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Randomized Controlled Trial
. 2017 Jun;27(5):403-412.
doi: 10.1089/cap.2015.0146. Epub 2016 Mar 15.

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

Michael G Aman  1 , Robert L Findling  2 , Antonio Y Hardan  3 , Robert L Hendren  4 , Raun D Melmed  5 , Ola Kehinde-Nelson  6 , Hai-An Hsu  6 , Joel M Trugman  6 , Robert H Palmer  6 , Stephen M Graham  6 , Allyson T Gage  6 , James L Perhach  6 , Ephraim Katz  6
Affiliations
Randomized Controlled Trial

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

Michael G Aman et al. J Child Adolesc Psychopharmacol. 2017 Jun.

Abstract

Objective: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.

Methods: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.

Results: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.

Conclusions: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Keywords: Children's Communication Checklist-2; Social Responsiveness Scale; autistic disorder; core symptoms of autism; memantine extended release; tolerability, safety, and adverse events.

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Conflict of interest statement

In the past 36 months, Dr. Aman received research contracts from, consulted with, served on advisory boards of, or performed investigator training for Biomarin Pharmaceuticals, Bristol-Myers Squibb, CogState, Inc., CogState Clinical Trials, Ltd., Confluence Pharmaceutica, Coronado Biosciences, Forest Research Institute, Hoffman-La Roche, Janssen Pharmaceuticals, Johnson & Johnson, Lumos Pharma, MedAvante, Inc., Novartis, Pfizer, ProPhase LLC, and Supernus Pharmaceuticals. Dr. Findling receives or has received research support from, or acted as a consultant and/or served on a speaker's bureau for Alcobra, American Academy of Child & Adolescent Psychiatry, American Physician Institute, American Psychiatric Press, AstraZeneca, Bracket, Bristol-Myers Squibb, CogCubed, Cognition Group, Coronado Biosciences, Dana Foundation, Elsevier, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson and Johnson, Jubilant Clinsys, KemPharm, Lilly, Lundbeck, Merck, NIH, Neurim, Novartis, Noven, Otsuka, Oxford University Press, Pfizer, Physicians Postgraduate Press, Purdue, Rhodes Pharmaceuticals, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Transcept Pharmaceuticals, Validus, and WebMD. Dr. Hardan previously received research funding from Forest; he has no current conflicts of interest to disclose. Dr. Hendren received research grants from Autism Speaks, BioMarin Pharmaceuticals, Curemark, Forest, Roche, Shire, Sunovion, and the Vitamin D Council; is on Advisory Boards for BioMarin Pharmaceuticals, Forest, Janssen, and Neuren; and is a reviewer for Autism Speaks, Brain Canada, and Simons Foundation. Dr. Melmed received research support from Alcobra, Bristol‐Myers Squibb Company, Forest Laboratories Inc, Neurim, Novartis Pharmaceuticals, Roche Pharmaceuticals, and Seaside Pharmaceuticals during the past year. Ms. Kehinde-Nelson, and Drs. Hsu, Trugman, Palmer, Graham, Gage, Perhach, and Katz were employees of the study sponsor at the time of the study and are present or former stockholders of Forest (now Allergan). Dr. Trugman is currently an employee of the study sponsor.

Figures

<b>FIG. 1.</b>
FIG. 1.
Combined study design and dosing for MEM-MD-57A Part 2 and the open-label extension (OLEX). Dose titration in MEM-MD-67 only for participants who were previously randomized to placebo. Participants taking memantine ER during MEM-MD-57A continued with same dose.
<b>FIG. 2.</b>
FIG. 2.
Combined study flow for trials MEM-MD-57A (Part 1 and Part 2) and MEM-MD-67 (open-label extention [OLEX]). ITT indicates intention-to-treat. MEM-MD-57A Part 2 autism safety population: Subjects (n = 114) had only autistic disorder according to the Diagnostic and Statstical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR). The larger safety population (n = 121) included children with pervasive developmental disorder not otherwise specified (PDD-NOS) and/or Asperger's disorder.
<b>FIG. 3.</b>
FIG. 3.
Changes from baseline in Social Responsiveness Scale (SRS) total raw score (autism intent-to-treat [ITT] population). In the lead-in trial (MEM-MD-57A Part 2), mixed-effects model with repeated measures (MMRM) approach based on observed cases was performed, and in the open-label extention (OLEX) study (MEM-MD-67) only descriptive statistics were analyzed; therefore, the presented changes from baseline are least squares means from the MMRM model for MEM-MD-57A Part 2, and ordinary means for MEM-MD-67. Mem, extended-release memantine; Pbo, placebo; SEM, standard error of the mean.
<b>FIG. 4.</b>
FIG. 4.
Score changes from baseline at Week 12 (MEM-MD-57A Part 2: Pbo, Mem) and Week 60 or end of study (MEM-MD-67: Pbo/Mem, Mem/Mem) in Children's Communication Checklist, 2nd ed. (CCC-2) Subscales (autism intent-to-treat [ITT] population). In MEM-MD-57A Part 2 the mixed-effect model repeated measures (MMRM) approach based on observed cases was performed, and in MEM-MD-67 only descriptive statistics were analyzed. Therefore, the score changes from baseline are least squares means from MMRM model for MEM-MD-57A Part 2 and ordinary means for MEM-MD-67. *p = 0.02. Mem, extended-release memantine; Pbo, placebo; SEM, standard error of the mean.
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