Withdrawal Study of Memantine in Pediatric Patients With Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified Previously Treated With Memantine

A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study of the Safety and Efficacy of Memantine in Pediatric Patients With Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) Previously Treated With Memantine

The purpose of this randomized withdrawal study is to evaluate the safety, tolerability, and efficacy of memantine compared with placebo in pediatric patients with autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS).

Study Overview

• Status: Completed
• Conditions: Autistic Disorder; Autism; Autism Spectrum Disorders; Asperger Syndrome; Asperger's Disorder; Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS)
• Intervention / Treatment: Drug: Memantine Hydrochloride (HCl); Drug: Memantine Hydrochloride (HCl); Drug: Placebo capsules

Detailed Description

This clinical study was a 12-week, multicenter, double-blind, placebo-controlled, randomized withdrawal study in pediatric outpatients with autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). Patients who completed at least 12 weeks of study drug exposure and met protocol specified responder criterion in lead in Study MEM-MD-91 (NCT01592786) at two consecutive visits separated by at least two weeks were eligible to transition to this study. The responder criterion was defined as having at least a 10 point improvement (reduction in score) in the Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 total raw score in Study MEM-MD-91.

Weight based dose limits were selected in this study to ensure that exposure in terms of area under the curve (AUC) was less than the predefined limit of 2100 ng·h/mL which represents 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 this study were as follows:

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

• Study Type: Interventional
• Enrollment (Actual): 479
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1020
    • Forest Investigative Site 204
  • Bruxelles, Belgium, 1090
    • Forest Investigative Site 203
• Colombia
  • Bello, Colombia
    • Forest Investigative Site 228
  • Bogotá, Colombia
    • Forest Investigative Site 226
• Estonia
  • Tallinn, Estonia, 10617
    • Forest Investigative Site 276
• France
  • Bron Cedex, France, 69677
    • Forest Investigative Site 329
• Hungary
  • Budapest, Hungary, 1026
    • Forest Investigative Site 381
  • Budapest, Hungary, 1083
    • Forest Investigative Site 376
  • Budapest, Hungary, 1089
    • Forest Investigative Site 378
• Iceland
  • Kopavogur, Iceland, 200
    • Forest Investigative Site 401
• Italy
  • Roma, Italy, 165
    • Forest Investigative Site 453
  • Siena, Italy, 53100
    • Forest Investigative Site 452
• Korea, Republic of
  • Seoul, Korea, Republic of, 110744
    • Forest Investigative Site 702
  • Seoul, Korea, Republic of, 120-752
    • Forest Investigative Site 703
  • Seoul, Korea, Republic of, 138-736
    • Forest Investigative Site 701
  • Gyeongsangnam-do
    • Yangsan-si, Gyeongsangnam-do, Korea, Republic of, 626-770
      • Forest Investigative Site 704
• New Zealand
  • Wellington, New Zealand, 6012
    • Forest Investigative Site 526
• Poland
  • Gdansk, Poland, 80-542
    • Forest Investigative Site 579
  • Gdansk, Poland, 80-952
    • Forest Investigative Site 578
  • Kobierzyce, Poland, 55-040
    • Forest Investigative Site 576
  • Warszawa, Poland, 02-957
    • Forest Investigative Site 577
• Serbia
  • Belgrade, Serbia, 11000
    • Forest Investigative Site 626
  • Belgrade, Serbia, 11000
    • Forest Investigative Site 627
  • Nis, Serbia, 18000
    • Forest Investigative Site 629
  • Novi Sad, Serbia, 21000
    • Forest Investigative Site 628
• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7530
      • Forest Investigative Site 676
• Spain
  • Barcelona
    • Sabadell, Barcelona, Spain, 8208
      • Forest Investigative Site 728
• Ukraine
  • Kharkiv, Ukraine, 61153
    • Forest Investigative Site 807
  • Kherson,Vil. Stepanivka, Ukraine, 73488
    • Forest Investigative Site 802
  • Kyiv, Ukraine, 04080
    • Forest Investigative Site 804
• United States
  • Alabama
    • Dothan, Alabama, United States, 36303
      • Forest Investigative Site 068
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Forest Investigative Site 005
    • Tucson, Arizona, United States, 85718
      • Forest Investigative Site 055
  • Arkansas
    • Little Rock, Arkansas, United States, 72202-3591
      • Forest Investigative Site 077
  • California
    • Glendale, California, United States, 91206
      • Forest Investigative Site 054
    • Imperial, California, United States, 92251
      • Forest Investigative Site 109
    • Los Angeles, California, United States, 90024
      • Forest Investigative Site 096
    • San Francisco, California, United States, 94143-0984
      • Forest Investigative Site 021
    • Santa Ana, California, United States, 92701
      • Forest Investigative Site 026
    • Stanford, California, United States, 94305-5719
      • Forest Investigative Site 002
  • Colorado
    • Boulder, Colorado, United States, 80304
      • Forest Investigative Site 078
    • Centennial, Colorado, United States, 80112
      • Forest Investigative Site 073
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Forest Investigative Site 052
  • Florida
    • Bradenton, Florida, United States, 32751
      • Forest Investigative Site 075
    • Gainesville, Florida, United States, 32607
      • Forest Investigative Site 080
    • Jacksonville, Florida, United States, 32216
      • Forest Investigative Site 117
    • Maitland, Florida, United States, 32751
      • Forest Investigative Site 065
    • Miami, Florida, United States, 33155
      • Forest Investigative Site 118
    • Oakland Park, Florida, United States, 33334
      • Forest Investigative Site 085
    • Orange City, Florida, United States, 32763
      • Forest Investigative Site 115
    • Orlando, Florida, United States, 32803
      • Forest Investigative Site 125
    • Orlando, Florida, United States, 32806
      • Forest Investigative Site 062
    • Tampa, Florida, United States, 33612
      • Forest Investigative Site 067
    • Wellington, Florida, United States, 33414
      • Forest Investigative Site 101
  • Illinois
    • Libertyville, Illinois, United States, 60048
      • Forest Investigative Site 102
    • Naperville, Illinois, United States, 60563
      • Forest Investigative Site 023
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Forest Investigative Site 082
    • Indianapolis, Indiana, United States, 46260
      • Forest Investigative Site 056
  • Kansas
    • Wichita, Kansas, United States, 67214-3199
      • Forest Investigative Site 106
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Forest Investigative Site 061
  • Louisiana
    • Lake Charles, Louisiana, United States, 70605
      • Forest Investigative Site 095
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Forest Investigative Site 086
  • Massachusetts
    • Newton, Massachusetts, United States, 02459
      • Forest Investigative Site 059
    • Springfield, Massachusetts, United States, 01199
      • Forest Investigative Site 108
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
      • Forest Investigative Site 116
    • Lincoln, Nebraska, United States, 68526
      • Forest Investigative Site 097
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Forest Investigative Site 130
    • Las Vegas, Nevada, United States, 89128
      • Forest Investigative Site 104
  • New Jersey
    • Neptune, New Jersey, United States, 07753
      • Forest Investigative Site 136
    • Toms River, New Jersey, United States, 08755
      • Forest Investigative Site 127
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108-5129
      • Forest Investigative Site 081
    • Albuquerque, New Mexico, United States, 87109
      • Forest Investigative Site 107
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Forest Investigative Site 072
  • Ohio
    • Avon Lake, Ohio, United States, 44012
      • Forest Investigative Site 069
    • Columbus, Ohio, United States, 43210
      • Forest Investigative Site 001
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73116
      • Forest Investigative Site 019
    • Tulsa, Oklahoma, United States, 74104
      • Forest Investigative Site 092
  • Oregon
    • Gresham, Oregon, United States, 97030
      • Forest Investigative Site 053
  • Pennsylvania
    • Johnstown, Pennsylvania, United States, 15904
      • Forest Investigative Site 132
    • McMurray, Pennsylvania, United States, 15317
      • Forest Investigative Site 131
    • Media, Pennsylvania, United States, 19063
      • Forest Investigative Site 100
  • South Carolina
    • Charleston, South Carolina, United States, 29407
      • Forest Investigative Site 105
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Forest Investigative Site 090
    • Nashville, Tennessee, United States, 37232
      • Forest Investigative Site 057
  • Texas
    • Houston, Texas, United States, 77090
      • Forest Investigative Site 051
    • The Woodlands, Texas, United States, 77381
      • Forest Investigative Site 070
  • Utah
    • Clinton, Utah, United States, 84015
      • Forest Investigative Site 028
    • Ogden, Utah, United States, 84405
      • Forest Investigative Site 141
    • Salt Lake City, Utah, United States, 84106
      • Forest Investigative Site 029
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Forest Investigative Site 064
    • Norfolk, Virginia, United States, 23507
      • Forest Investigative Site 113
  • Washington
    • Bothell, Washington, United States, 98011
      • Forest Investigative Site 071
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • Forest Investigative Site 119
  • Wisconsin
    • Middleton, Wisconsin, United States, 53562
      • Forest Investigative Site 063

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Completed at least 12 weeks of exposure to study drug in lead-in study MEM-MD-91 (NCT01592786)
2. Met responder criterion at two consecutive visits separated by at least two weeks in lead-in study MEM-MD-91
3. Provide written informed assent, when developmentally appropriate, to participate in the study before conduct of any study-specific procedures. The parent/guardian/LAR must provide written informed consent before the patient's participation in the study. A separate written informed consent for the caregiver must also be obtained before the conduct of any study specific procedures
4. Have a knowledgeable caregiver who is capable of providing reliable information about the patient's condition, attending all clinic visits with the patient, and overseeing the administration of study drug. Every effort should be made to maintain the same caregiver as used in the lead-in study throughout this study
5. Have normal results from the physical examination, laboratory tests, ECG, and vital signs at Visit 1 of this study (last visit of Study MEM-MD-91). Any abnormal findings must be deemed not clinically significant by the Investigator and documented
6. Be able to speak and understand English sufficiently (or their native language if this can be accommodated by the site), as well as have a caregiver and parent/guardian/LAR who is able to speak and understand English sufficiently (or their native language if this can be accommodated by the site), to comprehend the nature of the study and to allow for the completion of all study assessments
7. Have a family that is sufficiently organized and stable to guarantee adequate safety monitoring and continuous attendance to clinic visits for the duration of the study
8. Females who are 9 years and older or who have had onset of menses must have a negative urine pregnancy test at Visit 1
9. Age of 6 years to 12 years at the time of entry into lead in study MEM-MD-91

Exclusion Criteria:

1. Patients with a concurrent medical condition that might interfere with the conduct of the study, confound interpretation of the study results, or endanger the patient's well being
2. Significant risk of suicidality based on the Investigator's judgment, the Aberrant Behavior Checklist-Irritability subscale (ABC-I), or if appropriate, as indicated by a response of "yes" to questions 4 or 5 in the suicidal ideation section of the Children's C-SSRS (Columbia-Suicide Severity Rating Scale) or any suicidal behavior.
3. Patients with evidence or history of malignancy (other than excised basal cell carcinoma) or any significant hematologic, endocrine, cardiovascular (including any rhythm disorder), neurologic, respiratory, renal, hepatic, or gastrointestinal disease
4. Female patients of child-bearing potential who are not using or not willing to use a conventional method of contraception approved by the PI. Abstinence is an acceptable method of contraception
5. Patients requiring treatment with prohibited concomitant medications
6. Patients who, in the opinion of the Investigator, might not be suitable for the study
7. Employee or immediate relative of an employee of Forest Laboratories, Inc., any of its affiliates or partners, or the study center

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Memantine 1; Patients randomized to the full dose arm will continue taking memantine at the same tolerability and weight-based dose achieved in lead-in Study MEM-MD-91. Dosing will be once daily for up to 12 weeks.	Drug: Memantine Hydrochloride (HCl); Extended Release Dose ranging from 3-15mg/day; administered orally; Drug: Memantine Hydrochloride (HCl); Extended Release Dose ranging from 3mg every other day to 6mg/day; administered orally.
Experimental: Memantine 2; Patients randomized to the reduced dose arm will take memantine at the tolerability and weight based dose that they received in lead in Study MEM-MD-91 reduced by at least 50%. Dosing will be once daily for up to 12 weeks.	Drug: Memantine Hydrochloride (HCl); Extended Release Dose ranging from 3-15mg/day; administered orally; Drug: Memantine Hydrochloride (HCl); Extended Release Dose ranging from 3mg every other day to 6mg/day; administered orally.
Placebo Comparator: Placebo; Dosing will be once daily for up to 12 weeks.	Drug: Placebo capsules; Once daily, oral administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response (LTR) by the End of the Study (Based on Observed Cases)	Loss of Therapeutic response is defined as a worsening (increase) of at least 10 points in Social Responsiveness Scale (SRS) total raw score relative to the Visit 1 (randomization) score. The Social Responsiveness Scale (SRS) is a 65-item informant-rated assessment with total raw score 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.	Baseline (Visit 1) to week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Loss of Therapeutic (LTR) Response	Time to the first visit when a patient shows LTR following randomization to memantine or placebo.	Baseline to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Speech Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Syntax Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Semantics Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Coherence Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Initiation Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Scripted Language Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Context Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Nonverbal Communication Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Social Relations Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12
Change From Baseline in Children's Communication Checklist-2 (CCC-2) - Interests Subscale at Week 12	The Children's Communication Checklist-2 (CCC-2) is a validated, norm-referenced, informant-rated scale that evaluates difficulties (items 1-50) and strengths (items 51-70) in communication. There are 10 sub-scales consisting of 7 items each. 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).	Baseline (Visit 1) to week 12

Collaborators and Investigators

• Sponsor: Forest Laboratories
• Investigators: Study Director: Jordan Lateiner, MS, MBA, Forest Research Institute, Inc.- A Subsidiary of Forest Laboratories, Inc.

Publications and helpful links

General Publications

• Brignell A, Marraffa C, Williams K, May T. Memantine for autism spectrum disorder. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013845. doi: 10.1002/14651858.CD013845.pub2.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: May 3, 2012
• First Submitted That Met QC Criteria: May 4, 2012
• First Posted (Estimate): May 7, 2012

Study Record Updates

• Last Update Posted (Actual): April 24, 2019
• Last Update Submitted That Met QC Criteria: April 23, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Memantine; Asperger's; Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS); Pediatric Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Neurodevelopmental Disorders; Disease; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Developmental Disabilities; Asperger Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Memantine
• Other Study ID Numbers: MEM-MD-68