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.

Decades of Progress in the Psychopharmacology of Autism Spectrum Disorder

“…multi-site study in Europe on memantine in ASD and OCD struggled with serious recruitment difficulty was ultimately terminated (Hage et al, 2016;"Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes (TACTICS)," 2018). A series of 3 large, multi-site studies, one of which was a double-blind placebo-controlled randomized withdrawal trial, and the rest of which were open-label, had mixed results (Hardan et al, 2019). The initial study (MEM-MD-91) was open label and was used to identify memantine responders (as defined by ≥ 10 point reduction in SRS total raw score from baseline at 2 consecutive visits); 517 participants (59.6%) were deemed confirmed responders.…”

An Examination of Changes in Urinary Metabolites and Behaviors with the Use of Leucovorin Calcium in Children with Autism Spectrum Disorder (ASD)

“…Interestingly, there was a non-significant improvement in social responsiveness as assessed by parents (7.8 points, effect size = 0.52) which is a medium effect size. While a minimal clinically important difference (MCID) for the SRS in children with autism has not been determined in children with ASD, some authors have suggested using a change in the SRS of > 10 to indicate a MCID and to address the concern that smaller changes may be within the range of a placebo effect (Hardan et al 2019). The non-significant change of .8 points observed in this study is below this proposed MCID threshold but still a signal of a large enough change to warrant further investigation in larger, placebo-controlled studies.…”

Neurocognitive Outcomes from Memantine: A Pilot, Double-Blind, Placebo-Controlled Trial in Children with Autism Spectrum Disorder

“…Memantine and placebo were initiated at 3 mg and the dose was titrated up by 3 mg a week to a maximum of dose of 6, 9, or 12 mg depending on weight and tolerability with dose adjustments conducted between biweekly study visits as needed. Maximum daily doses per weight classes are as follows: 20-40 kg (6 mg), 40-60 kg (9 mg), and >60 kg (12 mg) and were informed by FDA submissions from Forest Pharmaceuticals for trials of memantine ER (Aman et al 2017; Hardan et al 2019). In the Forest Pharmaceuticals trial, the maximum dose for the highest weight category was 3 mg higher than this evaluation of neurocognitive outcomes.…”

“…Another report from the same investigative group reported on a series of trials of memantine ER in ASD: (1) a 50-week open-label, lead-in trial to identify responders; (2) a 12-week randomized, double-blind, placebo-controlled RCT; and (3) <48-week openlabel extension to the double-blind RCT that was discontinued early (Hardan et al 2019). Together, the studies enrolled 906 verbal children with ASD across 118 sites worldwide.…”

“…Toward this effort, we report on a 24-week randomized, double-blind, placebocontrolled trial focused on memory, language, and motor outcomes in children with ASD. The study follows several safety and efficacy protocol elements outlined in Aman et al ( 2017) and Hardan et al (2019) to facilitate comparison.…”