A 24-week randomized trial of controlled-release physostigmine in patients with
Alzheimer's disease.
Author(s): Thal LJ, Ferguson JM, Mintzer J, Raskin A, Targum SD.
Affiliation(s): Department of Neurosciences, University of California, San Diego School of
Medicine, La Jolla 92093-0624, USA.
Publication date & source: 1999, Neurology. , 52(6):1146-52
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.
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