Clinical Trials Register

Summary
EudraCT Number:	2012-001582-33
Sponsor's Protocol Code Number:	Er-01-Perf-Stroke
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:	2012-07-03
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

2012-001582-33

A.3

Full title of the trial

Intraindividual cross-over comparison of Gadobutrol and Gadoterate enhanced combined DSC-MR-Perfusion and MR-Angiography in patients with cerebrovascular disease

A.3.1

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

Comparison of two Gadolinium containing MR contrast media in patients with symptoms of cerebrovascular disease

A.3.2

Name or abbreviated title of the trial where available

Erlangen Perfusion Stroke

A.4.1

Sponsor's protocol code number

Er-01-Perf-Stroke

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 Hospital Erlangen
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	University of Erlangen; Bayer Healthcare
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	University Hospital Erlangen
B.5.2	Functional name of contact point	Prof. Dr. Arnd Dörfler
B.5.3	Address:
B.5.3.1	Street Address	Schwabachanlage 6
B.5.3.2	Town/ city	Erlangen
B.5.3.3	Post code	91054
B.5.3.4	Country	Germany
B.5.4	Telephone number	49091318539388
B.5.5	Fax number	49091318536179
B.5.6	E-mail	neuroradiologie@uk-erlangen.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
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) Intravenous use
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.3.9.3	Other descriptive name	GADOBUTROL
D.3.9.4	EV Substance Code	SUB07861MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/kg millimole(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.1
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	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	Dotarem
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/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravascular use (Noncurrent) Intravenous bolus use (Noncurrent) Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MEGLUMINE GADOTERATE
D.3.9.3	Other descriptive name	DOTAREM
D.3.9.4	EV Substance Code	SUB03121MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mmol/kg millimole(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.1
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	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

Patients with high grade carotid artery stenosis or acute cerebral ischemia

E.1.1.1

Medical condition in easily understood language

Patients with Stroke or Stenosis of main brain supplying arteries

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 prove that Gadobutrol provides superior characteristics as compared to Gadoterate in DSC-MR perfusion imaging and contrast-enhanced MR angiography in acute stroke patients and/or patients harboring an intracranial stenosis or extracranial ICA stenosis, assessed by two independent blinded readers.

E.2.2

Secondary objectives of the trial

• To assess the feasibility of a dual injection protocol in MRI in patients with acute stroke or cerebrovascular diseases.

• To evaluate descriptively whether Gadobutrol enhanced study protocol provides superior information to guide and tailor further diagnostic and / or therapeutic decisions in this kind of patient population.

• To evaluate descriptively whether Gadobutrol has a superior vessel contrast and contrast-to-noise ratio in CE-MRA studies (quantitative analysis).

• To evaluate descriptively whether the vessel conspicuity and stenosis characterization with the use of Gadobutrol is superior (qualitative analysis)

• To evaluate whether the signal drop after gadobutrol injection in DSC-MRP is superior based on a quantitative analysis of the signal intensity time curve

• To assess the correlation between the cardiac ejection fraction (if available) and the DSC-MRP quality.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. adult patients, age 18-85 years
2. with clinically suspected or definite ischemic stroke or an intracranial stenosis (> 50% degree) or extracranial stenosis of the internal carotid artery (> 70%)
3. clinically indicated initial and follow-up MR examinations of the brain with contrast injection
4. willing to undergo and comply with all study procedures
5. written informed consent

E.4

Principal exclusion criteria

1. who are in pregnancy or nursery. In women with child bearing potential a pregnancy test must be performed directly before each MR examination in order to safely exclude pregnancy. The manufacturer’s instructions for performing the urinary pregnancy test are to be followed.
2. with impaired renal function of CKD stadium 3 and higher (i.e. creatinine clearance < 60 ml/min/1.73m² (Cockroft-Gault formula) or patients on hemodialysis. In patients with known renal impairment, clearance will be calculated based on serum creatinine level using the Cockroft-Gault formula. Calculation of the clearance must be done before begin of study. Serum creatinine value must not be older than one week (7 days) before study related contrast injection.
3. with renal or liver transplant, including patients with scheduled liver transplant 4. with known allergy or any contraindication to Gadobutrol or Gadoterate.
5. presenting with a history of anaphylactoid or anaphylactic reaction to any drug or contrast agent.
6. with high grade cardiac arrhythmia
7. not being able to remain lying down for at least 30-45 min (e.g., patients with unstable angina, dyspnoea at rest, severe pain at rest, severe back pain)
8. having any physical or mental status that interferes with the informed consent procedure including self-signed consent.
9. with a contraindication for MRI (pacemaker, magnetic clips, severe claustrophobia etc.)
10. being clinically unstable or requiring emergency treatment
11. with close affiliation with the investigational site; e.g. a close relative of the investigator
12. who have received any investigational drug within 7 days prior to entering this study
13. who have received any contrast agent within 24 hours prior to entering this study
14. who have previously entered this study
15. participating in another clinical trial
16. having an underlying disease or concomitant medication which may interfere with efficacy evaluation.

E.5 End points

E.5.1

Primary end point(s)

All images will be evaluated for technical adequacy by on site and off site readers to check their eligibility. A blinded read will be performed off site using appropriate technology and equipment. The preparation of the reading will be adhering to international quality standards and documented accordingly. On site, the MR perfusion source data will be analyzed in a standardized way using the Siemens "MRPerf" software. This software generates color-coded parameter maps of mean transit time (MTT), time to peak (TTP), relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF). Furthermore, a global bolus plot (GBP) is calculated, showing the time course of the global T2* signal. CE-MRA will be reconstructed on site as rotating thick slice maximum intensity projections (MIP). The blinded readers will have access to the source data, as well as the MIPs. For both CE-MRA and DSC-MRP, the visual (qualitative) image analysis in the blinded read will comprise a dedicated simultaneous matched-pairs assessment from both examinations together. The blinded readers will assess the technical adequacy of the each examination. Images will be rated as
- 1 = excellent,
- 2 = adequate (with artefacts but tolerable for assessment)
- 3 = inadequate (not tolerable for further evaluation).
As primary efficacy endpoint, an overall assessment of image quality (visual conspicuity and delineation of supraaortic vessels) will be performed by the blinded readers for both CE-MRA and DSC-MRP images combined, respectively:
“MR study 1 better than MR study 2”
“both MR studies equal”
“MR study 2 better than MR study 1”

E.5.1.1

Timepoint(s) of evaluation of this end point

Endpoints assessed in a blinded read analysis after completion of the study

E.5.2

Secondary end point(s)

CE-MRA Signal-to-noise ratio will be measured for 23 supraaortic vessel segments:
• - Aortic arch
• - Brachiocephalic artery - Right subclavian - Right common carotid artery - Right external carotid artery - Right internal carotid artery
o o Extracranial segment o Petrous segment o Lacerum segment o Cavernous segment
- Right vertebral artery
o o Preforaminal segment o Foraminal segment o C1 loop
• - Vertebral artery - Left common carotid artery - Left external carotid artery - Left internal carotid artery
o o Extracranial segment o Petrous segment o Lacerum segment o Cavernous segment
• - Left subclavian - Left vertebral artery
o o Preforaminal segment o Foraminal segment o C1 loop
DSC-MRP As quantitative DSC-MRP parameters highly depend on the current circulation status of the patient, no quantitative assessment will be performed.

E.5.2.1

Timepoint(s) of evaluation of this end point

In a blinded read after the inclusion of all subjects

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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

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

Blinded Read performed by a CRO - Data analysis planned by an independent CRO

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

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)

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 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 2012-07-03.

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.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

2012-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-19

P. End of Trial
P.	End of Trial Status	Completed

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