Clinical Trials Register

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:	Ongoing
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

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2019-003461-17

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

IRON-HFpEF

A.4.1

Sponsor's protocol code number

71272

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Amsterdam UMC, location VUmc
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Vifor (International) AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amsterdam UMC, location VUmc
B.5.2	Functional name of contact point	dr. M.L. Handoko, cardiologist
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31204440123
B.5.6	E-mail	ml.handoko@amsterdamumc.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ferric Carboxymaltose (Ferinject®)
D.2.1.1.2	Name of the Marketing Authorisation holder	Vifor Pharma Nederland BV
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ferric carboxymaltose (Ferinject)
D.3.2	Product code	RVG 33865
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart failure with preserved ejection fraction

Hartfalen met behouden ejectie fractie

E.1.1.1

Medical condition in easily understood language

Diastolic heart failure

Diastolisch hartfalen

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Diagnosis of heart failure with preserved ejection fraction
a. signs/and symptoms of heartfailure (NYHA II or higher)
b. Left ventricular ejection fraction ≥50%
c. evidence of left ventricular diastolic dysfunction:
-pulmonary capillary wedge pressure (PCWP) at rest ≥ 15mmHg and/or PCWP during exercise ≥ 25mmHg
or if no right heart catheterisation has been performed:
-HFpEf score ≥ 6;
-diastolic dysfunction grade II or higher on echocardiogram + NTproBNP of >125 pg/mL
d. no other significant cardiac (e.g. significant valvular disease) or extra-cardiac con-dition (e.g. severe COPD) that explains symptoms
2. Optimal medical treatment
3. Clinically stable
4. Iron deficient (ferritin <100pg/L or ferritin 100-300pg/L and transferrin saturation or TSAT <20%).

1. Diagnose van hartfalen met behouden ejectie fractie
a. symptomen van hartfalen (NYHA II of hoger)
b. LVEF ≥ 50%
c. bewijs van linker ventrikel diastolische dysfunctie:
- PCWP in rust ≥ 15mmHg en/of PCWP tijdens inspanning ≥ 25mmHg
Indien geen rechter hart katheterisatie is verricht:
-HFpEf score ≥ 6; OF
-diastolische dysfunctie graad 2 of hoger op echocardiogram + NTproBNP >125 pg/mL
d. geen andere significante cardiale of non-cardiale aandoening die de symptomen verklaard
2. Optimale medicamenteuse therapie
3. Klinisch stabiel
4. ijzer deficient (ferritin <100pg/L of ferritin 100-300pg/L entransferrin saturation (TSAT) <20%).

E.4

Principal exclusion criteria

1. No informed consent
2. Contra indication ferric carboxy maltose
a. known allergic reaction to product; b. clinical signs of an acute infection; c. conditions with high risk for an allergic reaction (severe asthma or eczema, systemic lupus erhytematosus, rheumatoid arthtritis or concurrent use of significant immunosuppressive therapy); severe liver disease
3. History of (previous 2 months) or planned use of intravenous/oral iron, erythro-poietin or blood transfusion
4. Acute coronary syndrome, TIA/CVA, PCI/CABG/valve replacement or any major surgery within 3 months prior;
5. Unable to undergo the complete study protocol (i.e. right heart catheterisation, 6 minute walk distance)

1. Geen informed consent
2. Contra indicatie ferric carboxymaltose:
a. bekende allergie/overgevoeligheid product; b. actieve infectie; c. condities met verhoogd risico op allergische reacties (ernstig asthma/eczeem; systemische lupus erythematosus, reumatoide arthritis; gebruik van significante immunosuppresiva)
3. Recent gebruik of gepland gebruik van ijzer suppletie, erytropoteine of bloedtransfusie
4. Recente cerebrocardiovasculair event of grote operatie.
5. Niet in staat tot voltooiing studie protocol (oa rechter hartkatheterisatie, 6 minuten looptest)

E.5 End points

E.5.1

Primary 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.5.1.1

Timepoint(s) of evaluation of this end point

4 months

4 maanden

E.5.2

Secondary 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.5.2.1

Timepoint(s) of evaluation of this end point

4 months

4 maanden

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

last visit of last subject

laatste visite van laatste deelnemer

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-07

P. End of Trial
P.	End of Trial Status	Ongoing

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