Clinical Trials Register

Summary
EudraCT Number:	2012-005592-13
Sponsor's Protocol Code Number:	FERRICHFII
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-12-11
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

UK - MHRA

A.2

EudraCT number

2012-005592-13

A.3

Full title of the trial

Mechanisms of Exercise Benefit with Intravenous Iron in Chronic Heart Failure: The Ferric Iron in Heart Failure (FERRIC HF) II Trial

A.3.1

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

Mechanisms of Exercise Benefit with Intravenous Iron in Chronic Heart Failure

A.3.2

Name or abbreviated title of the trial where available

Mechanisms of Exercise Benefit with IV Iron in CHF

A.4.1

Sponsor's protocol code number

FERRICHFII

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	King's College London
B.1.3.4	Country	United Kingdom
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	King's College London British Heart Foundation Centre
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	King's College London
B.5.2	Functional name of contact point	Dr Darlington Okonko
B.5.3	Address:
B.5.3.1	Street Address	The James Black Center,125 Coldharbour Lane
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SE5 9NU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0044207848 5017
B.5.6	E-mail	darlington.okonko@kcl.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	King's College Hospital NHS Foundation Trust
B.1.3.4	Country	United Kingdom
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	King's College London British Heart Foundation Centre
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	King's College NHS Foundation Trust
B.5.2	Functional name of contact point	Dr Darlington Okonko
B.5.3	Address:
B.5.3.1	Street Address	The James Black Center, 125 Coldharbour Lane
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SE5 9NU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0044207848 5017
B.5.6	E-mail	darlington.okonko@kcl.ac.uk

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	MONOFER
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmacosmos A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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 iron (FE 3+)
D.3.9.1	CAS number	9004-66-04
D.3.9.3	Other descriptive name	IRON(III) ISOMALTOSIDE 1000
D.3.9.4	EV Substance Code	SUB74758
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	100
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

Chronic Heart Failure

E.1.1.1

Medical condition in easily understood language

Chronic Heart Failure

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10008908
E.1.2	Term	Chronic heart failure
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the effect of iv iron repletion on skeletal muscle oxidative capacity as quantified by PCr t1/2 and ADP t1/2 following gastrocnemius muscle exercise using 31-P MRS.

E.2.2

Secondary objectives of the trial

To determine:
• Change in skeletal muscle ferritin, free iron content, and transferrin receptor levels from baseline to 2 weeks post
treatment.
• Change in skeletal muscle fibre type, immunohistochemistry, and aerobic enzyme levels from baseline to 2 weeks
post treatment.
• Change in distance walked in 6 minutes from baseline to 2 weeks post treatment.
• Change in symptom status from baseline to 2 weeks post treatment.
• Change in haematological and biochemical indices from baseline to 2 weeks post treatment.
• Number and incidence of adverse events; changes in liver function tests and renal function tests; changes in vital
parameters.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

≥30 years of age and have signed written informed consent
• Stable symptomatic CHF; NYHA III/IV and LVEF ≤45%, or if NYHA II then LVEF must be ≤40% as assessed within last 6 months using echocardiographic or magnetic resonance imaging techniques.
• On optimal conventional therapy for at least 4 weeks prior to recruitment and without dose changes for at least 2 weeks.
• Screening Hb concentration < 12 g/dl in females and < 13 g/dL in males (anaemic group, 50% of study population) or ≥12 g/dL in females and ≥ 13 g/dL in males (non-anaemic group, 50% of study population).
• Ferritin <100 g/l or 100-300 g/l with TSAT <20%.
• Folate and Vitamin B12 levels ≥ lower limit of normal (according to local lab reference range).
• Resting blood pressure ≤160/100 mmHg.
• Negative pregnancy test in women of child-bearing age

E.4

Principal exclusion criteria

• History of acquired iron overload, known haemochromatosis or first relatives with haemochromatosis, and allergic disorders (asthma, eczema, and anaphylactic reactions).
• Known hypersensitivity to parental iron preparations or any of their excipients.
• Known active infection, bleeding, malignancy, haemolytic anaemia, and rheumatoid arthritis.
• History of chronic liver disease with alanine transaminase (ALT) or aspartate transaminase (AST) >3 times the upper limit of the normal range, severe chronic lung disease with FEV1 < 50% predicted, myelodysplastic disorder, and known HIV/AIDS disease.
• Coagulopathy or anticoagulation with warfarin or warfarin substitutes for a metallic valve or an LV thrombus diagnosed in the last 6 months.
• Contraindications to magnetic resonance imaging (pacemaker, cardiac resynchronization therapy device, internal cardiac defibrillator, metal prostheses, excessive claustrophobia)
• Recipient of immunosuppressive therapy or renal dialysis.
• Anticipated need for erythropoietin or a blood transfusion during the study.
• Unstable angina as judged by the investigator, severe uncorrected non-functional valvular disease or left ventricular outflow obstruction, obstructive cardiomyopathy, uncontrolled fast atrial fibrillation or flutter (>110 bpm), uncontrolled symptomatic brady- or tachyarrhythmias.
• Musculoskeletal limitation that, in the investigators judgement, would impair exercise testing.
• Pregnant or breast-feeding
• Inability to comprehend study protocol
• Parallel participation in another clinical trial

E.5 End points

E.5.1

Primary end point(s)

Change in skeletal muscle oxidative capacity as assessed by PCr t1/2 from baseline to 2 weeks post last treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

Endpoint will be evaluated at baseline and study end (2 weeks post last treatment)

E.5.2

Secondary end point(s)

• Change in skeletal muscle oxidative capacity as assessed by ADP t1/2 from baseline to 2 weeks post last treatment.
• Change in skeletal muscle oxidative capacity as reflected by mitochondrial oxygen consumption per mg of muscle tissue measured using a respirometer from baseline to 2 weeks post last treatment.
• Change in skeletal muscle ferritin, free iron content, and transferrin receptor levels from baseline to 2 weeks post last treatment.
• Change in skeletal muscle fibre type, immunohistochemistry, and aerobic enzyme mRNA and protein levels from baseline to 2 weeks post last treatment.
• Change in distance walked in 6 minutes from baseline to 2 weeks post last treatment.
• Change in cardiopulmonary exercise (CPEX) parameters (peak oxygen consumption and ventilation to carbon dioxide production ratio) from baseline to 2 weeks post last treatment.
• Change in symptom status (NYHA class, Kansas City Cardiomyopathy questionnaire [KCCQ], visual analogue fatigue scale [VAFS]) from baseline to 2 weeks post treatment.
• Change in haematological and biochemical indices (Hb, Hct, reticulocyte count, iron status, N-terminal brain natiuretic peptide [NT-BNP], cytokines and oxidative stress) from baseline to 2 weeks post treatment.
• Change in cardiac function and tissue doppler indices on echocardiography.
• Change in erythroid precursor and progenitor numbers on flow cytometry and cell culture.

E.5.2.1

Timepoint(s) of evaluation of this end point

Endpoint will be evaluated at baseline and study end (2 weeks after last treatment)

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

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

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

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

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

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)

Patients who received saline during the trial period will be offered a course of iv iron iron at the end if they remain iron
deficient. Patients will have their iron status regularly evaluated after the trial and will be supplemented as appropriate.

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

2014-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-12-20

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