A MULTICENTER DOUBLE-BLIND-STUDY OF CONTROLLED-RELEASE PHYSOSTIGMINE FOR THE TREATMENT OF SYMPTOMS SECONDARY TO ALZHEIMERS-DISEASE

Objective: A multicenter trial to evaluate the efficacy of controlled- release physostigmine salicylate, a cholinesterase inhibitor, was cond ucted in 1,111 mild-to-moderate Alzheimer's disease (AD) subjects. Des ign: During dose titration, subjects received 18, 24, or 30 mg of phys ostigmine or placebo daily. After a 2-week washout period, 366 subject s with putative improvement were randomized to receive either placebo or their best dose of physostigmine in a 6-week double-blind trial. No nresponding patients (439) were randomized to receive in a separate do uble-blind trial either placebo or their highest tolerated dose of phy sostigmine. The primary efficacy measures included the cognitive subsc ale of the Alzheimer Disease Assessment Scale (ADAS) and a Clinical Gl obal Impression of Change (CGIC). Secondary measures included the Mini -Mental State Examination and two activities-of-daily-living scales. R esults: At the end of the 6-week double-blind phase, physostigmine-tre ated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis. There was no significant improvement on the secondary outcome measures. Patients failing to respond to phy sostigmine during the dose titration phase failed to respond on any of the outcome measures during the double-blind period of re-exposure. C ommon adverse events included nausea, vomiting, diarrhea, and anorexia . There were no significant changes in Liver function tests. Conclusio n: This study demonstrated statistically significant differences betwe en physostigmine and placebo on both a performance-based cognitive fun ctioning instrument and a clinician's global evaluation. The magnitude of the effect size was small and occurred only in the subset of patie nts who responded in the initial dose titration study period. Neverthe less, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment .