeeld met SAE's
    6. Symptomen (NYHA, vermoeidheids-score en quality of life vragenlijsten (KCCQ en EQ5D)
    7. Inspanningstolerantie (6 minute walk test en fietsergometrie)
    8. Verandering in NTproBNP
    9. Verandering in microvasculaire function (substudy)
    E.5.2.1Timepoint(s) of evaluation of this end point
    4 months
    4 maanden
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    last visit of last subject
    laatste visite van laatste deelnemer
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care
    Standaard zorg
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-10-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-09-30
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