Efficacy and safety of eptastigmine for the treatment of patients with Alzheimer's disease

Objective: To evaluate the efficacy and safety of eptastigmine in patients with moderate to moderately severe AD. Background: Eptastigmine is a centra lly acting cholinesterase inhibitor. Methods: The study was carried out acc ording a multicenter, randomized, double-blinded, placebo-controlled, paral lel-group design. Patients received a 24-week treatment with placebo or ept astigmine 15 mg or 20 mg three times daily after a 4-week, stepwise dose es calation. The effects of treatment on cognition, global function, and activ ities of daily living were evaluated with the Alzheimer's Disease Assessmen t Cognitive Subscale (ADAS-Cog), the Clinician's Interview-Based Impression of Change Plus (CIBIC-Plus), and the Instrumental Activities of Daily Livi ng scale (IADL), respectively. Results: Thirty-six centers recruited 491 pa tients: 164 on placebo, 166 on eptastigmine 15 mg three times daily, and 16 1 on eptastigmine 20 mg three times daily. Percentages of patients completi ng double-blinded treatment were 87% in the placebo group and 86% in both t he eptastigmine-treated groups. At the end of treatment, the intent-to-trea t analysis on 463 patients showed a dose-dependent effect of eptastigmine o n all efficacy variables, with a statistically significant effect of the 20 mg three times daily dose compared with placebo on the ADAS-Cog, CIBIC-Plu s, and IADL. Patients on eptastigmine 15 mg three times daily performed sig nificantly better than placebo-treated patients only on the ADAS-Cog. Eleve n patients on placebo (7%), 13 patients on eptastigmine 15 mg three times d aily (8%), and 12 patients on eptastigmine 20 mg three times daily (8%) dis continued study treatment because of adverse events. Adverse events were re corded in 49% of patients on placebo compared with 54% on eptastigmine 15 m g three times daily and 48% on eptastigmine 20 mg three times daily. Cholin ergic side effects (nausea, vomiting, diarrhea, and abdominal pain) were re ported with similar frequency in the eptastigmine- and placebo-treated pati ents. There was a dose-dependent transient and mild neutropenic effect asso ciated with eptastigmine treatment, and one patient on 20 mg three times da ily had an asymptomatic pancytopenia. Conclusions: Eptastigmine produces si gnificant cognitive, clinical, and functional benefits in patients with pro bable AD. Although the cholinergic tolerability of eptastigmine was found t o be favorable, its potential adverse hematalogic effects limit its clinica l utility.