Clinical Trials Register

Summary
EudraCT Number:	2017-003439-12
Sponsor's Protocol Code Number:	TMP-0916_03
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-11-16
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

Germany - BfArM

A.2

EudraCT number

2017-003439-12

A.3

Full title of the trial

Safety and efficacy of postoperative i.v. iron substitution with Polyglucoferron compared to Ferric Carboxymaltose and oral iron in patients with diagnosed iron deficiency who develop anaemia pre- or postoperatively (IDA II)

A.3.1

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

Clinical trial to demonstrate safety and efficacy of an intravenous (i.v.) administration of Feramyl compared to i.v. Ferinject and to iron tablets in patients with iron deficiency anaemia diagnosis before or after a planned surgery

A.4.1

Sponsor's protocol code number

TMP-0916_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	Fraunhofer Gesellschaft for its Institute Fraunhofer für Translationale Medizin und Pharmakologie (ITMP)
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	iron4u Aps
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	Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
B.5.2	Functional name of contact point	Clinical Research
B.5.3	Address:
B.5.3.1	Street Address	Theodor-Stern-Kai 7
B.5.3.2	Town/ city	Frankfurt am Main
B.5.3.3	Post code	60596
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49(0)696301 80221
B.5.5	Fax number	+4924160855 0040
B.5.6	E-mail	ClinicalResearch@itmp.fraunhofer.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	No
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	Feramyl
D.3.4	Pharmaceutical form	Solution for 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 (III) hydroxide hydroxyethyl starch glucoheptonic acid complex
D.3.9.1	CAS number	CAS 15
D.3.9.3	Other descriptive name	IRON(III) HYDROXIDE POLY(O-2-HYDROXYETHYL) STARCH GLUCOHEPTONIC ACID COMPLEX
D.3.9.4	EV Substance Code	SUB179043
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.2.1.1.1	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	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.3.1	Product name	Ferinject
D.3.4	Pharmaceutical form	Solution for 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: 3
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	ferro sanol duodenal mite 50 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	UCB Pharma GmbH
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	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FERROUS (II) GLYCINE SULFATE COMPLEX
D.3.9.1	CAS number	14729-84-1
D.3.9.3	Other descriptive name	FERROUS (II) GLYCINE SULFATE COMPLEX
D.3.9.4	EV Substance Code	SUB26615
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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

pre-operative iron deficiency in patients with planned elective surgery and pre-/post-operative iron deficiency anamia

E.1.1.1

Medical condition in easily understood language

iron deficiency in patients with planned electivesurgery and pre-/post-operative iron anaemia

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10022974
E.1.2	Term	Iron deficiency anemia
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1) To demonstrate superiority of i.v. iron substitution with Polyglucoferron compared to oral iron therapy with Ferrous sulfate in focus on proportion of patients who achieve normalized Hb-levels (according to WHO definition) or increased Hb-level with at least 1.5 g/dl 28 days at visit 4 compared to BL

2) To demonstrate superiority in short term safety assessed of statistically significant lower levels of volume-corrected urine iron, estimated by the difference in v.c. iron urine measured before and after i.v. administration (first urine after the end of i.v. administration) of Polyglucoferron compared to Ferric Carboxymaltose

E.2.2

Secondary objectives of the trial

•Treatment effects on changes in haematologic and serologic iron parameters (Hb,TSAT,s-iron,s-transferrin,s-ferritin) from BL until V4
•Proportion of patients with normalization (WHO) of Hb at V4
•Treatment effects of Polyglucoferron i.v. and Ferric Carboxymaltose i.v. on s-phosphate levels at V4
•Overall tolerability and number, incidence, seriousness, severity and relationship of AEs/SAEs until 30d after last IMP
•Changes in laboratory parameters, vital signs and physical exam on each visit incl. blood pressure and heart rate
•AEs related to injection/infusion site reactions (i.v. groups) and hypersensitivity reactions
•All-cause mortality until V4
•The need of allogenic RBC transfusion (number of units and number of patients) from BL until V4
•Treatment effect on change in Quality of Life (SF-36) at V4 compared to BL
•Duration of hospital stay (days) until V4
•Analysis of total iron levels in plasma at BL after end of iron administration (for i.v. safety analysis group)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or female; aged ≥ 18 years
• Patients with planned surgery(e.g., orthopaedic/trauma, vascular, visceral, cardiac surgery)
• Confirmed and documented preoperative iron deficiency defined as S-ferritin <100 ng/mL
• Confirmed and documented anaemia (Hb <12 g/dL for female and <13 g/dL for male) up to 10 days before surgery or until 72 h after start of surgery
• Confirmed anaemia at Baseline (Hb <12 g/dL for female and <13 g/dL for male)
• Written informed consent; willing / able to comply with the protocol

E.4

Principal exclusion criteria

• Pregnancy in female patients or breastfeeding women
• Female patients not willing to use a safe method of contraception (PEARL index <1) for the full study period
• Severe physical inability, e.g., ASA physical status IV or V
• Patients receiving blood transfusion 24 week prior surgery
• Patients with severe anaemia defined as Hb ≤ 8 g/dL or with moderate anaemia with evidence of risk factors or signs of cardiac or cerebral ischaemia defined as clinical need for allogenic red blood cell transfusion (see section 4.4)
• Non-iron deficiency anaemia, e.g., known Vitamin B12 or folate deficiency, haemoglobinopathy, or unexplained anaemia
• Anticipated medical need for erythropoesis-stimulating agents during the main study period
• Patients with hemodynamic instability due to any ongoing bleeding. Absence of ongoing bleeding will be confirmed either by decision of two independent physicians or by removal of drainage, whichever occurs earlier in routine care
• Patients with any contraindication to the investigational products, e.g.,
o known sensitivity to iron or an ingredient of the investigational products
o Significant history of systemic allergic reactions
o Haemachromatosis, thalassemia or TSAT >50% as indicator of iron overload
o Acute or chronic intoxication
o Infection (patient on non-prophylactic antibiotics)
o Chronic liver disease and/or screening ALT or AST above three times the upper limit of the normal range
• Chronic kidney disease, defined as GFR <30 mL/min
• Immune-mediated diseases such as rheumatoid arthritis or inflammatory bowel disease if active and uncontrolled
• Primary haematologic disease
• Drug or alcohol abuse according to WHO definition
• Potentially unreliable patients, and those judged by the investigator to be unsuitable for the study
• Current or previous participation in another clinical trial during the last 90 days before screening

Exclusion criteria related to Ferrous sulfate:
• according to SmPC
• hypersensitivity to any ingredient in the formulation
• concomitant parenteral iron
• haemochromatosis, and other iron overload syndromes

Exclusion criteria related to Ferric Carboxymaltose:
• according to SmPC
• hypersensitivity to the active substance, to Ferric Carboxymaltose or any of its excipients
• known serious hypersensitivity to other parenteral iron products
• anaemia not attributed to iron deficiency
• evidence of iron overload or disturbances in the utilisation of iron

Exclusion criteria related to Polyglucoferron:
• hypersensitivity to any ingredient in the formulation
• known serious hypersensitivity to other parenteral iron products
• anaemia not attributed to iron deficiency
• evidence of iron overload or disturbances in the utilisation of iron

E.5 End points

E.5.1

Primary end point(s)

1) Proportion of patients who achieve normalized Hb-levels or increased Hb of at least 1.5 g/dl in the Polyglucoferron i.v. arm compared to oral iron substitution with Ferrous sulfate at visit 4 compared to BL

2) Pre-post difference of volume-corrected urine iron levels measured before and in the first urine after the end of i.v. administration, defined as short term safety surrogate marker after administration of the i.v. treatments, compared between Polyglucoferron and Ferric Carboxymaltose (volume corrected iron urine is defined as the ratio between urine iron and urine creatinine).

E.5.1.1

Timepoint(s) of evaluation of this end point

BL/V2 and V4

E.5.2

Secondary end point(s)

Secondary endpoints for efficacy:
• Proportion of patients with normalization (defined in WHO classification) of Hb at visit 4
• Mean change in Hb, TSAT, s-iron, s-transferrin and s-ferritin until visit 4

Secondary endpoints for safety:
• Mean change in s-phosphate levels at visits 4 (i.v. groups only)
• Overall tolerability and number, incidence, seriousness, severity, relationship of AEs/SAEs until 30 days after last IMP administration
• Changes in laboratory parameters, vital signs, and physical exam on each visit including blood pressure and heart rate
• AEs related to injection/ infusion site reactions (i.v. treatment arms only) and hypersensitivity reactions
• All-cause mortality until visit 4
Exploratory efficacy endpoints:
• Proportion of units of allogenic red blood cell transfusion from BL until visit 4
• treatment effect on Quality of Life (SF36) at visit 4 compared to BL
• Duration of hospital stay (days) until visit 4
• Analysis of total iron levels in plasma at BL after end of iron administration [for the i.v. groups (safety analysis group) only]

E.5.2.1

Timepoint(s) of evaluation of this end point

BL/V2, V3 and V4

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)

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

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

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

closure of last study site

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

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:

204

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

203

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

306

F.4.2

For a multinational trial

F.4.2.1

In the EEA

101

F.4.2.2

In the whole clinical trial

407

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

2018-02-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-15

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

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