A 40-week Phase 2B Randomized, Multicenter, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Memantine in Amyotrophic Lateral Sclerosis (P8-8.011)

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. Disclosure: Dr. Bhai has received personal compensation in the range of $500-$4,999 for serving as a Consultant for KabaFusion. Dr. Bhai has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Fong Law. Dr. Bowser has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for MT Pharma USA. Dr. Bowser has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Bowser has stock in nVector. Dr. Bowser has received intellectual property interests from a discovery or technology relating to health care. Mrs. MOSER has stock in Medtronic. Mrs. MOSER has stock in Johnson and Johnson. Ms. Taylor has nothing to disclose. Andrew Heim has nothing to disclose. Susan Woolley-Levine has nothing to disclose. Dr. Moore has nothing to disclose. Dr. Levine has received personal compensation for serving as an employee of CND Life Sciences. Dr. Levine has received personal compensation for serving as an employee of Corinthian reference Labs. Dr. Levine has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Nufactor. Dr. Levine has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Grifols. Dr. Levine has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for PNA. Dr. Levine has received stock or an ownership interest from CND Life Sciences. Dr. Levine has received stock or an ownership interest from Corinthian reference lab. Dr. Barohn has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for NuFactor. The institution of Dr. Barohn has received research support from FDA OPD R01. Dr. Barohn has received intellectual property interests from a discovery or technology relating to health care.