Clinical Trials Register

Summary
EudraCT Number:	2010-021526-36
Sponsor's Protocol Code Number:	LMU_Rad_MR_GadoMRA01
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-12-03
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

Germany - BfArM

A.2

EudraCT number

2010-021526-36

A.3

Full title of the trial

Dynamic and high-resolution MR angiography of the supraaortic vessels at 3 Tesla: Performance of Gadobutrol (Gadovist) in comparison to Gedobenate Dimeglumine (Multihance) and Gadoterate Meglumine (Dotarem) at equimolar dose (0.1 mmol/kg BW) in volunteers and patients with carotid artery stenosis

A.3.1

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

Comparison of the performance of three contrast agents (Gadovist, Dotarem and Multihance) in magnetic resonance imaging (MRI) in volunteers and patients with narrowing or constriction of the inner surface of the carotid artery

A.3.2

Name or abbreviated title of the trial where available

Gadovist in MR angiography

A.4.1

Sponsor's protocol code number

LMU_Rad_MR_GadoMRA01

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	Klinikum der Universität München
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	Bayer Schering Pharma AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Klinikum der Universität München
B.5.2	Functional name of contact point	Institut für Klinische Radiologie
B.5.3	Address:
B.5.3.1	Street Address	Marchioninistr. 15
B.5.3.2	Town/ city	München
B.5.3.3	Post code	81377
B.5.3.4	Country	Germany
B.5.4	Telephone number	00498970952750
B.5.5	Fax number	00498970958822
B.5.6	E-mail	webmaster.radiologie@med.uni-muenchen.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	Gadovist
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Vital 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	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	Gadobutrol
D.3.9.1	CAS number	138071-82-6
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/ml millimole(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Yes
D.3.11.13.1	Other medicinal product type	paramagnetic contrast agent for MRI
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	Dotarem
D.2.1.1.2	Name of the Marketing Authorisation holder	Guerbet
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	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	Gadoteric Acid
D.3.9.1	CAS number	72573-82-1
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/ml millimole(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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	Yes
D.3.11.13.1	Other medicinal product type	paramagnetic contrast agent for MRI
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	Multihance
D.2.1.1.2	Name of the Marketing Authorisation holder	Bracco Imaging Deutschland 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	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	GADOBENIC ACID
D.3.9.1	CAS number	113662230
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/ml millimole(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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	Yes
D.3.11.13.1	Other medicinal product type	paramagnetic contrast agent for MRI

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

Supraaortic vessel disease; suspicion or proven carotid artery stenosis / stenoses

E.1.1.1

Medical condition in easily understood language

narrowing or constriction of the inner surface of the large artery on both sides of the neck, usually caused by thickening of the artery wall due to a build-up of fatty materials

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	PT
E.1.2	Classification code	10007687
E.1.2	Term	Carotid artery stenosis
E.1.2	System Organ Class	10029205 - Nervous system 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

Primary objective are:
To compare the performance of 1 molar gadobutrol in dynamic and static high resolution supraaortic MR angiography with two different 0.5 molar Gd-chelates exhibiting weak (gadobenate dimeglumine) or no (gadoterate meglumine) protein binding at 3 Tesla using equimolar doses.

Primary objective of the volunteer study is to provide estimates of the overall assessment of contrast enhancement of the three contrast agents as the basis for the sample size calculation of the subsequent patient study.

Primary objective of the patient study is to show that the contrast enhancement of gadobutrol is not inferior to gadobenate dimeglumine (MultiHance®) and superior to gadoterate meglumine (Dotarem®).

E.2.2

Secondary objectives of the trial

Secondary objectives are:
• to compare vessel signal-to-noise (SNR) and contrast-to-noise (CNR) in high resolution MR angiography at the carotid bifurcation and at the intracranial internal carotid artery at the level of carotid T
• to compare vessel signal-to-noise (SNR) and contrast-to-noise (CNR) in dynamic MR angiography at the carotid bifurcation and at the intracranial internal carotid artery at the level of carotid T
• to document safety data for the three compounds

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Volunteer part:
1. age: at least 18 years
2. no history of cardiovascular disease
3. willing to undergo all study procedures
4. has voluntarily signed and dated the informed consent form
Women of childbearing potential:
5. a negative pregnancy test (urine test) on the day of contrast agent administration
6. use of a highly effective method of birth control during the duration of the study (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner)

Patient part:
1. age: at least 18 years
2. suspicion or proven carotid artery stenosis / stenoses
3. willing to undergo all study procedures
4. has voluntarily signed and dated the informed consent form
Women of childbearing potential:
5. a negative pregnancy test (urine test) on the day of contrast agent administration
6. use of a highly effective method of birth control during the duration of the study (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner)

E.4

Principal exclusion criteria

Volunteer part:
1. if female:, pregnant or nursing
2. history of renal disease, subjects in the perioperative liver transplantation period and / or with acute or chronic severe renal impairment
3. GFR <60ml/m²/1.73m² (MDRD) as determined from a serum creatinine value not older than 4 weeks before MR contrast agent injection
4. contraindications against MR imaging (e.g. subjects with implanted ferromagnetic objects (pacemaker, vascular clip))
5. contraindications against any of the three MR contrast agents (e.g. aggravation of anaphylactic-like reactions in patients on beta-blockers, and particularly in the presence of bronchial asthma, low seizure threshold in patients with CNS disorders, patients with uncorrected hypokalemia, severe cardiovascular disease)
6. severe claustrophobia
7. history of anaphylactoid or anaphylactic reaction to any allergen (e.g. hay fever, urticaria, asthma, history of sensitivity to benzyl alcohol, etc.) including drugs and contrast agents
8. having received any investigational drug within 7 days prior to entering this study
9. planned to receive any investigational drug during the study period
10. close affiliation with the investigational site (e.g., close relative of an investigator)
11. participating in another clinical trial
12. having been previously enrolled in this clinical trial
13. any medical condition that potentially reduces cardiac output

Patient part:
1. if female:, pregnant or nursing
2. history of renal disease, subjects in the perioperative liver transplantation period and / or with acute or chronic severe renal impairment
3. GFR <30ml/m²/1.73m² (MDRD) as determined from a serum creatinine value not older than 4 weeks before MR contrast agent injection
4. contraindications against MR imaging (e.g. subjects with implanted ferromagnetic objects (pacemaker, vascular clip))
5. contraindications against any of the three MR contrast agents (e.g. aggravation of anaphylactic-like reactions in patients on beta-blockers, and particularly in the presence of bronchial asthma, low seizure threshold in patients with CNS disorders, patients with uncorrected hypokalemia, severe cardiovascular disease)
6. severe claustrophobia
7. history of anaphylactoid or anaphylactic reaction to any allergen (e.g. hay fever, urticaria, asthma, history of sensitivity to benzyl alcohol, etc.) including drugs and contrast agents
8. having received any investigational drug within 7 days prior to entering this study
9. planned to receive any investigational drug during the study period
10. close affiliation with the investigational site (e.g., close relative of an investigator)
11. participating in another clinical trial
12. having been previously enrolled in this clinical trial
13. any medical condition that potentially reduces cardiac output
14. prior carotid artery stenting on investigated body side

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy analysis is based on the overall assessment of contrast enhancement comparing two pairs of contrast agents (volunteer study) and each two contrast agents (2 groups, patient study). The volunteer study is set up as exploratory pilot study and will provide estimates for the overall assessment of contrast enhancement of the three contrast agents as basis for the sample size of the patient study.
Overall assessment of contrast enhancement on a 3-point scale (better, equal, worse) in a matched pairs assessment from all MR imaging data. For the primary analysis, the assessments of the blinded readers will be combined after the blinded reading.

E.5.1.1

Timepoint(s) of evaluation of this end point

After acquisition of all MR images (volunteers and patients) and assessment by blinded readers.

E.5.2

Secondary end point(s)

1. Signal-to-Noise-Ratio and Contrast-to-Noise-Ratio at the following levels: carotid bifurcation, intracranial internal carotid artery at the level of the carotid T
2. Contrast enhancement rate in dynamic MR angiography at the following levels: carotid bifurcation, intracranial internal carotid artery at the level of the carotid T
3. Degree of stenosis (pre contrast agent; patients only)
4. AEs as elicited upon indirect questioning.
The secondary efficacy variables and safety variables will be analyzed descriptively. Two-sided 95% confidence intervals will be given where appropriate.

E.5.2.1

Timepoint(s) of evaluation of this end point

After acquisition of all MR images (volunteers and patients) and assessment by blinded readers.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

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

Yes

E.7.1.3.1

Other trial type description

diagnostic

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

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

intra-individual comparison

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

Yes

E.8.2.3.1

Comparator description

comparison between 3 contrast agents

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.8.4.1

Number of sites anticipated in 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

last patient last visit

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

Number of subjects for this age range:

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:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

150

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2010-12-03.

Yes

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)

Post-study therapy will follow routine clinical care

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

2011-04-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-12-01

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