A 24-week randomized trial of controlled-release physostigmine in patientswith Alzheimer's disease

Objective: To evaluate the safety and efficacy of controlled-release physos tigmine, an acetylcholinesterase inhibitor, in patients with probable AD of mild to moderate severity. Methods: A prospective, 24-week, randomized, mu lticenter, double-blind, parallel group study of patients was conducted. Th e study enrolled 475 patients at 24 sites. Patients met criteria for probab le AD and were randomized to one Of three arms: placebo, controlled-release (CR) physostigmine 30 mg daily, or CR physostigmine 36 mg daily. Dosage wa s escalated by a forced upward titration during the first 6 to 9 weeks of t he trial, then maintained at a constant dose to 24 weeks. Primary outcome m easures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (A DAS-Cog) and the Clinician's Interview-Based Impression of Change-Plus with caregiver input (CIBIC+). Secondary outcome measures included the Clinical Global Impression of Change (CGIC), the Geriatric Evaluation by Relatives Rating Instrument, and an Instrumental Activities of Daily Living Scale. Re sults: In an intent-to-treat population, the last observation carried forwa rd analysis revealed a 2.9-point ADAS-Cog (p = 0.002) difference between ph ysostigmine and placebo-treated patients for both dosages, and a 0.26 to 0. 31-point difference on the CIBIC + (p = 0.048). There were no significant d ifferences on the secondary outcome measures except for a difference on the CGIC when analyzed by use of the Cochran-Mantel-Haenszel statistic (p = 0. 014). There were significant increases in gastrointestinal side effects inc luding nausea, vomiting, diarrhea, anorexia! dyspepsia, and abdominal pain for patients on either dose of physostigmine resulting in a high dropout ra te. Agitation was decreased significantly. There was no evidence of cardiac rhythm disturbance or liver function abnormalities. Conclusion: CR physost igmine enhanced cognitive and global function. It is relatively safe for th e treatment of cognitive dysfunction secondary to AD. However, in light of the gastrointestinal side effects, a lower starting dose and a flexible tit ration schedule might lead to-a more favorable adverse event profile in the clinical arena.