Abstract
Background: In patients with Alzheimer's disease (AD), it is of interest to determine whether therapy can prevent worsening across multiple clinical domains. In a previously reported, randomized trial in moderate AD (NCT00469456), memantine was superior to placebo at improving functional communication, as recognized by caregivers. Here we focus on patients from that trial who experienced worsening on three possible outcomes: a clinician's assessment of global status (CGI-C), a measure of the patient's language and functional communication (the Functional Linguistic Communication Inventory [FLCI]), and a caregiver's assessment of the patient's functional communication skills (the combined Social Communication and Communication of Basic Needs subscales of the American Speech-Language-Hearing Association - Functional Assessment of Communication Skills of Adults scale [ASHA-FACS]). Methods: Native English-speaking outpatients with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized study of memantine (20 mg/day; ITT n = 133) versus placebo (ITT n = 124). Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. In this post hoc analysis (LOCF), we selected patients who experienced any decline from baseline on the three outcome measures (CGI-C >4, FLCI <0, or ASHA-FACS <0). We also examined the subsets of patients in the CGI-C >4 subset who evidenced greater-than-mild decline on the FLCI (FLCI <-3) and ASHA-FACS (ASHA-FACS <-10). We then used Generalized Estimating Equations to compare treatment groups in terms of proportions of patients who fulfilled these criteria for double and triple outcome measure combinations at endpoint and overall (i.e., throughout the trial). Results: In the three possible double-outcome measure combinations for patients experiencing any decline, memantine treatment (vs. placebo) significantly prevented worsening at endpoint and overall for the ASHA-FACS/CGI-C combination and overall for the ASHA-FACS/FLCI combination (P < 0.05). No significant differences in prevention of worsening were observed for the FLCI/CGI-C double-outcome combination or for the triple-outcome combination. In the group that experienced greater-than mild decline, all three double-outcome combinations and the triple-outcome combination demonstrated significant prevention of worsening in the memantine group at endpoint and overall (P < 0.05). Conclusions: In patients with moderate AD, memantine is associated with a prevention of worsening in functional communication and global clinical status.