← Back
NeuroTrials.ai
Neurology Clinical Trial Database

Donepezil Rogers

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease

Share Share Copied! Compare

Year of Publication: 1998

Authors: Rogers SL, Farlow MR, Doody RS, ..., Friedhoff LT; Donepezil Study Group

Journal: Neurology

Citation: Neurology 1998;50(1):136-145

Link: https://doi.org/10.1212/wnl.50.1.136

PDF: https://www.neurology.org/doi/pdf/10.1212/wnl.50.1.136

Clinical Question

Does donepezil, a selective acetylcholinesterase inhibitor, improve cognition and global clinical status in mild-to-moderate Alzheimer's disease?

Bottom Line

Donepezil 5 mg and 10 mg daily significantly improved cognition (ADAS-cog) and clinician global impression (CIBIC-plus) over 24 weeks in mild-to-moderate Alzheimer's disease. Benefit disappeared after a 6-week washout — a purely symptomatic effect. This trial established the foundation for the first well-tolerated, once-daily ChEI to receive FDA approval for AD.

Major Points

  • Phase 3, multicenter, 24-week double-blind placebo-controlled parallel-group trial with a 6-week single-blind placebo washout, conducted across U.S. sites
  • 473 patients with mild-to-moderate probable AD (NINCDS-ADRDA) randomized to placebo, donepezil 5 mg/day, or donepezil 10 mg/day
  • 10-mg group titrated from 5 mg over 4 weeks to minimize cholinergic AEs
  • Primary endpoints: ADAS-cog (cognition) and CIBIC-plus (clinician global rating of change). Secondary: MMSE, CDR-SB, patient-rated QoL
  • Both donepezil doses significantly superior to placebo on ADAS-cog at weeks 12, 18, and 24 (p<0.001); mean treatment differences ~2.5-2.9 points at week 24
  • CIBIC-plus significantly better in both donepezil groups vs placebo (p<0.01)
  • MMSE and CDR-SB favored donepezil; no consistent effect on patient-rated QoL
  • After 6-week placebo washout: ADAS-cog and CIBIC-plus scores converged with placebo — effect is purely symptomatic, not disease-modifying
  • AEs primarily cholinergic (nausea, diarrhea, insomnia, muscle cramps), mostly mild/transient, occurring predominantly during titration to 10 mg
  • Discontinuation due to AEs higher in the 10-mg arm; serum transaminase elevations — a major limitation of tacrine — were not seen with donepezil

Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial with open-label extension and placebo washout

Randomization: 1

Blinding: Double-blind (24-week treatment phase), single-blind (6-week placebo washout)

Enrollment Period: Mid-1990s

Follow-up Duration: 24-week treatment + 6-week placebo washout

Centers: 23

Countries: USA

Sample Size: 473

Analyzed: 473

Analysis: Intention-to-treat with last observation carried forward

Inclusion Criteria

  • Probable AD by NINCDS-ADRDA criteria
  • MMSE score 10-26
  • CDR 1 or 2
  • Stable general health and concurrent medications

Exclusion Criteria

  • Other CNS disease contributing to dementia
  • Active peptic ulcer disease
  • Significant hepatic, renal, endocrine, or cardiovascular disease
  • Prior ChEI use within 30 days
  • Psychotropic medications affecting cognitive assessment

Arms

FieldControlDonepezil 5 mgDonepezil 10 mg
N162154157
InterventionMatching placebo once dailyDonepezil 5 mg once dailyDonepezil 5 mg once daily for 4 weeks, then 10 mg once daily
Duration24 weeks + 6-week washout24 weeks + 6-week washout24 weeks + 6-week washout

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
ADAS-cog (cognitive sub-scale of Alzheimer's Disease Assessment Scale) and CIBIC-plus (Clinician's Interview-Based Impression of Change) at Week 24PrimaryADAS-cog worsened from baseline (placebo decline)ADAS-cog improved from baseline with 5 mg and 10 mg donepezilp<0.001 for ADAS-cog and p<0.01 for CIBIC-plus (both doses vs placebo)
Mean change in ADAS-cog at Week 24 (5 mg vs placebo)Secondary+1.8 points (worsening)-0.7 points (improvement)Difference ~2.5 pointsp<0.001
Mean change in ADAS-cog at Week 24 (10 mg vs placebo)Secondary+1.8 points (worsening)-1.1 points (improvement)Difference ~2.9 pointsp<0.001
CIBIC-plus ratings at Week 24 (5 mg)Secondarypredominantly no change or worseningsignificantly improved clinician-rated global impressionp<0.01
CIBIC-plus ratings at Week 24 (10 mg)Secondarypredominantly no change or worseningsignificantly improved clinician-rated global impressionp<0.01
MMSE change from baseline at Week 24Secondarydeclineimprovement in both donepezil dosesSignificant vs placebo
CDR-SB change from baseline at Week 24Secondarydeclineimprovement with donepezilSignificant vs placebo
Patient-rated Quality of Life (QoL)SecondaryNo changeNo consistent effectNot significant
ADAS-cog / CIBIC-plus after 6-week placebo washoutSecondaryUnchanged from end-of-treatmentReturned toward placebo-group levels — effect fully reversibleNo significant difference between groups after washout
Any adverse eventAdverse~72%~81% (5 mg); ~84% (10 mg)Higher in donepezil arms
NauseaAdverse~5%~8% (5 mg); ~17% (10 mg)Dose-dependent
DiarrheaAdverse~6%~9% (5 mg); ~17% (10 mg)Dose-dependent
InsomniaAdverse~5%~9% (5 mg); ~14% (10 mg)Dose-dependent
FatigueAdverse~3%~5% (5 mg); ~8% (10 mg)Dose-dependent
Muscle crampsAdverse~1%~6% (5 mg); ~8% (10 mg)Dose-dependent
Discontinuation due to adverse eventsAdverse~4%~4% (5 mg); ~13% (10 mg)Dose-dependent
Hepatotoxicity (transaminase elevation)AdverseNone observedNone observed — unlike tacrineNot applicable
Serious adverse eventsAdverseSimilar across armsSimilar across armsNot significant

Subgroup Analysis

Benefit on ADAS-cog was consistent across subgroups defined by age, sex, baseline MMSE severity, and concomitant medications. No a priori subgroup with differential response identified. 10 mg dose showed numerically larger effect than 5 mg but with more cholinergic AEs, largely during the 4-week titration phase.

Criticisms

  • Short 24-week treatment duration doesn't assess long-term benefit or delay of institutionalization
  • Washout confirmed symptomatic nature, limiting enthusiasm for disease-modification claims
  • MMSE-based enrollment excludes severe AD
  • Primarily US population limits external generalizability
  • Effect size on ADAS-cog (~2.5 points) is modest; clinical meaningfulness debated

Funding

Eisai Inc. and Pfizer (manufacturers of donepezil)

Based on: Donepezil Rogers (Neurology, 1998)

Authors: Rogers SL, Farlow MR, Doody RS, ..., Friedhoff LT; Donepezil Study Group

Citation: Neurology 1998;50(1):136-145

Content summarized and formatted by NeuroTrials.ai.