A 40-week Phase 2B Randomized, Multicenter, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Memantine in Amyotrophic Lateral Sclerosis
Salman Bhai1, Robert Bowser2, Suzan Moser3, Deborah Taylor3, Andrew Heim4, Susan Woolley-Levine5, Dan Moore6, Todd Levine7, Richard Barohn3
1Neurology, University of Texas Southwestern Medical Center, 2Barrow Neurological Institute, 3University of Missouri, 4University of Kansas Medical Center, 5Syneos Health, 6Calico Consulting, 7Honor Health
Objective:

This trial tests the safety and efficacy of memantine for the treatment of ALS.

Background:

Memantine is a rational therapeutic agent for ALS because it partially addresses known underlying pathophysiologic mechanisms by blocking glutamate-mediated excitotoxicity, mitigating protein misfolding, and downregulating inflammatory pathways. Additionally, memantine, in other neurodegenerative conditions, improves cognitive and behavioral symptoms, present in nearly half of all ALS patients.  Small studies have been conducted evaluating the efficacy of memantine with conflicting results, thus providing the impetus for this larger study.

Design/Methods:

This is a 40-week, multicenter, randomized, double-blind, placebo-controlled study testing the safety and efficacy of memantine for the treatment of ALS. Subjects were between the ages of 18-85 with a possible, laboratory-supported probable, probable, or definite ALS by El-Escorial criteria; a Revised ALS Functional Rating Scale (ALSFRS-R) score >25; and had onset of symptoms within the three years prior to enrollment. Due to the COVID19 pandemic, remote enrollment and monitoring were instituted. All subjects were given a schedule to increase the total daily dose of memantine from 10 mg to 40 mg. The primary outcome was the change in ALSFRS-R and secondary outcomes assessed changes in neurofilament and cognitive and behavioral scores (ALS-Cognitive Behavioral Screen [CBS] and Neuropsychiatric Inventory [NPI]).

Results:

We enrolled 99 subjects and randomized 89 subjects. Patients treated with memantine (n=58) did not show a significant difference compared to placebo (n=31) in the rate of ALSFRS-R decline (-1.26 vs -1.23 monthly rate of decline, p=0.92). ALS-CBS and NPI did not significantly differ between the two groups. Serious adverse events were reported in 26% and 6% of subjects in the memantine and placebo groups, respectively. Neurofilament data is currently being analyzed and will be reported at the conference.

Conclusions:

Memantine did not slow the progression of ALS nor did it ameliorate the neurocognitive or behavioral effects of ALS.

10.1212/WNL.0000000000204223