Clinical Trials Register

Summary
EudraCT Number:	2013-002409-75
Sponsor's Protocol Code Number:	Dota-PrimoLIV
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:	2013-08-23
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

2013-002409-75

A.3

Full title of the trial

Intra-individual, comparison of the MRI contrast agents gadoxetic acid (Primovist®) versus gadoterate meglumine (Dotarem®) in liver MRI of patients with HCC and underlying cirrhosis

Intraindividueller Vergleich der Kontrastmittel Primovist und Dotarem für die Leber-MRT bei Patienten mit hepatozellulärem Karzinom auf der Basis einer Leberzirrhose

A.3.1

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

Comparison of 2 contrast agents for Magnetic Resonance Imaging in patients with liver cancer

Vergleich von 2 Kontrastmitteln für die MRT der Leber bei Patienten mit Leberkrebs

A.4.1

Sponsor's protocol code number

Dota-PrimoLIV

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	Charite
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 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	Charité
B.5.2	Functional name of contact point	Radiologist, PI
B.5.3	Address:
B.5.3.1	Street Address	Charitéplatz 1
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	10117
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4930450527082
B.5.5	Fax number	+4930450527911
B.5.6	E-mail	timm.denecke@charite.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	Primovist
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
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	Primovist
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	GADOXETIC ACID
D.3.9.1	CAS number	135326-11-3
D.3.9.4	EV Substance Code	SUB07868MIG
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	0.25
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	contrast agent for magnetic resonance imaging
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.3.1	Product name	Dotarem
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	MEGLUMINE GADOTERATE
D.3.9.1	CAS number	98059-18-8
D.3.9.4	EV Substance Code	SUB03121MIG
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

Patients with liver cirrhosis and diagnosis of hepatocellular carcinoma based on noninvasive HCC diagnostic (EASL) criteria

Patienten mit Leberzirrhose und Diagnose eines hepatozellulären Karzinoms auf der Basis der nicht-invasiven EASL-Kriterien.

E.1.1.1

Medical condition in easily understood language

Patients with liver cirrhoses who suffer, in addition, from liver cancer.

Patienten mit Leberzirrhose und Leberkrebs.

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10024667
E.1.2	Term	Liver cirrhosis
E.1.2	System Organ Class	100000004871

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10049010
E.1.2	Term	Carcinoma hepatocellular
E.1.2	System Organ Class	100000004864

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 compare the peak maximum enhancement between both contrast agents in the lesion with reference to normal tissue (peak enhancement = SI post-contrast (lesion) - SI pre-contrast (lesion)).

Vergleich beider Kontrastmittel bezüglich der maximalen Kontrastmittelaufnahme in der Läsion relativ zum normalen Lebergewebe (max. enhancement = Signalintensität post Kontrast - prä Kontrast)

E.2.2

Secondary objectives of the trial

(1) Signal-to-noise (SNR) and contrast-to-noise (CNR) values (calculated based on signal intensity measurements); (2) Quantitative assessment of time-to-peak, upslope, time to 100% enhancement, percentage signal increase [(SIpost – Sipre)/SIpre] *100, and washout; (3) Qualitative assessment: Lesion conspicuity (margin, intensity, homogeneity)

(1) Signal-Rausch-Verhältnis und Kontrast-Rausch-Verhältnis; (2) Konstrastkinetik (Zeit bis zum maximalen Enhancement, Enhancement in Prozent bezogen auf den prä Kontrast-Wert; (3) qualitative Beurteilung der Läsion (Ränder, Kontrastintensität, Homogenität)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients at least 18 years of age
2. Patient has personally signed and dated the written informed consent form
3. Willing to undergo all study procedures
4. Liver cirrhosis Child score A or higher
5. Diagnosis of hepatocellular carcinoma based on noninvasive HCC diagnostic (EASL) criteria
6. Clinical indication for liver MRI

1. Alter mindestens 18 Jahre
2. Schriftliches eingehändiges Einverständnis
3. Bereitschaft, an allen Studienmassnahmen teilzunehmen
3. Leberzirrhose Child A oder höher
4. Diagnose eines hepatozellulären Karzinoms auf der Basis der nicht-invasiven EASL-Kriterien
5. MRT der Leber klinische indiziert

E.4

Principal exclusion criteria

1. Female patients who are in (or suspected of) pregnancy or nursery. In women of child bearing potential a pregnancy test must be performed before inclusion in this study.
2. Patients with impaired renal function (GFR < 30 ml/min/1.73m², MDRD formula, creatinine value ≤ 4 weeks)
3. Patients with a known allergy and/or hypersensitivity to MR contrast agents or history of anaphylactoid or anaphylactic reaction to any contrast media, or being at high risk for hypersensitivity reactions. The risk of hypersensitivity is higher in patients with history of bronchial asthma and history of allergic disorders; hypersensitivity reactions can be more intense in patients on beta-blockers
4. Patients with contraindications to MR imaging (severe claustrophobia, non-compatible implants like cardiac pacemaker, ferromagnetic clips, implanted infusion pumps, implanted electrical nerve stimulation devices, cochlear implant, any metallic foreign bodies)
5. Patients with known allergy and/or hypersensitivity or any contraindication to Dotarem and/or Primovist and/or patients assumed to be at increased risk for adverse events after application of MR contrast agents (e.g., seizure, increase in creatinine values)
6. Patients with any physical or mental status interfering with the informed consent procedure including self-signed informed consent
7. Being unstable or requiring emergency treatment
8. Patients requiring or scheduled for liver transplantation
9. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily
10. with close affiliation with the investigational site; e.g. a close relative of the investigator
11. Participating in another diagnostic clinical trial
12. Having previously entered this study.
13. Being hospitalized following an official order

1. Schwangere / stillende Frauen oder vermutete Schwangerschaft. Bei Frauen in gebärfähigem Alter muss ein Schwangerschaftstest vor dem Studieneinschluss erfolgen.
2. Eingeschränkte Nierenfunktion (GFR < 30 ml/min/1.73 m2, berechnet nach MDRD Formel; Kreatininwert nicht älter als 4 Wochen)
3. Patienten mit bekannter Allergie gegen MR Kontrastmittel oder früherer anaphylaktoider oder anaphylaktischer Reaktion gegen Kontrastmittel: oder Patienten mit hohem Risiko für Hypersensitivitätsreaktionen. Das Risiko von Hypersensitivitätsreaktionen ist höher bei Patienten mit Asthma bronchiale oder allergischen Erkrankungen, intensive Hypersensitivitätsreaktionen können bei Patienten mit Beta-Blocker-Medikation auftreten.
4. Kontraindikationen für eine MRT-Untersuchung (schwere Platzangst, nicht-kompatible Implantate wie Herzschrittmacher, ferromagnetische Clips, implantierte Infusionspumpen, implantierte Nervenstimulatoren, Cochleaimplantate, jegliche metallische Fremdkörper)
5. bekannte Allergie oder Kontraindikation gegen Primovist oder Dotarem; oder Patienten, bei denen ein erhöhtes Risiko für unerwünschte Wirkungen (z.B. Krampfanfälle, Kreatininerhöhung) nach Applikation von MR-Kontrastmitteln erwartet wird
6. jeglicher Zustand, der die informierte Einwilligung des Patienten an der Studienteilnahme beeinträchtigt (einschließlich des Unvermögens, die Einwilligungserklärung eigenhändig zu unterschreiben)
7. instabile Patienten oder Patienten, die eine Notfallbehandlung benötigen
8. Patienten die für eine Lebertransplantation vorgesehen sind oder eine solche benötigen
9. behördlich untergebrachte Personen, z.B. (Justiz-)Vollzugsanstalt, oder Notfallsituation
10. enge (persönliche) Beziehung zur Untersuchungsstelle (z.B. Angehöriger eines Prüfarztes)
11. Teilnahme an einer anderen diagnostischen Studie
12. Vorherige Teilnahme an dieser Studie
13. Hospitalisierung aufgrund einer behördlichen Anweisung

E.5 End points

E.5.1

Primary end point(s)

Maximum enhancement (calculated as: SI post-contrast [lesion] - SI pre-contrast [lesion]).

Maximale Kontrastmittelanreicherung in der Läsion (berechnet als Signalintensität prä - post Kontrast)

E.5.1.1

Timepoint(s) of evaluation of this end point

independent image analysis after conclusion of the clinical part of the study

unabhängige Bildauswertung nach Ende der klinischen Phase

E.5.2

Secondary end point(s)

(1) Time-to-peak
(2) Upslope
(3) Time to 100% enhancement
(4) percentage increase in enhancement (SIpost – SIpre)/SIpre *100
(5) Washout
(6) qualitative assessment of lesion conspicuity (Margin, Intensity, Homogeneity )

(1) "time-to-peak"
(2) Anstiegssteilheit der Kontrastmittelaufnahme
(3) Zeit bis 100% enhancement
(4) Konstratanreicherung in Prozent (Signalintensität post - prä)/Signalintensität prä * 100
(5) Auswaschgeschwindigkeit des Kontrastmittels
(6) qualitative Beurteilung der Läsion (Ränder, Kontrastaufnahme, Homogenität)

E.5.2.1

Timepoint(s) of evaluation of this end point

independent image analysis after conclusion of the clinical part of the study

unabhängige Bildauswertung nach Ende der klinischen Phase

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

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

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

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

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

LVLS

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)

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.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.

Keine.

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

2014-01-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-04-13

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