A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group

Objective. —To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease. Design. —A 30-week randomized, double-blind, placebo-controlled, parallel-group trial. Setting. —Outpatients at 33 US centers. Patients. —Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health. Interventions. —Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks. Primary Outcome Measures. —Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale—Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA). Results. —A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P≤.05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P≤.001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P≤.002) and ADAS-Cog and FCCA (P≤.001), as well as caregiver-global and quality-of-life assessments (P≤.05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (16%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine. Conclusions. —Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study. (JAMA. 1994;271:985-991)