Clinical Trials Register

Summary
EudraCT Number:	2016-000068-40
Sponsor's Protocol Code Number:	FAIR-HF2
National Competent Authority:	Slovenia - JAZMP
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-06-26
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

Slovenia - JAZMP

A.2

EudraCT number

2016-000068-40

A.3

Full title of the trial

Intravenous iron in patients with systolic heart failure and iron deficiency to improve morbidity & mortality – FAIR–HF2

Intravensko železo za zmanjšanje obolevnosti in umrljivosti pri bolnikih s sistoličnim srčnim popuščanjem in pomanjkanjem železa – FAIR-HF2

A.3.1

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

Study to investigate the improvement on morbitity and mortality and frequence of disease by intravenous iron therapy in patients with disturbance of heart function and iron deficiency

A.4.1

Sponsor's protocol code number

FAIR-HF2

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	Deutsches Zentum für Herz-Kreislauf-Forschung
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 SA
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.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 injection/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

Systolic heart failure associated with iron deficiency

Sistolično srčno popuščanje in pomanjkanje železa

E.1.1.1

Medical condition in easily understood language

Reduced heart's pumping associated with iron deficiency

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	10074631
E.1.2	Term	Systolic 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

The primary objective of the FAIR-HF2 trial is to show that treatment of patients with systolic heart failure and iron deficiency with i.v. iron (Ferric Carboxymaltose, FCM) versus placebo (i.v. NaCl) can reduce the rate of the combined endpoint of recurrent heart failure hospitalisations and cardiovascular death.

Primarni cilj preskušanja FAIR-HF2 je pokazati, da zdravljenje pacientov s sistoličnim srčnim popuščanjem (SP) in pomanjkanjem železa (PŽ) z intravenskim dovajanjem železa (železove karboksimaltoze, ŽKM) v primerjavi z uporabo placeba (intravensko dovajanje NaCl) zmanjša pojavnost kombiniranega opazovanega dogodka ponavljajočih se hospitalizacij zaradi srčnega popuščanja in smrti iz kardiovaskularnih (KV) vzrokov.

E.2.2

Secondary objectives of the trial

Secondary objectives include the demonstration that in these patients treatment with FCM versus placebo can reduce the rate of recurrent cardiovascular hospitalisations, the rate of recurrent hospitalisations of any kind, and of all-cause mortality. An additional aim is to show the cost-effectiveness of the intervention.

Sekundarni cilji so pokazati, da lahko zdravljenje z ŽKM namesto s placebom pri teh pacientih zmanjša pogostnost ponavljajočih se hospitalizacij zaradi KV vzrokov, pogostnost kakršnih koli ponavljajočih se hospitalizacij in celokupno umrljivost. Dodatni cilj je pokazati še stroškovno učinkovitost intervencije.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with chronic HFrEF (CHF) of at least 3 months duration and a history of documented LVEF<45%.
2. Confirmed presence of ID (ferritin < 100 ng/mL or ferritin 100 – 299 ng/mL with TSAT < 20 %)
3. Serum haemoglobin of 9.5 - 14.0 g/dL
4. At time of screening considered re-stabilised and planned for discharge within next 24 h (NYHA 2 or 3), or stable ambulatory with a HF hospitalisation in the past 12 months (NYHA 2-4), or stable ambulatory with BNP > 100 pg/mL or NT-proBNP > 300 pg/mL or MRproANP > 120 pmol/L (NYHA 2-4)
5. Written informed consent

1. Pacienti, pri katerih je najmanj 3 mesece prisotno kronično srčno popuščanje HFrEF (KSP) in z anamnezo dokazanega LVEF < 45 %
2. Potrjeno PŽ (feritin < 100 ng/ml ali feritin = 100–299 ng/ml pri manj kot 20-odstotni transferinski nasičenosti)
3. Serumski hemoglobin 9,5–14,0 g /dl
4. V času presejalnega pregleda označeni za stabilizirane in predvideni za odpust v naslednjih 24 h (NYHA razred 2 ali 3) ali stabilni med ambulantnim zdravljenjem, a v zadnjih 12 mesecih (NYHA razred 2–4) hospitalizirani zaradi SP, ali stabilni med ambulantnim zdravljenjem in z vrednostmi BNP > 100 pg/ml ali NT-proBNP > 300 pg/ml ali MR-proANP > 120 pmol/l (NYHA razred 2–4)
5. Pisna prostovoljna privolitev po poučitvi

E.4

Principal exclusion criteria

1. Hypersensitivity to the active substance, to FCM or any of its excipients
2. Known serious hypersensitivity to other parenteral iron products
3. Anaemia not attributed to iron deficiency, e.g. other microcytic anaemia
4. Evidence of iron overload or disturbances in the utilisation of iron
5. History of severe asthma with known FEV1 <50%
6. Acute bacterial infection
7. Presence of a deficiency for vitamin B12 and/or serum folate (if present, this needs to be corrected first)
8. Use of renal replacement therapy
9. Treatment with an erythropoietin stimulating agent (ESA), any i.v. iron and/or a blood transfusion in the previous 6 weeks prior to randomisation.
10. More than 500 meters in the initial 6-minutes walking-test Note: We aim to recruit at least half of the patients with an initial 6-minute walking-test below 375 meters

1. Preobčutljivost za aktivno učinkovino, ŽKM ali katero koli od njenih pomožnih snovi
2. Znana resna preobčutljivost na druge železove izdelke za parenteralno uporabo
3. Anemija, ki ni posledica pomanjkanja železa, npr. druge mikrocitne anemije
4. Znaki preobremenjenosti organizma z železom oziroma motenj pri uporabi železa
5. Huda astma z znanim podatkom o FEV1 < 50 % v anamnezi
6. Akutna bakterijska okužba
7. Pomanjkanje vitamina B12 in/ali serumskega folata (v primeru pomanjkanja je najprej treba urediti le-tega)
8. Nadomestno ledvično zdravljenje
9. Zdravljenje s sredstvi za spodbujanje eritropoeze (ESA), kakršnim koli intravenskim dajanjem železa in/ali transfuzijo krvi v 6 tednih pred randomizacijo.
10. Več kot 500 metrov na začetnem 6-minutnem testu hoje
Opomba: Cilj je vključiti vsaj polovico pacientov z začetnim 6-minutnim testom hoje manj kot 375 metrov.

E.5 End points

E.5.1

Primary end point(s)

Combined rate of recurrent hospitalisations for heart failure and of CV
death during follow-up

Kombinirana pogostnost ponavljajočih se hospitalizacij zaradi srčnega
popuščanja in smrti zaradi KV vzrokov v obdobju spremljanja.

E.5.1.1

Timepoint(s) of evaluation of this end point

During follow-up

Tekom spremljanja

E.5.2

Secondary end point(s)

- Combined rate of recurrent CV hospitalisations and of CV death during follow-up
- Rate of recurrent HF hospitalisations
- Rate of recurrent CV hospitalisations
- CV mortality
- All-cause mortality
- Rate of recurrent hospitalisations of any kind
- Combined rate of recurrent hospitalisations for any reason and allcause mortality
- Changes in 6-minute walk-test, NYHA functional class, EQ-5D, and PGA of wellbeing during follow-up (from baseline to various time-points of follow-up)
- Exploratory: Changes in renal, cardiovascular, inflammatory and metabolic parameters from baseline to end of follow-up
Further analyses:
- For the primary clinical efficacy endpoint, as well as other important clinical endpoints – especially recurrent heart failure hospitalisations, recurrent CV hospitalisations; CV death, all-cause-death, and combinations thereof - a joint meta-analysis with all other relevant controlled clinical trials testing ferric car-boxymaltose and/ or other iv iron formulations versus placebo (e.g. FAIR-HF 1, AFFIRM-HF, CONFIRMHF) will be performed.

• Kombinirana pogostnost ponavljajočih se hospitalizacij zaradi KV vzrokov in smrti zaradi KV vzrokov v obdobju spremljanja
• Pogostnost ponavljajočih se hospitalizacij zaradi SP
• Pogostnost ponavljajočih se hospitalizacij zaradi KV-vzrokov
• Umrljivost zaradi KV-vzrokov
• Celokupna umrljivost
• Pogostnost vsakršnih ponavljajočih se hospitalizacij
• Kombinirana pogostnost vseh ponavljajočih se hospitalizacij in celokupne umrljivosti
• Spremembe pri 6-minutnem testu hoje, spremembe funkcionalnega razreda po NYHA, EQ-5D in osebni oceni dobrega počutja (PGA) v obdobju spremljanja (razlike med izhodiščno vrednostjo in vrednostjo na različnih časovnih točkah v obdobju spremljanja)
• Eksploratorno: spremembe v ledvičnih, kardiovaskularnih, vnetnih in presnovnih parametrih na začetku in na koncu obdobja spremljanja

Nadaljnje analize:
• Za primarni klinični cilj učinkovitosti, pa tudi za druge pomembne klinične cilje – zlasti za ponavljajoče se hospitalizacije zaradi srčnega popuščanja, ponavljajoče se hospitalizacije zaradi KV-vzrokov: smrti zaradi KV-vzrokov, vseh smrti in kombinacij le-teh – bo narejena skupna metaanaliza z vsemi drugimi relevantnimi nadzorovanimi kliničnimi preizkušanji, ki preizkušajo železovo karboksimaltozo in/ali druge intravenske železove formulacije v primerjavi s placebom (npr. FAIR-HF, AFFIRM-HF, CONFIRM-HF4).

E.5.2.1

Timepoint(s) of evaluation of this end point

At least after 12 month of follow up

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)

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Serbia

Germany

Hungary

Italy

Poland

Portugal

Slovenia

Spain

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:

600

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

700

F.4.2.2

In the whole clinical trial

1200

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

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

2017-12-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-06

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

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