Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease: results of a pooled analysis of two randomized, double-blind, placebo-controlled trials in Japan

Abstract

Background: With the increase in the aging population, there is a pressing need to provide effective treatment options for individuals with Alzheimer's disease (AD). Memantine is an N-methyl-D-aspartate receptor antagonist used to treat AD in > 80 countries worldwide, and studies in the USA and Europe have shown it to be effective in improving language deficits; however, there are currently no data on language improvements in Japanese patients treated with memantine.

Objectives: To clarify the efficacy and safety of memantine in Japanese outpatients with moderate to severe AD, using a pooled analysis of two multicenter randomized placebo-controlled trials, a phase 2 dose-finding study and a phase 3 study.

Results: The final analysis comprised 633 patients (318 receiving memantine and 315 placebo). Memantine produced better outcomes in terms of Severe Impairment Battery-Japanese version, Clinician's Interview-Based Impression of Change plus-Japanese version, Behavioral Pathology in AD Rating Scale, and language scores, versus placebo. The overall incidence of adverse events and adverse reactions was similar between groups.

Conclusion: In this pooled analysis of Japanese patients, memantine achieved better outcomes than placebo in terms of cognition, including attention, praxis, visuospatial ability and language, and behavioral and psychological symptoms, including activity disturbances and aggressiveness.

Figure 1.

Patient disposition in the two studies combined . Seven patients were excluded from the full analysis set because of a lack of post-baseline efficacy data. Of these seven patients, three patients in each memantine group did not undergo post-baseline assessments because of eligibility violations or data for the primary efficacy endpoints (Severe Impairment Battery-Language-Japanese and Clinician's Interview-Based Impression of Change plus-Japanese) were missing, and one patient in the placebo group was suspected of having Creutzfeldt–Jacob disease, which was verified by genetic analysis, and was withdrawn from the study before the postbaseline evaluations.

Figure 2.

Time course of change in total Severe Impairment Battery-Japanese version scores for OC (full analysis set) and change from baseline to week 24 with LOCF. The difference between the FAS (633 patients; memantine, n = 618; placebo, n = 615) and LOCF (631 patients) is due to a lack of baseline data in two patients.

Figure 3.

Summary statistics of domain-specific changes in Severe Impairment Battery-Japanese version scores from baseline to week 24 (full analysis set, last observation carried forward analysis). The difference between the FAS (633 patients; memantine, n = 618; placebo, n = 615) and LOCF (631 patients) is due to a lack of baseline data in two patients.

Figure 4.

Time course of mean changes from baseline in Severe Impairment Battery Language-Japanese version scores for OC (full analysis set) and change from baseline to week 24 with LOCF. The difference between the FAS (633 patients; memantine, n = 618; placebo, n = 615) and LOCF (631 patients) is due to a lack of baseline data in two patients.

Figure 5.

A. Proportion of patients showing worsening of Severe Impairment Battery-Language-Japanese version (SIB-J) scores at week 24 (full analysis set, last observation carried forward analysis) stratified by SIB-L-J baseline score (≤ 20 or > 20). B. Time course of changes in the proportion of patients with worsening in SIB-J score stratified by SIB-L-J baseline score (≤ 20 or > 20).

Figure 6.

Time course of global assessment score based on the Clinician's Interview-Based Impression of Change plus-Japanese (CIBIC plus-J) for OC and change from baseline to week 24 with LOCF. The difference between the FAS (633 patients; memantine, n = 618; placebo, n = 615) and LOCF (632 patients) is due to a lack of baseline data in one patient.

Figure 7.

Time course of change in total Behavioral Pathology in Alzheimer's Disease Rating Scale score for OC and change from baseline to week 24 with LOCF. The difference between the FAS (633 patients; memantine, n = 618; placebo, n = 615) and LOCF (632 patients) is due to a lack of baseline data in one patient.

Figure 8.

Summary statistics of domain-specific score changes in Behavioral Pathology in Alzheimer's Disease Rating Scale from baseline to week 24 (last observation carried forward analysis).

Figure 9.

The occurrence of new symptoms of aggressiveness in patients without aggressiveness at baseline.