Clinical Trials Register

Summary
EudraCT Number:	2015-005744-34
Sponsor's Protocol Code Number:	iCHF-2
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-09-28
Trial results	View 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

Germany - BfArM

A.2

EudraCT number

2015-005744-34

A.3

Full title of the trial

Randomized, Double-Blinded, Controlled Trial of Intravenous Iron in Patients With Cardiovascular Disease and Concomitant Iron Deficiency

Eine multizentrische, prospektive, randomisierte, kontrollierte Interventionsstudie bei Patienten mit Herz-und-Gefäßerkrankungen und begleitendem Eisenmangel

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Intravenous Iron in Patients with Cardiovascular Disease and Concomitant Iron Deficiency

Intravenöse Eisengabe bei Patienten mit
Herz-und-Gefäßerkrankungen und begleitendem Eisenmangel

A.4.1

Sponsor's protocol code number

iCHF-2

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	University Medical Centre Hamburg-Eppendorf
B.1.3.4	Country	Germany
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	Bundesministeriums für Bildung und Forschung (BMBF)
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Europäische Forschungsrat
B.4.2	Country	European Union
B.4.1	Name of organisation providing support	Förderverein Universitäres Herzzentrum Hamburg e.V.
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Vifor Pharma
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	University Medical Centre Hamburg-Eppendorf
B.5.2	Functional name of contact point	Mahir Karakas
B.5.3	Address:
B.5.3.1	Street Address	Martinistrasse 52
B.5.3.2	Town/ city	Hamburg
B.5.3.3	Post code	20246
B.5.3.4	Country	Germany
B.5.4	Telephone number	004940741057975
B.5.5	Fax number	004940741055619
B.5.6	E-mail	m.karakas@uke.de

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	Ferinject
D.2.1.1.2	Name of the Marketing Authorisation holder	Vifor France
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FERRIC CARBOXYMALTOSE
D.3.9.1	CAS number	9007-72-1
D.3.9.4	EV Substance Code	SUB66620
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	SODIUM CHLORIDE 0.9%
D.3.9.4	EV Substance Code	SUB171043
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/V) percent weight/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.9
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients With Cardiovascular Disease and Concomitant Iron Deficiency

Cohort A: Acute myocardial infarction (AMI)
Cohort B: Paroxysmal atrial fibrillation or persitent atrial fibrillation (AF)
Cohort C: Reduced HF (HF)

Patienten mit Herz-und-Gefäßerkrankungen und begleitendem Eisenmangel

Kohorte A: Herzinfarkt
Kohorte B: Vorhofflimmern
Kohorte C: Herzinsuffizienz

E.1.1.1

Medical condition in easily understood language

Patients With Cardiovascular Disease and Concomitant Iron Deficiency

Cohort A: heart attack
Cohort B: atrial fibrillation
Cohort C: heart failure

Patienten mit Herz-und-Gefäßerkrankungen und begleitendem Eisenmangel

Kohorte A: Herzinfarkt
Kohorte B: Vorhofflimmern
Kohorte C: Herzschwäche

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	10071667
E.1.2	Term	Persistent atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

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	10034039
E.1.2	Term	Paroxysmal atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

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	10050527
E.1.2	Term	Ejection fraction
E.1.2	System Organ Class	10022891 - Investigations

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	10000891
E.1.2	Term	Acute myocardial infarction
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the iCHF-2 trial is to show that treatment of patients with cardiovascular disease and concomitant iron deficiency (ID) with i.v. iron (Ferric Carboxymaltose, FCM) versus control (i.v. NaCl) can improve functional status.

Verbesserung des funktionellen Status durch die i.v. Gabe von Eisencarboxymaltose (FCM) im Vergleich zu Placebo (i.v. NaCl) bei Patienten mit Herz- und Gefäßerkrankungen und Eisenmangel.

E.2.2

Secondary objectives of the trial

not applicable

nicht zutreffend

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Cohort A (AMI): Acute Myocardial Infarction within 10 days (randomization/ first iron supple-mentation/ MRI must be performed within 10 days after AMI), without prior heart failure (defined as any known previous report of LVEF ≤ 45%)
Cohort B (AF): Paroxysmal Atrial fibrillation or persistent AF
Cohort C (HF): LVEF ≤ 45 % (documented within the last 12 months prior to screening), all NYHA classes allowed
2. Confirmed presence of ID (ferritin < 100 ng/mL or ferritin 100 - 299 ng/mL with TSAT < 20 %)
3. Haemoglobin ≤ 15.5 g/dL
4. Patients aged at least 18 years
5. Provided written informed consent
6. Females/Males who agree to comply with the applicable contraceptive requirements of the pro-tocol

1. Kohorte A (Herzinfarkt): Akuter Myokardinfarkt binnen 10 Tagen vor Randomisierung
Kohorte B (Vorhofflimmern): Paroxysmales oder persistierendes Vorhofflimmern
Kohorte C (Herzinsuffizienz): Linksventrikuläre Ejektionsfraktion ≤ 45 % (innerhalb der letzten 12 Monate vor Screening dokumentiert), alle New York Heart Association (NYHA) Klassen erlaubt
2. Bestätigter aktueller Eisenmangel (Ferritin < 100 ng/mL oder Ferritin 100 – 299 ng/mL mit Transferrinsättigung < 20 %)
3. Hämoglobin ≤ 15.5 g/dL
4. Patienten mind. 18 jahre alt
5. Schriftliche Einverständniserklärung
6. Frauen / Männer, die bereit sind sich an die kontrazenptiven Vorgaben zu halten

E.4

Principal exclusion criteria

1. Evidence of iron overload or disturbances in the utilisation of iron
2. History of severe asthma, eczema or other atopic allergy
3. History of immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis)
4. Treatment with an erythropoietin stimulating agent (ESA), any i.v. iron and/or a blood transfusion in the previous 6 weeks prior to randomisation
5. Oral iron therapy at doses > 100 mg/day at randomisation
6. Current use of renal replacement therapy
7. Patient at an immediate need of transfusion (hemoglobin below 7.5 g/dL or at the discretion of the investigator)

1. Nachweis von Eisenüberladung oder einer Störung in der Verwertung von Eisen
2. Krankengeschichte von schwerem Asthma, schweren Ekzemen, oder atopischen Allergien
3. Krankengeschichte von immunologischen oder entzündlichen Zuständen (systemischer Lupus erythematosus, rheumatoide Arthritis)
4.Behandlung mit einem Erythropoetin-stimulierenden Mittel, Gabe von i.v. Eisen und/oder Bluttransfusionen in den letzten 6 Wochen vor Randomisierung
5. Orale Eisentherapie bei einer Dosis von > 100 mg/Tag bei Randomisierung
6. Nierenersatzverfahren (Dialyse)
7. Patient mit dringlicher Notwendigkeit einer Transfusion ( Hämoglobin unter 7,5 g/dL oder in Ermessen des behandelnden Arztes)

E.5 End points

E.5.1

Primary end point(s)

Cohort A (AMI): Change in left-ventricular ejection fraction (LVEF) as determined by cardiac-MRI.
Cohort B (AF): Delta between treatment groups in burden of atrial fibrillation from day 90 to 365 as assessed by a routinely implanted event recorder.
Cohort C (HF): Change in LVEF as determined by cardiac-MRI.

Kohorte A (Herzinfarkt): Veränderung der mittels Goldstandard Kardio-MRT bestimmten linksventrikulären Pumpfunktion (LVEF)
Kohorte B (Vorhofflimmern): Delta zwischen Behandlungsgruppen der mittels Goldstandard Intrakardiales EKG (in der klinischen Routine implantiert) bestimmten arrhythmischen Belastung
Kohorte C (Herzinsuffizienz): Veränderung der mittels Goldstandard Kardio-MRT bestimmten linksventrikulären Pumpfunktion (LVEF)

E.5.1.1

Timepoint(s) of evaluation of this end point

Cohort A (AMI): Change from baseline to week 16
Cohort B (AF): Delta between treatment groups from day 90 to 365
Cohort C (HF): Change from baseline to week 16

Kohorte A ( Herzinfarkt): von Randomisierung bis Monat 4
Kohorte B (Vorhofflimmern): von Tag 90 bis Tag 365
Kohorte C (Herzinsuffizienz): von Randomisierung bis Monat 4

E.5.2

Secondary end point(s)

Cohort-specific secondary endpoints:
Cohort A: Change in myocardial salvage, extent of myocardial scar, and area at risk as determined by cardiac MRI
Cohort B: Burden of AF, Arrhythmic burden other than AF
Cohort C: Change in myocardial salvage, extent of myocardial scar, and area at risk as determined by cardiac MRI.
General secondary endpoints (stratified for each cohort):
1. Change in ventricular and atrial diameters, and change of mass index from baseline to follow-up cardiac MRI (only cohorts A and C; see MRI protocol for further read-outs).
2. Change of glomerular filtration rate (as determined by Cystatin C-based calculation)
3. Change of NYHA class
4. Change of distance walked at 6-minute walking test
5. Change of cardiometabolic and transcriptomic biomarkers (troponin T, NT-proBNP)
6. Change of QoL questionnaire (EQ-5D), PGA (patients’ global assessment) questionnaire, questionnaire for sleep quality (Pittsburgh Sleep Quality Index; PSQI), questionnaire for cognitive impairment (Mini mental state exam; MMSE), and questionnaire for depression (Becks depression inventory; BDI).
7. Percentage of patients meeting key safety endpoints defined as time to death, hospitalization for worsening heart failure, myocardial infarction, unscheduled coronary revascularisation, atrial fibrillation (only cohort A and cohort C), ventricular fibrillation, cardiac arrest, stent thrombosis, stroke, cardiac death, or death.

Kohorten-spezifische sekundäre Endpunkte:
Veränderung der primären Endpunkte bis zum maximalen Follow-Up
Grundätzliche sekundäre Endpunkte:
1. Veränderung der Nierenfunktion
2. Veränderung der NYHA-Klasse
3. Veränderung der Gehstrecke im 6-Minuten-Gehtest
4. Veränderung der Haupt-Laborparameter (Hämoglobin, Ferritin, Transferrinsättigung [TSAT])
5. Veränderung der kardiometabolischen und transkriptomischen Biomarker (Troponin T, NT-proBNP)
6. Veränderung der Fragebogen-Messgrößen [Lebensqualität (EQ-5D), Wohlbefinden (PGA), Schlafqualität (Pittsburgh Sleep Quality Index; PSQI), Kognitive Funktion (Mini mental state exam; MMSE), Depression (Becks depression inventory; BDI)
7. Anteil der Patienten die vordefinierte Sicherheitsendpunkte erreichen (Tod, Hospitalisation wegen Herzinsuffizienz, Herzinfarkt, ungeplante Myokardrevaskularisation, Vorhofflimmern (nur Kohorten A und C), Kammerflimmern, Herzstillstand, Stentthrombose, Herztod, Tod)

E.5.2.1

Timepoint(s) of evaluation of this end point

Cohort-specific secondary endpoints:
Cohort A: Change from baseline to week 16
Cohort B: Burden of AF between day 90 and 365, day 90 and 730, day 90 and day 1095 (or maximum day of event recording) Arrhythmic burden other than AF between day 90 and days 365/ 730/ 1095 (or maximum day of event recording)
Cohort C: Change from baseline to week 16

General secondary endpoints (stratified for each cohort):
1. Change from baseline to follow-up cardiac MRI (only cohorts A and C)
2. , 3., 4., 6. Change from baseline to week 16, baseline to week 52
5. Change from baseline to week 16, week 52 and year 3 in cohort B.
7. After 12 month (Cohort A and C) or 36 month (Cohort B)

Kohorten-spezifische sekundäre Endpunkte:
Kohorte A: Veränderungen bis Woche 16
Kohorte B: Vorkommen von Vorhofflimmern an Tag 90 bis 365, an Tag 90 bis Tag 730 / 1095 (oder maximaler Beobachtungstag). Arrhythmien (unabhängig von Vorhofflimmern) zwischen Tag 90 bis Tag 365/ 730/ 1095 (oder maximaler Beobachtungstag).
Kohorte C: Veränderungen bis Woche 16

Grundsätzliche sekundäre Endpunkte:
1. Veränderungen bis Herz-MRT Follow-up nach 12 Monaten (Kohorte A und C)
2., 3., 4., 6. Veränderung von Baseline bis Woche 16, Veränderungen von Baseline bis Woche 52
5. Veränderung von Baseline bis Woche 16 / 52 und nach 36 Monaten in Kohorte B.
7. Nach 12 Monaten (Kohorte A und C) oder 36 Monaten (Kohorte B)

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

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)

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

LVLS

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

140

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

240

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)

None

keine

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

2019-01-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-12-15

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