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    Clinical Trial Results:
    A 10-Week, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Donepezil Hydrochloride (Aricept) in the Treatment of the Cognitive Dysfunction Exhibited by Children with Down Syndrome, Aged 6 to 10

    Summary
    EudraCT number
    2016-004949-92
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    10 Dec 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Apr 2019
    First version publication date
    07 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E2020-A001-336
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00754013
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Eisai Medical Services Inc.
    Sponsor organisation address
    100 Tice Boulevard, Woodcliff Lake, United States,
    Public contact
    Eisai Medical Information, Eisai Inc., 011 888247-2378, esi-medinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai Inc., 011 888247-2378, esi-medinfo@eisai.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Dec 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2008
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to determine the efficacy and safety of donepezil hydrochloride (Aricept) in the treatment of cognitive dysfunction shown by children with Down syndrome, aged 6 to 10 years.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Oct 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    9
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    9
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study planned to recruit subjects at 26 centers in the United States. However, the study was terminated early and only 5 centers enrolled subjects during the period of 06 Oct 2008 to 10 Dec 2008.

    Pre-assignment
    Screening details
    Due to early termination of the study by the Sponsor, only 9 participants were enrolled into the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Donepezil HCl
    Arm description
    Donepezil was titrated to a dose of approximately 0.1-0.2 mg/kg/day as liquid containing 1 mg/1 mL of donepezil.
    Arm type
    Experimental

    Investigational medicinal product name
    Donepezil HCl
    Investigational medicinal product code
    Other name
    Aricept
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Blinded oral donepezil hydrochloride (HCl), was started at 1.25 mL daily, followed by 2-week titration intervals over a period of 6 weeks until a maximum dose of 5 mg/kg/day or 10 mg/kg/day was reached. Due to early termination of the study, no participant reached either targeted maximum.

    Arm title
    Placebo
    Arm description
    Donepezil matched placebo was titrated in the similar way as the donepezil arm.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo in a 1:1:1 ratio.

    Number of subjects in period 1
    Donepezil HCl Placebo
    Started
    4
    5
    Completed
    0
    0
    Not completed
    4
    5
         didn't return after study terminated
    3
    4
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Donepezil HCl
    Reporting group description
    Donepezil was titrated to a dose of approximately 0.1-0.2 mg/kg/day as liquid containing 1 mg/1 mL of donepezil.

    Reporting group title
    Placebo
    Reporting group description
    Donepezil matched placebo was titrated in the similar way as the donepezil arm.

    Reporting group values
    Donepezil HCl Placebo Total
    Number of subjects
    4 5 9
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9 ± 0.8 8 ± 1.4 -
    Gender categorical
    Units: Subjects
        Female
    2 3 5
        Male
    2 2 4
    Race/Ethnicity
    Units: Subjects
        White (n)
    4 5 9

    End points

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    End points reporting groups
    Reporting group title
    Donepezil HCl
    Reporting group description
    Donepezil was titrated to a dose of approximately 0.1-0.2 mg/kg/day as liquid containing 1 mg/1 mL of donepezil.

    Reporting group title
    Placebo
    Reporting group description
    Donepezil matched placebo was titrated in the similar way as the donepezil arm.

    Primary: Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) Sum of the 9 Sub-domain V-Scores (3 Scores for Each of the Communication, Daily Living Skills, And Socialization Domains) Using Last Observation Carried Forward

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    End point title
    Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) Sum of the 9 Sub-domain V-Scores (3 Scores for Each of the Communication, Daily Living Skills, And Socialization Domains) Using Last Observation Carried Forward [1]
    End point description
    The primary objective of the study was evaluation of the efficacy and safety of donepezil hydrochloride in the treatment of the cognitive dysfunction exhibited by children with Down syndrome (DS), aged 6 to 10, as assessed by analysis of VABS-II/PCRF in the domains of communication, daily living skills, and socialization, and as assessed by standard safety measurements. The planned efficacy analysis was on the intent-to-treat (ITT) population. This study was terminated early. Primary efficacy data were not analyzed since only 9 of the 140 planned subjects had been enrolled.
    End point type
    Primary
    End point timeframe
    Visit 0 (Screen), Visits 1 (Baseline), 2, and 3 (or Early Termination)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to early termination of the study, no analyses were performed.
    End point values
    Donepezil HCl Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Units on a scale
        number (not applicable)
    Notes
    [2] - This study was terminated early. Analyses were not performed.
    [3] - This study was terminated early. Analyses were not performed.
    No statistical analyses for this end point

    Secondary: Mean Change From (Baseline) to Visit 3 (Week 10 or Early Termination) in VABS-II/PCRF Sum of The 9 Sub-domain V-Scores (3 Scores for Each of The Communication, Daily Living Skills, And Socialization Domains) Using Last Observation Carried Forward

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    End point title
    Mean Change From (Baseline) to Visit 3 (Week 10 or Early Termination) in VABS-II/PCRF Sum of The 9 Sub-domain V-Scores (3 Scores for Each of The Communication, Daily Living Skills, And Socialization Domains) Using Last Observation Carried Forward
    End point description
    The planned secondary objectives of the study included further evaluation of efficacy as assessed by additional analyses of the VABS-II/PCRF, by analyses of the Test of Verbal Expression and Reasoning (TOVER), a subject-performance-based measure of expressive language function, and by the Forward Memory and Attention Sustained sub-tests of the Leiter International Performance Scale - Revised (Leiter-R), a cognitive assessment instrument for children and adolescents that is not language dependent. In addition, observed case analyses of these assessments at Week 4 and Week 10 were planned. This study was terminated early. Secondary efficacy data were not analyzed since only 9 of the 140 planned subjects had been enrolled.
    End point type
    Secondary
    End point timeframe
    Visit 1 (Baseline) to Visit 3 (Week 10 or early termination)
    End point values
    Donepezil HCl Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Units on a scale
        number (not applicable)
    Notes
    [4] - This study was terminated early. Analyses were not performed.
    [5] - This study was terminated early. Analyses were not performed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose until 30 days after the last dose of study treatment, up to approximately 3 months.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Donepezil HCl
    Reporting group description
    Donepezil was titrated to a dose of approximately 0.1-0.2 mg/kg/day as liquid containing 1 mg/1 mL of donepezil.

    Reporting group title
    Placebo
    Reporting group description
    Donepezil matched placebo was titrated in the similar way as the donepezil arm.

    Serious adverse events
    Donepezil HCl Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Donepezil HCl Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 5 (60.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Bruxism
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Tongue disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the study terminating early, only 9 subjects were enrolled and these subjects receive only limited exposure to study medications with no subject reaching his/her maximum targeted dose. Therefore, the planned efficacy criteria was not analyzed.
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