Study of Pharmacokinetics, Safety, Efficacy, and Tolerability of Memantine in Children With Autism

This study has been completed.
Sponsor:
Collaborator:
Merz Pharmaceuticals GmbH
Information provided by (Responsible Party):
Forest Laboratories
ClinicalTrials.gov Identifier:
NCT00872898
First received: March 30, 2009
Last updated: November 26, 2013
Last verified: November 2013
  Purpose

The purpose of this study is to investigate the safety and efficacy of memantine extended release, as well as its extent of absorption in pediatric patients with autism.


Condition Intervention Phase
Autism
Drug: Memantine - Extended Release (ER)
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Open-label (Part One) and a Randomized, Double-blind, Placebo-Controlled (Part Two) Study of the Pharmacokinetics, Safety, Efficacy, and Tolerability of Memantine in Pediatric Patients With Autism

Resource links provided by NLM:


Further study details as provided by Forest Laboratories:

Primary Outcome Measures:
  • Extent of Absorption of Memantine (Part One) [ Time Frame: Baseline to 144 hours. Measurements were taken 0 (predose), 4, 8, 24, 30, 48, 96 and 144 hours post-dose ] [ Designated as safety issue: Yes ]
    Area under the plasma concentration vs. time curve (AUC) for memantine, as measured in units of nanogram x hours per milliliter.

  • Change in Total Raw Score of Social Responsiveness Scale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Social Responsiveness Scale (SRS) is a 65-item informant-rated assessment, ranging from 0 (no impairment) to 195 (severe social impairment).

    Each item is associated with 1 of 5 subscales (social awareness, social cognition, social communication, social motivation and autistic mannerisms). Each item is rated on a 4-point scale from 1 (not true) to 4 (almost always true). The scores are then transposed to a scale from 0 to 3 and scores are summed within each of the 5 subscales. A higher score indicates greater severity of social impairment.



Secondary Outcome Measures:
  • Core Autism Treatment Scale-Improvement: Total Score [ Time Frame: At Week 12 ] [ Designated as safety issue: No ]

    The Core Autism Treatment Scale-Improvement (CATS-I) is based on rating 14 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 14 (improved) to 98 (worsened).

    The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).


  • Core Autism Treatment Scale-Improvement: Social Interaction [ Time Frame: At Week 12 ] [ Designated as safety issue: No ]

    The Core Autism Treatment Scale-Improvement (CATS-I) Social Interaction Subscale is based on rating 9 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 9 (improved) to 63 (worsened).

    The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).


  • Core Autism Treatment Scale-Improvement: Communication [ Time Frame: At Week 12 ] [ Designated as safety issue: No ]

    The Core Autism Treatment Scale-Improvement (CATS-I) Communication Subscale is based on rating 5 items from 1 (very much improved) to 7 (very much worse) with a total score ranging from 5 (improved) to 35 (worsened).

    The Core Autism Treatment Scale-Improvement (CATS-I) is designed to utilize a comparison between pretreatment ratings of Core Autism Treatment Scale-Severity (CATS-S) and ratings of improvement after start of therapy (CATS-I). Both parts of the CATS contain 14 items testing for social interaction (items 1-9) and communication (items 10-14). Each of these items is rated from 1 (indicating most benign) to 7 (indicating most severe).


  • Change in Children's Communication Checklist-2 (CCC-2) - Speech Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Speech Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Syntax Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Semantics Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Coherence Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Initiation Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Scripted Language Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Context Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Context Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Nonverbal Communication Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Social Relations Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).


  • Change in Children's Communication Checklist-2 (CCC-2) - Interests Subscale [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]

    The Children's Communication Checklist-2 (CCC-2) Interests Subscale consists of 7 items rated from 0 (less than once a week or never) to 3 (several times [more than twice] a day or always), with a total raw score of 0 (mildest) to 21 (most severe).

    The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties children may have (across 10 different subscales, consisting of 7 items each) that affect communication (items 1-50), as well as strengths that children may demonstrate when communicating with others (items 51-70).



Enrollment: 124
Study Start Date: April 2009
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Once daily oral administration of memantine for 12 weeks.
Drug: Memantine - Extended Release (ER)
Memantine - 3mg and 6mg capsules, dose ranging 3 - 18 mg/day in 4 weight groups, administered orally.
Other Name: Namenda ER
Placebo Comparator: 2
Once daily oral administration of placebo for 12 weeks.
Drug: Placebo
Placebo capsules, once daily, oral administration.

Detailed Description:

This is a multicenter, two-part study in pediatric (ages 6 to 18 years) patients diagnosed with autism.

Patients participating in Part One will receive a single open-label dose of memantine. Blood samples for pharmacokinetic analysis will be collected.

Part Two is a randomized, double-blind, placebo-controlled 12-week efficacy and safety study evaluating change in all core domains (social interactions, communication, and restricted interests and repetitive behaviors) of autism.

In the Forest autism trials conducted in children ages 6-12, dosing with an extended release formulation of memantine was weight-based. These weight based dose limits were selected to ensure exposure in terms of area under the curve (AUC) was less than the predefined limit of 2100 ng∙h/mL that represented a 10-fold lower exposure than observed at the NOAEL (No observed adverse effect level) of 15 mg/kg/day in juvenile rats.

The weight-based dose limits in these studies were as follows:

  • Group A: ≥ 60 kg; max 15 mg/day
  • Group B: 40-59 kg; max 9 mg/day
  • Group C: 20-39 kg; max 6 mg/day
  • Group D: < 20 kg; max 3 mg/day
  Eligibility

Ages Eligible for Study:   6 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males or females ages 6 to 12 years
  • Diagnosis of autistic disorder, according to DSM-IV-TR using Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule (modules 2 & 3).
  • A knowledgeable caregiver capable of providing reliable information about the patient's condition, able to attend all clinic visits with the patient
  • Patients over age 12, only if they completed Study MEM-PK-21

Exclusion Criteria:

  • Medical history of active epilepsy/seizure disorder except simple febrile seizures
  • Participation in any other clinical investigation using an experimental drug within 30 days of the start of this study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00872898

Locations
United States, Arizona
Forest Investigative Site
Phoenix, Arizona, United States, 85006
United States, California
Forest Investigative Site
Sacramento, California, United States, 95817
Forest Investigative Site
San Francisco, California, United States, 94143
Forest Investigative Site
Santa Ana, California, United States, 92705
Forest Investigative Site
Stanford, California, United States, 94305
United States, Florida
Forest Investigative Site
Jacksonville Beach, Florida, United States, 32250
Forest Investigative Site
St Petersburg, Florida, United States, 33701
United States, Illinois
Forest Investigative Site
Hoffman Estates, Illinois, United States, 60169
Forest Investigative site
Naperville, Illinois, United States, 60563
United States, Indiana
Forest Investigative Site
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Forest Investigative Site
Cambridge, Massachusetts, United States, 02138
United States, New Jersey
Forest Investigative Site
Toms River, New Jersey, United States, 08755
Forest Investigative Site
Voorhees, New Jersey, United States, 08043
United States, New York
Forest Investigative Site
Manhasset, New York, United States, 11030
United States, Ohio
Forest Investigative Site
Cleveland, Ohio, United States, 44106
Forest Investigative Site
Columbus, Ohio, United States, 43210
United States, Oklahoma
Forest Investigative Site
Oklahoma City, Oklahoma, United States, 73116
Sponsors and Collaborators
Forest Laboratories
Merz Pharmaceuticals GmbH
Investigators
Study Director: Ephraim Katz, PhD Forest Research Institute, a subsidiary of Forest Laboratories, Inc.
  More Information

No publications provided

Responsible Party: Forest Laboratories
ClinicalTrials.gov Identifier: NCT00872898     History of Changes
Other Study ID Numbers: MEM-MD-57A
Study First Received: March 30, 2009
Results First Received: August 1, 2013
Last Updated: November 26, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Forest Laboratories:
autism
memantine
pediatric
Forest Laboratories
Autism in pediatric patients

Additional relevant MeSH terms:
Autistic Disorder
Child Development Disorders, Pervasive
Mental Disorders Diagnosed in Childhood
Mental Disorders
Memantine
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 20, 2014