Clinical Trials Register

Summary
EudraCT Number:	2010-023788-16
Sponsor's Protocol Code Number:	P-Monofer-CABG-01
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-02-09
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

Denmark - DHMA

A.2

EudraCT number

2010-023788-16

A.3

Full title of the trial

A Randomized, Prospective, Double-Blind, Comparative Placebo-Controlled Study of Intravenous Iron Isomaltoside 1000 (Monofer®) Administered by Infusions to Non-anemic Patients Undergoing Elective or Sub-Acute CABG, Valve Replacement or a Combination thereof.

Et randomiseret, prospektivt, dobbeltblindet, komparativt placebokontrolleret forsøg med intravenøst jernisomaltosid 1000 (Monofer®) administreret ved infusion til non-anæmiske patienter, der får foretaget elektiv eller subakut koronar bypassoperation (CABG), hjerteklapudskiftning eller en kombination heraf.

A.3.1

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

A randomized, dobbelblind, controlled trial comparing the effect on hemoglobin level by administration of an iron supplement (Monofer ®) into a vein versus placebo (saline) in non-anemic patients in connection with the execution of planned or sub-acute heart bypass surgery (CABG) , heart valve replacement, or a combination thereof.

Et randomiseret, dobbelblindet, kontrolleret forsøg, der sammenligner effekten på blodprocenten ved indgift af et jerntilskud (Monofer®) i en blodåre versus placebo (saltvand) hos non-anæmiske patienter i forbindelse med udførelse af planlagt eller sub-akut hjerte bypassoperation (CABG), hjerteklap udskiftning eller en kombination heraf.

A.3.2

Name or abbreviated title of the trial where available

P-Monofer-CABG-01

A.4.1

Sponsor's protocol code number

P-Monofer-CABG-01

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	Pharmacosmos A/S
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmacosmos A/S
B.5.2	Functional name of contact point	CMO
B.5.3	Address:
B.5.3.1	Street Address	Roervangsvej 30
B.5.3.2	Town/ city	Holbaek
B.5.3.3	Post code	DK-4300
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4559485935
B.5.5	Fax number	+4559485960
B.5.6	E-mail	llt@pharmacosmos.com

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, injektions- og infusionsvæske, opløsning
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.3.1	Product name	Monofer
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	Iron Isomaltoside 1000
D.3.9.1	CAS number	9004-66-4
D.3.9.3	Other descriptive name	Iron isomalto-oligosaccharide complex
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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

Non-anemic Patients Undergoing Elective or Sub-Acute CABG, Valve Replacement or a Combination thereof

Non-anæmiske Patienter, der får foretaget elektiv eller subakut CABG, hjerteklapudskiftning eller en kombination heraf

E.1.1.1

Medical condition in easily understood language

Non-anemic Patients undergoing planned or sub-acute heart bypass surgery (CABG), heart valve replacement or a combination thereof.

Non-anæmiske Patienter der får foretaget planlagt eller sub-akut hjerte bypassoperation (CABG), hjerteklap udskiftning eller en kombination heraf.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10054312
E.1.2	Term	Anemia postoperative
E.1.2	System Organ Class	100000004863

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 demonstrate that intravenous iron isomaltoside 1000 (Monofer®) is superior compared to placebo in leading to a less decrease in the haemoglobin level in non-anemic patients undergoing cardiac surgery

At påvise superioritet af intravenøst jernisomaltosid 1000 (Monofer®) i forhold til placebo i forhold til at nedsætte et fald i hæmoglobinindholdet hos non-anæmiske patienter, der får foretaget hjerteoperationer

E.2.2

Secondary objectives of the trial

• The secondary purpose of the study is to compare the effect of jernisomaltosid 1000 and placebo on:
 Need for blood transfusion
 Iron Related Parameters
 Time of Hospitalization
 Functional capabilities
 Safety

• De sekundære formål i studiet er at sammenligne effekten af jernisomaltosid 1000 og placebo på:
 Behov for blodtransfusion
 Jernrelaterede parametre
 Indlæggelsestid
 Funktionel formåen
 Sikkerhed

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to be suitable for inclusion in the study, the subjects meet the following criteria:
1. Men and women over 18 years.
2. Non-anemic Patients undergoing elective or subacute CABG, heart valve replacement or a combination thereof.
3. Women: Hb ≥ 12.0 g / dl (7.45 mmol / l), men: Hb ≥ 13.0 g / dl (8.1 mmol / l).
4. Willingness to participate after informed consent.

For at være egnet til inklusion i forsøget skal forsøgspersonerne opfylde følgende kriterier:
1. Mænd og kvinder over 18 år.
2. Non-anæmiske Patienter, der får foretaget elektiv eller subakut CABG, hjerteklapudskiftning eller en kombination heraf.
3. Kvinder: Hb ≥ 12.0 g/dl (7,45 mmol/l), mænd: Hb ≥ 13,0 g/dl (8,1 mmol/l).
4. Villighed til at deltage efter informeret samtykke.

E.4

Principal exclusion criteria

Individuals who meet one or more of the following criteria are unsuitable for inclusion in the study:
1. Participants who have received blood transfusion within 30 days prior to screening, and / or during the elective CABG or subacute, heart valve replacement, or a combination thereof.
2. Iron Overload or disturbances in utilization of iron (eg. Haemochromatosis and haemosiderosis)
3. Serum ferritin> 800 ng / ml.
4. Known hypersensitivity to any of the excipients of the study drug.
5. Multiple allergies in medical history.
6. Decompensated cirrhosis and hepatitis.
7. Alanine aminotransferase (ALT)> 3 times upper limit of normal.
8. Acute infections (after clinical assessment).
9. Rheumatoid arthritis with symptoms or signs of active joint inflammation.
10. The patient is pregnant or breast-feeding. (To exclude pregnancy, women must be postmenopausal (at least 12 months since the last menstrual period) or sterilized or, for women of childbearing potential, use one of the following methods of contraception throughout the trial and for a period after termination representing at least 5 biological plasma half-lives of study drug: P contraceptives, intrauterine devices, parenteral contraception with depot effect (prolonged release formulation with progestin), subdermal implant, vaginal ring or transdermal patches).
11. Participation in another clinical trial, in a period prior to screening corresponding to less than 5 half-lives of the experimental drug.
12. Untreated Vitamin B12 or folate deficiency.
13. Another iv or oral iron therapy within 4 weeks prior to screening visit.
14. Erythropoietin treatment within 4 weeks prior to screening visit.
15. Impaired renal function defined by se-creatinine> 150μmol / l

Personer, der opfylder et eller flere af følgende kriterier, er uegnede til inklusion i forsøget:
1. Deltagere som har modtaget blodtransfusion indenfor 30 dage før screening og/eller under den elektive eller subakutte CABG, hjerteklapudskiftning eller en kombination heraf.
2. Jernoverload eller forstyrrelser i jernudnyttelsen (f.eks. hæmokromatose og hæmosiderose)
3. Serumferritin >800 ng/ml.
4. Kendt overfølsomhed over for et eller flere af hjælpestofferne i forsøgslægemidlet.
5. Multiple allergier i anamnesen.
6. Dekompenseret levercirrhose og hepatitis.
7. Alaninaminotransferase (ALT) > 3 gange øvre normalgrænse.
8. Akutte infektioner (efter klinisk vurdering).
9. Rheumatoid arthritis med symptomer eller tegn på aktiv ledinflammation.
10. Patienten er gravid eller ammer. (For at udelukke graviditet skal kvinder være postmenopausale (mindst 12 måneder siden sidste menstruation) eller steriliseret eller, for fødedygtige kvinder, anvende en af følgende antikonceptionsmetoder i hele forsøgsperioden og i en periode efter forsøgets afslutning svarende til mindst 5 biologiske plasmahalveringstider af forsøgslægemidlet: P-piller, spiral, parenteral antikonception med depotvirkning (depotpræparat med gestagen), subdermalt implantat, vaginalring eller depotplastre).
11. Deltagelse i et andet klinisk forsøg i et tidsrum inden screeningen svarende til mindre end 5 halveringstider af det pågældende forsøgslægemiddel.
12. Ubehandlet vitamin B12- eller folatmangel.
13. Anden iv eller peroral jernbehandling inden for 4 uger før screeningsbesøget.
14. Behandling med erythropoietin inden for 4 uger før screeningsbesøget.
15. Påvirket nyrefunktion defineret ved se-creatinin > 150μmol/l

E.5 End points

E.5.1

Primary end point(s)

The trial's primary endpoint is:
 Changes in hemoglobin concentration from baseline (ie preoperatively - the day before surgery or surgery day) for 4 weeks postoperatively.

Forsøgets primære endpoint er:
 Ændring i hæmoglobinkoncentrationen fra baseline (dvs. præoperativt – dagen før operationen eller operationsdagen) til 4 uger postoperativt.

E.5.1.1

Timepoint(s) of evaluation of this end point

4 weeks postoperatively

4 uger postoperativt.

E.5.2

Secondary end point(s)

The secondary end points of the study are:
• Proportion of patients that are anaemic (women < 12 g/dL and men < 13 g/dL) at day 5 and week 4
• Proportion of patients able to maintain Hb between 9.5 and 12.5 g/dL (both values included) at day 5 and week 4.
• Number of patients in each randomisation group who need blood transfusion and number of transfusions administered
• Change from baseline (preoperatively - the day before surgery or same day) in concentrations of serum ferritin, serum iron, TfS, and reticulocytes at day 5 and week 4
• Number of postoperative days to discharge
• Changes in New York Heart Association (NYHA) classification from baseline to 4 weeks post operatively
• Number of patients in each randomisation group who experience any study drug related adverse events (AEs/SAEs/SUSARs)

Forsøgets sekundære endpoints er:
• andel patienter, der er anæmisk (kvinder < 12 g/dL og mænd <13 g/dL) på dag 5 og uge 4
• andel patienter i stand til at opretholde Hb mellem 9,5 og 12,5 g/dL (begge værdier inkluderet) på dag 5 og uge 4.
• antal transfusionskrævende patienter og antal foretagne transfusioner i hver randomiseringsgruppe
• ændring i koncentrationen af serumferritin, serumjern (TfS) og reticulocytter fra baseline (dvs. præoperativt – dagen før operationen eller operationsdagen) til dag 5 og uge 4
• antal dage postoperativt til udskrivning
• ændring i New York Heart Association (NYHA) klassificering fra baseline til 4 uger postoperativt
• antal patienter i hver randomiseringsgruppe, som kommer ud for forsøgsmedicinrelaterede uønskede hændelser (AE/SAE/SUSAR)

E.5.2.1

Timepoint(s) of evaluation of this end point

4 weeks postoperatively

4 uger postoperativt.

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

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)

Yes

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

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

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

LSLV

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

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.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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

ingen

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

2011-03-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-08-02

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