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    Summary
    EudraCT Number:2019-003558-98
    Sponsor's Protocol Code Number:CHDR1939
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-01-08
    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 number2019-003558-98
    A.3Full title of the trial
    Randomized, double-blind, placebo-controlled, two way crossover, single centre study evaluating the acute and chronic effect of clonazepam on cognitive tests and patient-reported outcome measures in patients with ARID1B-related intellectual disability.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial to investigate the effects of clonazepam on patients with ARID1B-related intellectual disability.
    A.3.2Name or abbreviated title of the trial where available
    Clonazepam in ARID1B Evaluation
    A.4.1Sponsor's protocol code numberCHDR1939
    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 SponsorCentre for Human Drug Research
    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 supportCHDR
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre for Human Drug Research
    B.5.2Functional name of contact pointRob Zuiker
    B.5.3 Address:
    B.5.3.1Street AddressZernikedreef 8
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333CL
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310715246400
    B.5.6E-mailclintrials@chdr.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 Yes
    D.2.1.1.1Trade name Rivotril
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameRivotril
    D.3.4Pharmaceutical form Oral drops
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCLONAZEPAM
    D.3.9.1CAS number 1622-61-3
    D.3.9.4EV Substance CodeSUB06728MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number1
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral drops
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    ARID1B-related intellectual disability
    E.1.1.1Medical condition in easily understood language
    ARID1B-related intellectual disability
    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 test the hypothesis that clonazepam administration has acute beneficial effects compared to placebo on neurocognitive tests.
    • To test the hypothesis that multiple-doses clonazepam has beneficial effects compared to placebo on behaviour and cognitive function in ARID1B patients as measured by the ABC, and CGI-I scale.
    • Assess safety and tolerability of clonazepam in ARID1B patients.
    • To assess the potential of at-home neurocognitive tests for the evaluation of treatment effects in children with neurodevelopmental disorders.
    • To assess and compare the difference in predictive capability between linear and nonlinear (NONMEM) regression of the saliva:plasma relationship.
    E.2.2Secondary objectives of the trial
    Assess safety and tolerability of clonazepam in ARID1B patients.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A, saliva PK.
    • Healthy male or female volunteers
    • Informed consent provided by volunteer

    Part B, ARID1B patients.
    • Informed consent provided by both parents, or the legal guardian prior to any study mandated procedure.
    • Known mutation in ARID1B
    • Assent provided by the participant.
    • Aged 6 years or older
    E.4Principal exclusion criteria
    Part A
    • Disorder that could interfere with saliva production.
    • Known hypersensitivity to clonazepam, other benzodiazepines or other excipients of the study medication.
    • Treatment with another investigational drug within 3 months prior to screening or more than 4 times a year.
    • History or clinical evidence of any disease and/or existence of a surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug.
    • History of severe respiratory problems or severe liver- or renal insufficiency.
    • Other medical or psychosocial history making the participant unsuitable for participation as determined by the treating paediatrician.
    • History or clinical evidence of alcoholism within the 3-year period prior to screening (i.e. regular use of more than 21 units of alcohol/week).
    • Clinically significant findings on physical examination.
    • Medications with a strong influence on CYP3A4 metabolism
    • Subjects with a BMI > 30 and/or cardiovascular, respiratory or immune system disorders

    Part B, ARID1B patients.
    • Clear indication of not wanting to participate during the study
    • Use of benzodiazepines or any other medication or drug with the potential to influence study related endpoints in the investigator’s opinion (including e.g. CYP3A4-related drugs).
    • Known hypersensitivity to clonazepam, other benzodiazepines or other excipients of the study medication.
    • History of severe respiratory problems or severe liver- or renal insufficiency.
    • Other medical or psychosocial history making the participant unsuitable for participation as determined by the treating paediatrician.
    E.5 End points
    E.5.1Primary end point(s)
    Part A: serum and saliva. Part B: saliva only.
    • The maximum serum concentration, Cmax
    • The time to reach maximum serum concentration, tmax
    • The terminal disposition rate constant (λz) with the respective half-life, t½
    • The area under the serum concentration-time curve from zero to infinity, AUC0-inf
    • The area under the serum concentration-time curve from zero to t of the last measured concentration above the limit of quantification, AUC0-last
    • Clearance, Cl
    • Volume of distribution, Vz

    Trial@home endpoints
    • Physical activity
    • Sleep (duration, %light sleep, amount of times woken up)
    • Heart rate
    • Daily symptom scores
    • Tapping frequency, adaptive tracking, animal fluency (twice-weekly )

    Pharmacodynamic endpoints
    • NeuroCart
    o Adaptive Tracking
    o Animal fluency test
    o Body Sway
    o Saccadic Eye Movements
    o Smooth Pursuit Eye Movements
    o Tapping frequency

    • Questionnaires
    o ABC questionnaire (parents, teacher)
    o Clinician’s Global Impression of improvement (CGI-I)
    E.5.1.1Timepoint(s) of evaluation of this end point
    baseline to EoS
    E.5.2Secondary end point(s)
    Tolerability / safety endpoints
    • Adverse events
    • Vital signs measurements
    • General physical examination findings (only performed when clinically indicated)
    E.5.2.1Timepoint(s) of evaluation of this end point
    from baseline to EoS
    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 Yes
    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 Yes
    E.8.1.1Randomised Yes
    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 Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Part A : Open label randomised placebo parallel group. Part B : double blind, cross over, placebo
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 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
    Last visit last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    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 Yes
    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
    Subjects with intellectual disability.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    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)
    As soon as trial results are known and show benefit for patients with ARID1B, treatment will commence in collaboration with treating physicians.
    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 Decision2020-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-03
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