Clinical Trials Register

Summary
EudraCT Number:	2014-003576-23
Sponsor's Protocol Code Number:	GDX-44-004
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-02-02
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

Czechia - SUKL

A.2

EudraCT number

2014-003576-23

A.3

Full title of the trial

P03277 Dose Finding Study in Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)

P03277 Studie zaměřená na vyhledání dávky při zobrazování centrálního nervového systému (CNS) magnetickou rezonancí (MR)

A.4.1

Sponsor's protocol code number

GDX-44-004

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	GUERBET
B.1.3.4	Country	France
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	GUERBET
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GUERBET
B.5.2	Functional name of contact point	Valérie BRAKNI
B.5.3	Address:
B.5.3.1	Street Address	B.P. 57400 - 95943
B.5.3.2	Town/ city	Roissy CDG Cedex
B.5.3.3	Post code	57400-95943
B.5.3.4	Country	France
B.5.4	Telephone number	+33145916914
B.5.5	Fax number	+33145917689
B.5.6	E-mail	valerie.brakni@guerbet-group.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	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.3.2	Product code	G03277.066
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 use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	P03277
D.3.9.3	Other descriptive name	P03277
D.3.9.4	EV Substance Code	SUB120767
D.3.10	Strength
D.3.10.1	Concentration unit	mol/l mole(s)/litre
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	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	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.3.1	Product name	Multihance
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 use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Gadobenic acid
D.3.9.3	Other descriptive name	GADOBENATE DIMEGLUMINE
D.3.9.4	EV Substance Code	SUB20638
D.3.10	Strength
D.3.10.1	Concentration unit	mol/l mole(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	529
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

Subject presenting, at the time of inclusion, with known or highly suspected focal areas of disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors, focal inflammatory or demyelinating disorders) including at least one expected enhancing lesion of minimum 5 mm (long axis)

E.1.1.1

Medical condition in easily understood language

lesion of the brain or spine

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10067294
E.1.2	Term	Brain lesion
E.1.2	System Organ Class	100000004852

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10041552
E.1.2	Term	Spinal cord injury
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

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 determine a safe and effective dose of P03277 based on a comparison of Contrast to Noise Ratio (CNR) between several doses, 0.025, 0.05, 0.1, 0.2 mmol/kg, of P03277 and MultiHance® at 0.1 mmol/kg.

E.2.2

Secondary objectives of the trial

•To assess technical adequacy of images
•To evaluate capacity of lesion detection: number, size and location of lesions detected
•To evaluate diagnostic information using lesion visualization variables (lesion border delineation, internal morphology and degree of contrast enhancement)
•To evaluate diagnostic confidence
•To compare overall diagnostic preference between P03277 and MultiHance®
•To assess P03277 dose / response relationship for CNR and lesion visualization variables
•To evaluate the impact of P03277 and MultiHance®-enhanced MRI on subject treatment plan
•To assess the safety profile of P03277 as compared to MultiHance® after intravenous administration

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Female or male adult subject (subject having reached legal majority age)up to 75 years old.
2.Subject presenting, at the time of inclusion, with known or highly suspected focal areas of disrupted Blood Brain Barrier (BBB) (e.g., primary and secondary tumors, focal inflammatory disorders or demyelinating disorders) including at least one expected enhancing lesion of minimum 5 mm (long axis). This lesion must have been detected on a previous imaging procedure (computerized Tomography (CT) or MRI) performed within 12 months prior to Visit 1.
3.Subject scheduled for a routine CNS contrast-enhanced MRI examination for clinical reasons and agreeing to have a second contrast-enhanced MRI examination for the purpose of the study.
4.Subject able and willing to participate to the study.
5.Subject having read the information and having provided his/her consent to participate in writing by dating and signing the informed consent prior to any study related procedure being conducted.
6.Subject affiliated to national health insurance according to local regulatory requirements.

E.4

Principal exclusion criteria

1.Subject presenting with acute or chronic Grade III (at least) renal insufficiency, defined as an estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m² based on one eGFR assessment performed the day of the MRI prior to the first contrast agent injection.
2.Subject presenting with known class III/IV congestive heart failure according to the New York Heart Association classification (NYHA).
3. Subject presenting with acute relapse of multiple sclerosis.
4.Pregnant or breast-feeding female subject (a female subject of childbearing potential or with amenorrhea for less than 12 months must have a negative urine or serum pregnancy test within 24 hours prior to study MRI and must be using a medically approved contraception method* until the last study visit).
5.Subject having received any investigational medicinal product within 30 days prior to study entry.
6.Subject previously enrolled in this study.
7.Subject presenting with any contraindication to MRI examinations.
8.Subject with known contra-indication(s) to the use or with known sensitivity to one of the products under investigation or other GBCAs.
9.Subject having received any contrast agent (MRI or CT) within 3 days prior to study products administration, or scheduled to receive any contrast agent during the course of the study or within 24 hours after the second study product administration.
10.Subject having received any treatment or medical procedure (e.g. chemotherapy, radiotherapy, biopsy or surgery etc…) within 7 days prior to the first MRI or is expected/ scheduled to have a change in any treatment or medical procedure (e.g. chemotherapy, radiotherapy, biopsy or surgery etc…) in-between the 2 MRI examinations.This includes any subject who requires an urgent diagnosis and /or treatment.
11.Subject with anticipated, current or past condition (medical, psychological, social or geographical) that would compromise the subject’s safety or her/his ability to participate in the study.
12.Subject unlikely to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits and/or unlikelihood of completing the study.
13.Subject related to the Investigator or any other study staff or relative directly involved in the study conduct.
* medically approved contraception methods include: female sterilization, barrier methods of contraception (condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository), use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception, placement of an Intrauterine Device (IUD) or Intrauterine System (IUS).

E.5 End points

E.5.1

Primary end point(s)

Contrast to Noise Ratio (CNR) for maximum 3 enhanced lesions.

E.5.1.1

Timepoint(s) of evaluation of this end point

Only lesions detected by both MRIs after lesion tracking will be used. Image evaluations will be done for each MRI (from V2 and V3).

E.5.2

Secondary end point(s)

1.Technical adequacy of images (on-site and off-site reads)
Images will be evaluated as adequate or not. Images are considered technically inadequate if artifacts completely compromise image interpretability.
2.Lesion detection capacity (on-site and off-site reads):
Number, size and location of lesions detected, and the presence or absence of enhancement will be recorded.
3.Diagnostic information using lesion visualization variables (on-site and off-site reads):
Three variables (lesion border delineation, internal morphology and degree of contrast enhancement) will be assessed on combined unenhanced and enhanced MRI on a 4-point scale.
4.Diagnostic confidence (on-site and off-site reads):
Diagnosis and diagnostic confidence will be recorded for each subject.
5 Overall diagnostic preference in a global matched-pairs fashion (off-site read).
6.P03277 dose / response relationship for CNR and lesion visualization variables.
7.Impact of contrast agent-enhanced MRI on subject treatment plan (on-site read).
8.Safety assessments: vital signs, 12-lead ECGs, injection site tolerance, clinical laboratory parameters (blood and urine) and adverse events (AEs) monitoring

E.5.2.1

Timepoint(s) of evaluation of this end point

• Image evaluations will be done for each MRI (from V2 and V 4).
• ECG and vital signs - prior to each injection (V2 and V4), 45mins plus/minus 15 mins, 2-4 hr and 1 day after (V3 and V5).
• Injection site reactions - during each injection (V2 and V4), 45mins plus/minus 15 mins, 2-4 hr and 1 day after (V3 and V5).
• AEs – V1-V5
• Clinical labs – V2-V5

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

gadobenate dimeglumine

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

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

Belgium

Czech Republic

Hungary

Italy

Mexico

Poland

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

The study will be considered as completed once all the images collected for all the subjects will have been reviewed by all the independent blinded readers.

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

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:

220

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

280

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

2016-05-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-01-23

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