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    Summary
    EudraCT Number:2013-001832-23
    Sponsor's Protocol Code Number:NEU_CH_7911
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-10-23
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2013-001832-23
    A.3Full title of the trial
    A RANDOMIZED, PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF CIRCADIN® TO ALLEVIATE SLEEP DISTURBANCES IN CHILDREN WITH NEURODEVELOPMENTAL DISABILITIES
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating if Circadin (compared to placebo) helps children with neurodevelopmental disabilities to better sleep
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberNEU_CH_7911
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01906866
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/117/2012
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNeurim Pharmaceuticals (1991) Ltd.
    B.1.3.4CountryIsrael
    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 supportNeurim Pharmaceuticals (1991) Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNeurim Pharmaceuticals (1991) Ltd.
    B.5.2Functional name of contact pointClincial Trial Management
    B.5.3 Address:
    B.5.3.1Street Address27 Habarzel St.
    B.5.3.2Town/ cityTel Aviv
    B.5.3.3Post code69710
    B.5.3.4CountryIsrael
    B.5.6E-mailAnatF@neurim.com
    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 Circadin
    D.2.1.1.2Name of the Marketing Authorisation holderRAD Neurim Pharmaceuticals EEC Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCircadin
    D.3.4Pharmaceutical form Prolonged-release tablet
    D.3.4.1Specific paediatric formulation Yes
    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 INNMelatonin
    D.3.9.1CAS number 73-31-4
    D.3.9.3Other descriptive nameMELATONIN
    D.3.9.4EV Substance CodeSUB14496MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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 placeboTablet
    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
    SLEEP DISTURBANCES IN CHILDREN WITH NEURODEVELOPMENTAL DISABILITIES
    E.1.1.1Medical condition in easily understood language
    Problems with sleeping in children with neurodevelopmental disabilities
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10040997
    E.1.2Term Sleep disturbances
    E.1.2System Organ Class 100000004873
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the treatment effect of Circadin 2/5 mg to that of placebo on sleep maintenance (total sleep time [TST]) as assessed by the Sleep and Nap Diary after 13 weeks of double-blind treatment.
    E.2.2Secondary objectives of the trial
    To compare treatment effect of Circadin 2/5mg to placebo on
    - sleep latency, duration of wake after sleep onset period, number of awakenings and duration of the longest sleep period as derived from a Sleep and Nap Diary after 13 weeks double-blind treatment.
    - children’s social functioning at home, in school, and community settings as assessed by the CGAS after 13 weeks double-blind treatment.
    - children’s behavior at home and in school as assessed by the SDQ after 13 weeks double-blind treatment.
    - sleep parameters as measured by actigraphy after 13 weeks double-blind treatment.
    To compare safety and tolerability of Circadin to placebo and evaluate safety and tolerability throughout the study incl. runout period using AE eliciting method TESS Questionnaire.
    To assess vital signs and physical examination in Circadin and placebo groups.
    To compare the number of dropouts between Circadin 2/5 mg and placebo during 13 weeks double-blind treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for study entry, all patients must satisfy all of the following criteria at screening.
    1. Must be children 2 to 17.5 years of age at Visit 2 who comply with taking the study drug.
    2. Must have written informed consent provided by a legal guardian and assent (if needed).
    3. Must have a documented history of ASD according to ICD-10 or DSM-5/4 or neurodevelopmental disabilities caused by neurogenetic diseases (Smith-Magenis syndrome [SMS], Angelman syndrome, Bourneville’s disease [tuberous sclerosis]) as confirmed by case note review showing that diagnosis was reached through assessment by a community paediatrician or paediatric neurologist or other health care professionals experienced in the diagnosis, who took into account early developmental history and school records.
    4. Must have current sleep problems including: A minimum of 3 months of impaired sleep defined as <6 hours of continuous sleep with more than 0.5 hour sleep latency from light off in 3 out of 5 nights based on parent reports and patient medical history.
    5. May be on a stable dose of non-excluded medication for 3 months, including anti-epileptics, anti-depressants (SSRIs), stimulants, all mood changing drugs and beta blockers.
    6. The sleep disturbance is not due to the direct physiological effects of the medication (SSRIs, stimulants, etc.).
    At the end of 4 weeks of sleep hygiene training and 2 weeks of run-in, children will be eligible to continue the study if they comply with the following:
    1. Continue to fulfil sleep problem criteria (see Inclusion Criterion 4).
    2. Parents demonstrate compliance in Sleep and Nap Diary completion (5 out of 7 nights).
    3. Continue to fulfil all other eligibility criteria.
    E.4Principal exclusion criteria
    1. Have had treatment with any form of melatonin within 2 weeks prior to Visit 1.
    2. Have a known allergy to melatonin or lactose.
    3. Have a known moderate to severe sleep apnea.
    4. Have untreated medical/ineffectively treated/psychological condition that may be the etiology of sleep disturbances.
    5. Did not respond to previous Circadin therapy based on past medical history records in the last 2 years.
    6. Are taking or have been taking disallowed medication within 2 weeks prior to Visit 1.
    7. Are females of child bearing potential that are not using contraceptives and/or are breastfeeding and that are sexually active (abstinence is an acceptable method of contraception).
    8. Pregnant females
    9. Are currently participating in a clinical trial or have participated in a clinical trial involving medicinal product within the last 3 months prior to the study (this does not include patients who participated in the Phase I PK study who can be already included in the study).
    10. Children with known renal or hepatic insufficiency
    E.5 End points
    E.5.1Primary end point(s)
    Total sleep time as assessed by a Sleep and Nap Diary
    E.5.1.1Timepoint(s) of evaluation of this end point
    after the 13- week double-blind treatment period
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints
    • Sleep latency as assessed by a Sleep and Nap Diary
    • Duration of wake after sleep onset from the Sleep and Nap Diary
    • Number of awakenings from the Sleep and Nap Diary
    • Longest sleep period from the Sleep and Nap Diary
    • Social functioning at home, in school, and in community settings as assessed by the CGAS
    • Behavior at home and in school as assessed by the SDQ
    • Number of dropouts
    • Assessment of sleep parameters by actigraphy

    Secondary Safety Endpoints
    • Adverse events using the TESS Questionnaire.
    • Vital signs
    • Physical examination
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary Efficacy Endpoints: after 13 weeks of double-blind treatment.

    Secondary Safety Endpoints:
    - AEs: throughout the study and upon study withdrawal
    - Vital signs and physical exam: at each visit including the run-out period.
    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 No
    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) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    United States
    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.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 120
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 60
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 60
    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 Yes
    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
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 120
    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)
    N/A
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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