A 24-week randomized trial of controlled-release physostigmine in patients with Alzheimer's disease.

OBJECTIVE

To evaluate the safety and efficacy of controlled-release physostigmine, an acetylcholinesterase inhibitor, in patients with probable AD of mild to moderate severity.

METHODS

A prospective, 24-week, randomized, multicenter, double-blind, parallel group study of patients was conducted. The study enrolled 475 patients at 24 sites. Patients met criteria for probable AD and were randomized to one of three arms: placebo, controlled-release (CR) physostigmine 30 mg daily, or CR physostigmine 36 mg daily. Dosage was escalated by a forced upward titration during the first 6 to 9 weeks of the trial, then maintained at a constant dose to 24 weeks. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-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.

RESULTS

In an intent-to-treat population, the last observation carried forward analysis revealed a 2.9-point ADAS-Cog (p = 0.002) difference between physostigmine 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 differences 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 including nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain for patients on either dose of physostigmine, resulting in a high dropout rate. Agitation was decreased significantly. There was no evidence of cardiac rhythm disturbance or liver function abnormalities.

CONCLUSION

CR physostigmine enhanced cognitive and global function. It is relatively safe for the treatment of cognitive dysfunction secondary to AD. However, in light of the gastrointestinal side effects, a lower starting dose and a flexible titration schedule might lead to a more favorable adverse event profile in the clinical arena.