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    Summary
    EudraCT Number:2013-003215-21
    Sponsor's Protocol Code Number:DGD-44-063
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-07-09
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2013-003215-21
    A.3Full title of the trial
    DOTAREM® Pharmacokinetics, Safety and Efficacy Study in Pediatric Subjects Aged <2 Years (Term Newborn Infants to Toddlers 23 Months of Age Inclusive)
    Klinikai vizsgálat a DOTAREM Farmakokinetikájára, Biztonságára és Hatékonyságára 2 éves kor alatti csecsemőknél (újszülöttektől 23 hónapos kort elért vizsgálati alanyokat beleértve)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the product flow, breakdown and elimination of DOTAREM from the blood and its safety and efficacy in children aged > 2 years
    A.4.1Sponsor's protocol code numberDGD-44-063
    A.5.4Other Identifiers
    Name:INDNumber:65.041
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGUERBET
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGUERBET
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGUERBET
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street AddressBP57400
    B.5.3.2Town/ cityROISSY CDG CEDEX
    B.5.3.3Post code95943
    B.5.3.4CountryFrance
    B.5.4Telephone number33145915000
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Dotarem 0.5 mmol/ml
    D.2.1.1.2Name of the Marketing Authorisation holderGuerbet
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDotarem 0.5 mmol/ml, solution for injection in vials
    D.3.2Product code G449.06
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGADOTERIC ACID
    D.3.9.1CAS number 72573-82-1
    D.3.9.4EV Substance CodeSUB07865MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number279.32
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeParamagnetic contrast agent
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pediatric subject aged <2 years (term newborn infants to toddlers 23 months of age inclusive) scheduled to undergo routine gadolinium-enhanced Magnetic Resonance Imaging of any body region
    E.1.1.1Medical condition in easily understood language
    Children aged <2 years for which a Magnetic Resonance Imaging with the injection of a contrast agent has been scheduled
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10058644
    E.1.2Term Nuclear magnetic resonance imaging whole body
    E.1.2System Organ Class 10022891 - Investigations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate pharmacokinetics profile in plasma of DOTAREM following single intravenous injection in pediatric subjects aged up to 23 months (inclusive)
    E.2.2Secondary objectives of the trial
    -To evaluate the DOTAREM safety (clinical and biological) following single administration up to 7 ± 1 day.
    -To evaluate efficacy of DOTAREM-enhanced MRI in brain (intracranial), spine and associated tissues in a subgroup of at least 20 subjects as assessed by on-site investigator
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Pediatric subject aged <2 years (term newborn infants to toddlers 23 months of age inclusive). Term is defined as ≥37 weeks of amenorrhea
    •Subject is scheduled to undergo routine gadolinium-enhanced MRI of any body region (e.g. CNS, cardiac) at the dose of 0.1 mmol/kg BW (0.2 mL/kg BW)
    •Subject with normal renal function for its age, - according to estimated glomerular filtration rate calculated based on the Schwartz formula
    •Subject whose parents or legal guardian (where applicable) has/have provided his/her/their fully informed written consent for the participation of the child in the trial. Parents or guardian must have the ability to read, understand and willingness to sign the informed consent form
    •Subject with health insurance, according to the local regulatory requirement
    E.4Principal exclusion criteria
    •Subject planned for intervention (e.g. surgery) between the screening visit and up to 24 hours after DOTAREM injection
    •Subject whose preceding or subsequent treatment to DOTAREM injection (e.g., blood loss or receiving blood, treatment with diuretics, etc…) would alter DOTAREM pharmacokinetics parameters
    •Subject with subsequent planned treatment after DOTAREM injection that would prevent obtaining the required blood samples (e.g., emergency surgery, etc…)
    •Subject with a history of a bleeding disorder
    •Subject with known severe liver disease
    •Subject with electrolyte or fluid imbalance that presents undue risk
    •Subject undergoing a change in chemotherapy within 48 hours prior to and up to 24 hours after DOTAREM injection
    •Subject who received or will receive any other contrast agent within 72 hours prior to DOTAREM injection or up to 24 hours after DOTAREM injection
    •Subject with contraindication for MRI such as iron metal implants (e.g. aneurysm clips)
    •Subject with history of anaphylactoid or anaphylactic reaction to any allergen including drugs and contrast agents
    •Subject who received will receive any investigational product within 7 days before DOTAREM injection or during study participation
    •Any condition which, based on the investigator's clinical judgement, would prevent the subject from participating in all study assessments and visits
    E.5 End points
    E.5.1Primary end point(s)
    DOTAREM pharmacokinetics in plasma:
    •The start of administration is set as time point 0 (T0), and blood samples will be collected during three time windows as 10 to 60 min, 2.0 to 4.0 hours and 6.0 to 8.0 hours post-injection, at time points which are allocated by randomization.
    •DOTAREM concentrations in plasma will be analyzed using a validated LC-MS-MS method.
    •The following pharmacokinetic parameters from plasma samples will be determined from typical and individual DOTAREM concentration-time profiles: AUC, β, t½β, ClT, Vd.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The start of administration is set as time point 0 (T0), and blood samples will be collected during three time windows as 10 to 60 min, 2.0 to 4.0 hours and 6.0 to 8.0 hours post-injection
    E.5.2Secondary end point(s)
    Clinical and biological safety:
    •Height and weight at screening visit
    •Vital signs (blood pressure and heart rate) at several time points/intervals (at baseline (prior to injection), post injection immediately after MRI, between 2 and 4 hours and at 24 ± 4 hours)
    •Blood samples for safety laboratory variables centrally analyzed (biochemistry and hematology) at screening and post injection at 24 ± 4 hours
    •Estimated glomerular filtration rate (eGFR) centrally analyzed at screening and post injection at
    24 ± 4 hours
    •Urine samples for safety assessment (urinalysis with dipstick) at screening and post injection at 24 ± 4 hours
    •Tolerance at the injection site over 24 ± 4 hours after injection.
    •Adverse events will be monitored from the beginning of subject’s participation in the study (ICF signature) to the end of a 7 ± 1 day follow-up period.
    DOTAREM-MRI efficacy evaluation in brain (intracranial), spine and associated tissues (pre and post contrast assessment):
    •Lesion visualization: lesions will be assessed by on-site radiologist using a 3-point scale for 3 co-endpoints (lesion border delineation, internal morphology and contrast enhancement).
    •Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR) and Pre-Post Contrast Variation (ΔCNR) will be computed.
    •Quality of T1 weighted images will be assessed using a 3 graded scale.
    E.5.2.1Timepoint(s) of evaluation of this end point
    •Height and weight at screening visit
    •Vital signs at baseline (prior to injection), post injection immediately after MRI, between 2 and 4 hours and at 24 ± 4 hours
    •Blood samples for safety laboratory variables centrally a nalyzed at screening and post injection at 24 ± 4 hours
    •Estimated glomerular filtration rate (eGFR) centrally analyzed at screening and post injection at
    24 ± 4 hours
    •Urine samples for safety assessment (urinalysis with dipstick) at screening and post injection at 24 ± 4 hours
    •Tolerance at the injection site over 24 ± 4 hours after injection.
    •Adverse events from the beginning of subject’s participation in the study (ICF signature) to the end of a 7 ± 1 day follow-up period.
    •MRI efficacy (pre and post contrast assessment) evaluated at D0
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 50
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 8
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 42
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children aged less than 2 years alo can not give consent. Parents or legal representatives will consent for the participating child
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-10-19
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