Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies

Abstract

Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

Keywords: Asperger’s disorder; Social Responsiveness Scale; autism spectrum disorders; clinical trial; medication; memantine; pervasive developmental disorder-not otherwise specified; randomized withdrawal; school-age children.

Figure 1.

Trial MEM-MD-91 Study Flow. ITT: intention-to-treat.

Figure 2.

Trial MEM-MD-68 Study Flow. ITT: intention-to-treat, LTR: loss of therapeutic response.

Figure 3.

Trial MEM-MD-91 Study Flow.

Figure 4.

Cumulative percentage of patients achieving a 10-point minimum improvement in SRS total raw score from baseline among a) all patients, and b) confirmed responders (Open-label Trial MEM-MD-91). CDF: cumulative distribution function, PDD-NOS: pervasive developmental disorder-not otherwise specified, SRS: social responsiveness scale.

Figure 5.

Survival distribution for LTR by treatment group (Double-blind, Placebo-controlled trial MEM-MD-68). P1 is the P value for the treatment comparison between memantine full-dose and placebo based on log-rank test stratified by Autism Spectrum Disorder subtype. P2 is the P value for the treatment comparison between memantine reduced-dose and placebo based on log-rank test stratified by Autism Spectrum Disorder subtype.

Figure 6.

Cumulative percentages of patients achieving a given change from baseline in SRS total raw score (Double-blind, Placebo-controlled trial MEM-MD-68). CDF: cumulative distribution function, SRS: social responsiveness scale.

Figure 7.

Cumulative percentages of patients achieving a given change from baseline in SRS total raw score by treatment group and overall (inset) (Open-label Trial MEM-MD-69). CDF: cumulative distribution function, SRS: social responsiveness scale.