Efficacy and safety of high-dose tacrine: A 30-week evaluation

Tacrine, a reversible, centrally active cholinesterase inhibitor, was evaluated for treatment of Alzheimer disease (AD) in doses up to 160 mg over a 30-week treatment period in a double-blind, placebo-controlled, parallel-group study. Men and women aged 50 years or older in otherwise good health with probable AD of mild-to-moderate severity were randomized to one of four treatment groups. Group I received placebo. Group II began tacrine at 40 mg/day for 6 weeks, then was given 80 mg/day for 24 weeks. Groups III and IV began tacrine at 40 mg/day for 6 weeks, then increased to 80 mg/day for 6 weeks and 120 mg/day for 6 weeks; Group III remained on tacrine 120 mg/day for a total of 18 weeks, and Group IV was escalated to 160 mg/day for the final 12 weeks. The primary outcome measures were the Clinician Interview-Based Impression (CIBI), the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog), and the Final Comprehensive Consensus Assessment (FCCA). Of 663 patients who entered the study, 279 completed the entire 30 weeks. Dose-response trends were statistically significant for all three primary outcome measures (p ≤ 0.001). Pairwise comparisons of tacrine 160 mg/day vs. placebo significantly favored tacrine on CIBI (p = 0.002), ADAS-Cog (p < 0.001), and FCCA (p < 0.001). Tacrine plasma levels were highly correlated with dose and response. Primary reasons for withdrawal in tacrine-treated patients were asymptomatic alanine aminotransferase (ALT) elevations (28%) and gastrointestinal complaints (16%). ALT elevations were reversible on treatment discontinuation, and 87% of discontinued patients were successfully rechallenged and maintained on long-term tacrine therapy. After 30 weeks of treatment, high doses of tacrine produced significant dose-related improvements on objective, performance-based tests (ADAS-Cog, Mini-Mental State Examination), which were clearly evident to the clinician as determined by the CIBI and FCCA. Family members reported significant improvements in quality-of-life measures.