The 30 week trial conducted by Knapp and colleagues ⁹was one of the two pivotal trials for FDA approval of tacrine. The study was a double-blind, placebo-controlled, multi-center trial that enrolled 663 subjects. Dosages ranged from 80-160mg/day. A clear dose response relationship for tacrine was demonstrated; a mean drug-placebo difference at endpoint on the ADAS-Cog was 4.1 points for all evaluable patients in the (160 mg/day - p<0.001) group.

Comparative change in ADAS-Cog scores over 30 weeks 9

Statistically significant improvement was also noted on the CIBIC (p<0.002). When the data was analyzed by intent-to-treat analysis, it was determined that although the treatment effect was still significant, the mean drug-placebo ADAS-Cog difference at endpoint was 2.2 points. Of note is the fact that only 27% of the patients in the 160mg/day group tolerated this dose for the entire study period. The primary reasons for withdrawal from the study were asymptomatic hepatic transaminase elevations (28%) and GI distress in 16% of subjects.

Liver

Due to issues surrounding hepatotoxicity, mandatory monitoring of liver function tests throughout therapy, high incidence of peripheral cholinergic adverse effects, and the availability of safer alternative CHE-I, tacrine is rarely used.

 

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