P4‐230: Substituting placebo in long‐term trials with pre‐symptomatic Alzheimer's disease patients: The placebo group simulation approach (PGSA)

Abstract

Background: Top-line results of a 24-week, multinational, randomized, placebo-controlled trial in patients with moderate to severe Alzheimer’s disease (AD) receiving stable concurrent cholinesterase inhibitor treatment (MEM-MD-50, NCT00322153) demonstrated the efficacy of a new, extended-release (ER) formulation of memantine (28 mg, once daily) on primary outcome measures (SIB and CIBIC-plus), as well as on the NPI and a verbal fluency test. In this post-hoc analysis, we examined the effects of memantine ER on individual SIB domains, as well as on aggregated domains defined previously (Schmitt et al., 2006). Methods: Treatment groups were compared in terms of mean change from Baseline at Endpoint for nine SIB domains (Social Interaction, Memory, Orientation, Language, Attention, Praxis, Visuospatial Ability, Construction, and Orienting to Name) and combinations of domains aggregated using a face-valid approach into three higher-order subscales: MEMORY (memory, attention, orientation, orienting to naming), LANGUAGE (language, social interaction), and PRAXIS (praxis, visuospatial ability, construction). Between-group comparisons were based on the intent-to-treat population (placebo: n 1⁄4 328; memantine ER: n 1⁄4 333) and performed by means of an ANCOVAmodel with treatment group and study center as factors and baseline value as covariate, using observed cases (OC) and the last observation carried forward (LOCF) approach to missing data. In addition, a mixed-effects model with repeated measures (MMRM) that included terms for treatment group, visit, treatment-by-visit interaction, baseline score, baseline-by-treatment interaction, and center was used to compare the groups across the entire trial. No adjustments for multiple comparisons were made. Results: Significant advantage of memantine ER over placebo was observed for the domains of Memory (OC, P 1⁄4 0.021; LOCF, P 1⁄4 0.016; MMRM, P 1⁄4 0.008), Language (OC, P 1⁄4 0.003; LOCF, P 1⁄4 0.004; MMRM, P 1⁄4 0.001), Attention (OC, P 1⁄4 0.014; LOCF, P 1⁄4 0.003; MMRM, P 1⁄4 0.004), Praxis (OC, P 1⁄4 0.015; LOCF, P 1⁄4 0.002; MMRM, P 1⁄4 0.002), Orientation (LOCF, P 1⁄4 0.043; MMRM, P 1⁄4 0.028), and Construction (OC, P 1⁄4 0.042), and for all three higher-order subscales (MEMORY: OC, P 1⁄4 0.002; LOCF, P 1⁄4 0.003; MMRM P < 0. 001; LANGUAGE: OC, LOCF, P 1⁄4 0.003; MMRM, P 1⁄4 0.001; PRAXIS: OC, P 1⁄4 0.012; LOCF, P 1⁄4 0.004; MMRM, P 1⁄4 0.004). Conclusions: In this post-hoc analysis, memantine ER was associated with significant improvement relative to placebo on several cognitive domains, including memory, language, praxis, and attention.