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    Clinical Trial Results:
    An Open-Label Study Of The Safety And Tolerability Of Memantine In Pediatric Patients With Autism, Asperger’s Disorder, Or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS).

    Summary
    EudraCT number
    2012-001616-33
    Trial protocol
    GB   HU   BE   ES   NL   EE   IS   IT  
    Global end of trial date
    09 Jul 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Aug 2018
    First version publication date
    10 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEM-MD-91
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01592786
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Forest Laboratories LLC, a subsidiary of Allergan, plc
    Sponsor organisation address
    1 Grand Canal Square, Docklands, Ireland, Dublin 2
    Public contact
    Clinical Trial Information Desk, Forest Laboratories LLC, a subsidiary of Allergan, plc, 001 866-369-5227 ,
    Scientific contact
    Joel Trugman, Forest Laboratories LLC, a subsidiary of Allergan, plc, 001 201-427-8000 , Joel.Trugman@actavis.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the safety and tolerability of memantine in pediatric (6-12 years old) patients with autism, Asperger’s Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and to identify responders for participation in the follow-up randomized withdrawal study
    Protection of trial subjects
    At each study center, the Investigator was responsible for ensuring that the investigation was conducted according to the signed Investigator agreement, the protocol, good clinical practice guidelines, and applicable regulations; for protecting the rights, safety, and welfare of patients under the Investigator’s care; and for the control of investigational products under investigation. The Investigator at each study center was responsible for the management of the study, which consisted of maintaining the study file and patient records, corresponding with the IRB/IEC, and completing the electronic case report forms (eCRFs).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Estonia: 6
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Iceland: 5
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Serbia: 21
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Ukraine: 16
    Country: Number of subjects enrolled
    United States: 714
    Worldwide total number of subjects
    906
    EEA total number of subjects
    116
    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)
    793
    Adolescents (12-17 years)
    113
    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
    Patient recruitment occurred over an eleven month period, from June of 2011 to May of 2012, at 118 study sites, located in the Untied States and 17 other countries. Australia: Belgium: Canada: Colombia Estonia: France: Hungary: Iceland: Italy: New Zealand: Poland: Singapore: South Africa: South Korea Spain: Ukraine

    Pre-assignment
    Screening details
    Enrolled patients went through a 2-week screening period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Memantine Hydrochloride (HCl) ER
    Arm description
    Memantine Hydrochloride (HCl) extended-release 3-mg capsules once daily, oral administration. Dosing was 3-mg, 6-mg, 9-mg, 12-mg, or 15-mg per day, based upon patient weight.
    Arm type
    Experimental

    Investigational medicinal product name
    Memantine
    Investigational medicinal product code
    Other name
    Ebixa, Namenda, Axura, Akatinol, Abixa, Memox
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Memantine Hydrochloride (HCl) extended-release 3-mg capsules once daily, oral administration. Dosing was 3-mg, 6-mg, 9-mg, 12-mg, or 15-mg per day, based upon patient weight.

    Number of subjects in period 1
    Memantine Hydrochloride (HCl) ER
    Started
    906
    Completed
    765
    Not completed
    141
         Consent withdrawn by subject
    23
         Adverse event, non-fatal
    61
         Other Reason
    3
         Lost to follow-up
    21
         Lack of efficacy
    19
         Protocol deviation
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    906 906
    Age categorical
    Units: Subjects
        Children (6-12 years)
    906 906
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9 ( 1.9 ) -
    Gender categorical
    Units: Subjects
        Female
    144 144
        Male
    762 762
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Of the 906 patients who enrolled in the study 903 received at least 1 dose of open-label treatment to comprise the Safety Population.

    Subject analysis set title
    Intent to Treat Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent to Treat (ITT) population included the 868 patients in the Safety population who also had at least 1 post–Visit 1 assessment of the SRS total raw score.

    Subject analysis sets values
    Safety Population Intent to Treat Population
    Number of subjects
    903
    868
    Age categorical
    Units: Subjects
        Children (6-12 years)
    903
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9 ( 1.9 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    144
        Male
    759

    End points

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    End points reporting groups
    Reporting group title
    Memantine Hydrochloride (HCl) ER
    Reporting group description
    Memantine Hydrochloride (HCl) extended-release 3-mg capsules once daily, oral administration. Dosing was 3-mg, 6-mg, 9-mg, 12-mg, or 15-mg per day, based upon patient weight.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Of the 906 patients who enrolled in the study 903 received at least 1 dose of open-label treatment to comprise the Safety Population.

    Subject analysis set title
    Intent to Treat Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent to Treat (ITT) population included the 868 patients in the Safety population who also had at least 1 post–Visit 1 assessment of the SRS total raw score.

    Primary: Number of Social Responsiveness Scale (SRS) Confirmed Responders

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    End point title
    Number of Social Responsiveness Scale (SRS) Confirmed Responders [1]
    End point description
    A confirmed SRS responder was defined as a patient who had at least 12 weeks of exposure to memantine, and a ≥ 10-point reduction in the SRS total raw score relative to baseline at 2 consecutive visits separated by at least 2 weeks. The SRS is a 65-item, caregiver-rated assessment scale that measures observable items on social behavior and social language use, as well as characteristics of autism in a naturalistic social setting. Each item is rated on a scale from 0 (never true) to 3 (almost always true). The SRS total raw score ranges from 0 to 195; a higher score indicates greater severity of social impairment.
    End point type
    Primary
    End point timeframe
    Visit 1 (Baseline) to Visit 8 (week 48/Final Visit)
    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: No inferential statistical analyses were performed for the efficacy parameters.
    End point values
    Intent to Treat Population
    Number of subjects analysed
    868
    Units: Patients
        Confirmed Responders
    517
        Non-Responders
    351
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data was collected over a 14 month period from June 2012 to August 2013 at 118 study sites in the US and 17 other countries.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Memantine Hydrochloride (HCl)
    Reporting group description
    Memantine Hydrochloride (HCl) extended-release 3-mg capsules once daily, oral administration. Dosing was 3-mg, 6-mg, 9-mg, 12-mg, or 15-mg per day, based upon patient weight.

    Serious adverse events
    Memantine Hydrochloride (HCl)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 903 (0.66%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Accidental exposure
         subjects affected / exposed
    1 / 903 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 903 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 903 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    2 / 903 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Disinhibition
         subjects affected / exposed
    1 / 903 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Memantine Hydrochloride (HCl)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    193 / 903 (21.37%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    72 / 903 (7.97%)
         occurrences all number
    86
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    49 / 903 (5.43%)
         occurrences all number
    57
    Pyrexia
         subjects affected / exposed
    52 / 903 (5.76%)
         occurrences all number
    59
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    57 / 903 (6.31%)
         occurrences all number
    69

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2013
    Amendment #1 specifies the following changes to the original protocol MEM-MD-91, dated April 05, 2012: Increasing sample size from approximately 192 enrolled patients to approximately 800 to 900 enrolled patients. Rationale: The Number of Patients (Planned and Analyzed) section has been amended to change the planned sample size such that a sufficient number of patients can be enrolled in MEM-MD-68 from this lead-in study. The sample size of MEM-MD-68 has been increased based on the discussion with the FDA. In order to provide sufficient patients transitioning to a follow-up randomized withdrawal study (MEM-MD-68), approximately 800 to 900 patients will be enrolled into this study. Adding information regarding the Data Safety Monitoring Board (DSMB) Rationale: This section has been added to include information about the DSMB. No safety issue necessitated the use of the DSMB. An Ethics Committee requested that a DSMB be established. Clarifying if administration of the Columbia-Suicide Severity Rating Scale (C-SSRS) is appropriate given a patient’s developmental and/or situational status. Rationale: This section was revised to clarify if administration of the C-SSRS is appropriate given a patient’s developmental and/or situational status. All references to the Social Responsiveness Scale (SRS) Patient Autoscore version have been revised. Rational: The Social Responsiveness Scale (SRS) Patient Autoscore version has not been provided to the sites. The SRS total raw score should be calculated before the patient/caregiver leave the site. Immediate Reporting of Serious Adverse Events Rationale: This section was revised to indicate where the SAE Form fax number and Medical Emergency phone number for sites outside the United States and Canada can be found. Contact Information Rationale: Appendix II was revised to indicate where the contact information and Medical Emergency phone number for sites outside the United States and Canada can be found.

    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.
    None reported
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