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    Summary
    EudraCT Number:2017-001438-25
    Sponsor's Protocol Code Number:VWM1
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2018-11-28
    Trial 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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-001438-25
    A.3Full title of the trial
    A Pilot Study to Explore the Safety, Tolerability, Pharmacokinetic Profile, and Potential Efficacy of Guanabenz in Patients With
    Early Childhood Onset Vanishing White Matter (VWM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Therapeutic trial in patients with early-childhood onset vanishing white matter
    A.4.1Sponsor's protocol code numberVWM1
    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 SponsorVU University Medical Center
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportVU University Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVU University Medical Center
    B.5.2Functional name of contact pointPrincipal Investigator
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081HV
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31204444856
    B.5.6E-mailms.vanderknaap@vumc.nl
    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 No
    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 nameGuanabenz
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    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 No
    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
    Vanishing white matter
    E.1.1.1Medical condition in easily understood language
    Progressive brain disorder mainly occurring in young children with early fatality.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    to evaluate the safety and tolerability profile of guanabenz in pediatric patients with VWM
    E.2.2Secondary objectives of the trial
    • To evaluate the PK profile of guanabenz in pediatric patients with VWM.
    • To collect data on quantitative MRI parameters relevant to brain white matter integrity.
    • To collect data on quality of life, disability and survival.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Each patient’s parents/legal guardians must sign an informed consent form (ICF) indicating that they understand the purpose of and procedures required for this study, are willing for their child to participate in the study and attend all scheduled visits, and are willing and able to comply with all study-related procedures, including maintaining contact with the site for at least 1 year, and adhere to the prohibitions and restrictions as specified in the protocol.
    Note: For each patient, at least one parent/legal guardian, according to the local regulations, must give written consent.
    2. Male or female whose age at screening is <8 years.
    3. Genetically proven VWM with 2 clinically relevant mutations in one of the EIF2B1-5 genes and a brain MRI compatible with the diagnosis.
    4. Disease onset before the age of 4 years.
    5. Able to stand up and walk at least 10 steps with or without the support of one hand.
    Note: The “support of one hand” should be light. It does not refer to full support or to physically propelling the child forward.
    6. Lives within drivable distance from the VUmc site.
    For historical controls:
    1. Be in the same stratum as at least one patient included in the present study with respect to age at disease onset, disease duration at study entry, and disease severity category on the basis of the patient’s genotype.
    2. VWM diagnosis after 2001, the year the gene defect for VWM was identified, after which it was realized that the defect affects the ISR and circumstances activating the ISR should be avoided, such as febrile infections.
    E.4Principal exclusion criteria
    1. Clinically asymptomatic.
    2. Comorbidity with another genetic defect.
    3. Presence of an unrelated serious condition (eg, developmental anomaly, cardiac, liver or kidney disease).
    4. Participation in another clinical study with therapeutic intervention.
    5. Unable or unwilling to come to the VUmc site as required by the protocol.
    6. Unable to undergo MRI due to metal-containing implants, such as cochlea implant, neurostimulator or pacemaker.
    7. Family situation in which adherence to the study medication or follow-up procedures cannot be guaranteed.
    8. Known allergy or hypersensitivity to guanabenz or to any of the other components of the formulation used in this study.
    E.5 End points
    E.5.1Primary end point(s)
    • All adverse events and serious adverse events collected from the start of study treatment until the end of the study, applying the most recent version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, version 5.0, 27-Nov-2017).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1,5 years after FPI and end of study (approximately 4 years)
    E.5.2Secondary end point(s)
    • Guanabenz PK parameters, such as Cmax, AUC, half-life, and trough concentration (Ctrough), at steady state
    • Quantitative brain MRI parameters:
     Diffusion Tensor Imaging (DTI)
     Chemical Shift Imaging (CSI)
     Neurite Orientation Dispersion and Density Imaging (NODDI)
     Myelin Water Fraction Imaging (MWFI)
    • Clinical parameters:
     Health Utility Index (HUI)
     Gross Motor Function Classification System (GMFCS)
     Manual Ability Classification System (MACS)
     Communication Function Classification System (CFCS)
    • Survival

    E.5.2.1Timepoint(s) of evaluation of this end point
    1,5 years after FPI and end of study (approximately 4 years)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    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 No
    E.8.5The trial involves multiple Member States No
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 20
    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) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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
    patients between 2 and 11 years with potential mental retardation
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    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)
    Continued treatment with the IMP if benefit is observed.
    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 Decision2018-11-07
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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