Clinical Trials Register

Summary
EudraCT Number:	2010-023471-26
Sponsor's Protocol Code Number:	P-Monofer-CKD-03
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:	2011-04-18
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

2010-023471-26

A.3

Full title of the trial

A Phase III, Randomized, Comparative, Open-label Study of Intravenous Iron Isomaltoside 1000 (Monofer®) Administered as Maintenance Therapy by Single or Repeated Bolus Injections in Comparison with Intravenous Iron Sucrose in Subjects with Stage 5 Chronic Kidney Disease on Dialysis Therapy (CKD-5D).

A.3.1

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

Et randomiseret, komparativt, ikke-blindt fase III-forsøg med intravenøst jernisomaltosid 1000 (Monofer®), indgivet som vedligeholdelsesbehandling med enkelte eller gentagne bolusinjektioner sammenlignet med intravenøst jernsukrose hos forsøgspersoner med kronisk nyresygdom i stadie 5, som er i dialyse.

A.4.1

Sponsor's protocol code number

P-Monofer-CKD-03

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	Pharmacosmos A/S
B.4.2	Country	Denmark
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	Clinical R&D
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	04559485935
B.5.5	Fax number	04559485960
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
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 bolus use (Noncurrent)
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.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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.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.2.1.1.1	Trade name	Venofer
D.2.1.1.2	Name of the Marketing Authorisation holder	Vifor France SA
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	Venofer
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Iron(III)-hydroxide sucrose complex
D.3.9.1	CAS number	8047-67-4
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	20
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

Stage 5 Chronic Kidney Disease on Dialysis Threapy (CKD5D)

Dialyseterapi krævende kronisk nyresygdom

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10064848
E.1.2	Term	Chronic kidney disease
E.1.2	System Organ Class	10038359 - Renal and urinary 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

To demonstrate that intravenous iron isomaltoside 1000 (Monofer®) is noninferior to IV iron sucrose determined as ability to maintain Hb in subjects with CKD5D who are on maintenance iron therapy.

E.2.2

Secondary objectives of the trial

The secondary objectives are:
• To obtain safety reassurance with the use of iron isomaltoside 1000 (Monofer®) for the maintenance of Haemoglobin in subjects with CKD-5D who are on maintenance iron therapy
• To evaluate the safety of intravenous iron isomaltoside 1000 (Monofer®) in comparison with iron sucrose administered intravenously in patients with CKD-5D
• To compare iron related hematological parameters (haemoglobin (Hb), Transferrin Saturation (TfS), serum iron, serum ferritin levels and reticulocyte count)
• To assess subjects who discontinue study due to lack of response or intolerance
• Assess changes in Quality of Life (QoL) by Linear Analog Scale Assessment (LASA)
• Assess Restless Legs Syndrome (RLS) symptoms and change in these symptoms during the study.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects with a diagnosis of CKD-5D, in dialysis therapy for at least 90 days prior to inclusion, will be
included if they meet all of the following criteria:
1. Men or women, aged 18 years or greater.
2. Subjects diagnosed with CKD-5D and in haemodialysis therapy for at least 90 days.
3. Life expectancy beyond 12 months by Principal Investigator’s judgement.
4. Willingness and ability to participate after Informed Consent.
5. Hb concentrations between 10.0 g/dL and 12.5 g/dL (both values included) both at screening
Visit 1a and at Screening Visit 1b. (Screening Visit 1a and Visit 1b must be separated by at
least 1 week).
6. Serum ferritin < 800 ng/mL.
7. Transferrin Saturation < 35%.
8. Subjects receiving ESA treatment with dose stable for the previous 4 weeks prior to inclusion
(with only 1 missed dose to be allowed. Does to be kept stable during the study period).
9. Subjects receiving no IV iron or an average of no more than 100 mg/week for the previous 4
weeks (with only 1 missed dose to be allowed. Does to be kept stable during the study
period).

Forsøgspersoner, som er diagnosticeret med CKD-5D, og som har været i dialyse i mindst 90 dage inden inklusion, inkluderes, hvis de opfylder følgende kriterier:
1. Mænd og kvinder over 18 år.
2. Forsøgspersoner, som er diagnosticeret med CKD-5D, og som har været i hæmodialyse i mindst 90 dage.
3. Forventet levetid over 12 måneder efter den forsøgsansvarlige investigators vurdering
4. Forsøgspersonen er villig og i stand til at deltage efter afgivelse af informeret samtykke.
5. Hb-koncentrationer mellem 10,0 g/dl og 12,5 g/dl (inklusiv begge værdier) både ved screeningsbesøg 1a og 1b. (Der skal gå mindst 1 uge mellem screeningsbesøg 1a og 1b).
6. Serumferritin < 800 ng/ml.
7. Transferrinmætning < 35 %.
8. Forsøgspersoner, som har fået ESA-behandling ved stabil dosis i de sidste 4 uger inden screening (det er kun tilladt at have undladt at tage 1 dosis. Dosen skal være stabil gennem studiet).
9. Forsøgspersoner, som ikke har fået intravenøst jern eller gennemsnitligt højst 100 mg/uge i de sidste 4 uger (det er kun tilladt at have undladt at tage 1 dosis. Dosen skal være stabil gennem studiet).

E.4

Principal exclusion criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Anaemia caused primarily by factors other than renal related anaemia.
2. Iron overload or disturbances in utilization of iron (e.g. haemochromatosis and
haemosiderosis).
3. Patients currently undergoing treatment with immunosuppresives (low dose steroids are
allowed during the study conduct for dosages no more than 10 mg prednisolone/day or
equivalent. If possible the dosage should be kept constant through the study).
4. Difference of Hb 1.0 g/dL between screening Visits 1a and 1b.
5. Patients with a history of multiple allergies.
6. Decompensated liver cirrhosis or active hepatitis [Alanine Aminotransferase (ALT) > 3 times
normal] or history of Hepatitis B or C.
7. Active acute or chronic infections (assessed by clinical judgement), supplied with White Blood
Cells (WBC) and C-Reactive Protein (CRP).
8. Rheumatoid arthritis with symptoms or signs of active joint inflammation.
9. Pregnancy or nursing. (To avoid pregnancy, women have to be postmenopausal (at least 12
months must have elapsed since last menstruation), surgically sterile, or women of child
bearing potential must use one of the following contraceptives during the whole study period
and after the study has ended for at least 5 times plasma biological half-life of the
investigational medicinal product: Contraceptive pills, Intrauterine Devices (IUD),
contraceptive depot injections (prolonged-release gestagen), subdermal implantation, vaginal
ring, and transdermal patches).
10. Blood transfusion within the previous 12 weeks.
11. Planned elective surgery in the next 8 weeks.
12. Participation in any other clinical trial within the past 30 days, or if longer, where the study
drug has not passed five half-lives prior to screening.
13. Untreated Vitamin B12 or folate deficiency.
14. Any other medical condition that, in the opinion of Principal Investigator, may cause the
subject to be unsuitable for the completion of the study or place the subject at potential risk
from being in the study. Examples include Uncontrolled Hypertension, Unstable Ischemic
Heart Disease or Uncontrolled Diabetes Mellitus.

Personer, der opfylder et eller flere af følgende kriterier, er uegnede til inklusion i forsøget:
1. Anæmi forårsaget primært af andre faktorer end nyrerelateret anæmi.
2. Jernoverbelastning eller forstyrrelser i jernudnyttelsen (f.eks. hæmokromatose og hæmosiderose).
3. Patienter, som aktuelt behandles med immunosuppresiva. (lav dosis steroider er tilladte gennem studiet, hvis dosis svarer til højest 10 mg prednisolone/dag eller ækvivalent. Hvis det er muligt, skal dosis være stabil gennem studiet).
4. Forskel på Hb ≥ 1,0 g/dl mellem screeningsbesøg 1a og 1b.
5. Multiple allergier i anamnesen.
6. Dekompenseret levercirrhose eller aktiv hepatitis [alaninaminotransferase (ALT) > 3 x normalværdien] eller hepatitis B eller C i anamnesen.
7. Aktive akutte eller kroniske infektioner (vurderet ved klinisk skøn), understøttet af leukocyttal (WBC) og C-reaktivt protein (CRP).
8. Rheumatoid arthritis med symptomer eller tegn på aktiv ledinflammation.
9. 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).
10. Blodtransfusion inden for de sidste 12 uger.
11. Planlagt elektiv operation inden for de næste 8 uger.
12. Deltagelse i et andet klinisk forsøg inden for de sidste 30 dage eller i et tidsrum inden screeningen svarende til mindre end 5 halveringstider af det pågældende forsøgslægemiddel.
13. Ubehandlet B12-vitamin- eller folatmangel.
14. Enhver anden medicinsk tilstand, som efter den forsøgsansvarlige investigators skøn kan gøre forsøgspersonen uegnet til gennemførelse af forsøget eller udsætte forsøgspersonen for en potentiel risiko ved deltagelse. Som eksempler kan nævnes: ukontrolleret hypertension, ustabil iskæmisk hjertesygdom og ukontrolleret diabetes mellitus.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is:
1. Proportion of patients able to maintain haemoglobin between 10 and 12.5 g/dl (both values
included) at week 6.

Forsøgets primære endpoint er:
1. Andel af patienter som kan opretholde et hæmoglobin niveau mellem 10 og 12.5 g/dl (inklusiv begge værdier) til uge 6.

E.5.1.1

Timepoint(s) of evaluation of this end point

week 6

Uge 6

E.5.2

Secondary end point(s)

The secondary end points of the study are:
1. Change in Hb concentration from baseline to week 2, 4, and 6.
2. Safety laboratory assessments at baseline and 1, 2, 4 and 6 weeks.
3. Change in concentrations of serum iron, TfS, serum ferritin and reticulocyte count from
baseline to week 1, 2, 4 and 6.
4. Number of subjects in each randomization group who discontinue study because of lack of
response or intolerance of investigational drugs.
5. Change in total QoL score (LASA) from baseline to week 4 and 6.
6. Change in RLS symptoms (CH-RLSq score) from baseline to week 6 in subjects with RLS
symptoms at baseline.
7. Number of subjects who experience any Adverse Drug Reaction (ADR) including any
Suspected Unexpected Serious Adverse Reaction (SUSAR).

De sekundære endpoints er:
1. Ændring i Hb-koncentration fra baseline til uge 2, 4 og 6.
2. Sikkerhedsmæssige laboratorievurderinger ved baseline og efter 1, 2, 4 og 6 uger.
3. Ændring i koncentrationen af serumjern, TfS, serumferritin og retikulocytter fra baseline til uge 1, 2, 4 og 6.
4. Antallet af forsøgspersoner i hver randomiseringsgruppe, som udtræder af forsøget på grund af manglende respons eller intolerance over for forsøgslægemidlerne.
5. Ændring i total QoL-score (LASA) fra baseline til uge 4 og 6.
6. Ændring i RLS-symptoner (CH-RLS-score) fra baseline til uge 6 hos forsøgspersoner med RLS-symptomer ved baseline.
7. Antal forsøgspersoner, som får uønskede lægemiddelreaktioner, herunder uventede og alvorlige formodede lægemiddelreaktioner (SUSAR).

E.5.2.1

Timepoint(s) of evaluation of this end point

1. from baseline to week 2, 4 and 6.
2. from baseline and 1, 2, 4 and 6 weeks.
3. from baseline to week 1, 2, 4 and 6.
5. from baseline to week 4 and 6.
6. from baseline to week 6

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

Yes

E.8.4

The trial involves multiple sites in the 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

Denmark

India

Sweden

Switzerland

United Kingdom

United States

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

Last visit of the last subject expected 1 November 2012

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.4.2

For a multinational trial

F.4.2.1

In the EEA

170

F.4.2.2

In the whole clinical trial

350

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)

After the end of the study or if subject is withdrawn from the study, the subject will be treated according to standard hospital practice.

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

2011-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-04-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-10-28

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