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Open-Label, Multicenter, Phase 3 Extension Study of the Safety and Efficacy of Donepezil in Patients With Alzheimer Disease
Rachelle S. Doody, MD, PhD;
David S. Geldmacher, MD;
Barry Gordon, MD, PhD;
Carlos A. Perdomo, MS;
Raymond D. Pratt, PhD;
for the Donepezil Study Group
Arch Neurol. 2001;58:427-433.
ABSTRACT
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Background Donepezil hydrochloride is a selective acetylcholinesterase inhibitor
approved for the symptomatic treatment of mild to moderately severe Alzheimer
disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated
that donepezil treatment (5 and 10 mg/d) significantly improves cognition
and global function.
Objective To investigate the long-term benefits of donepezil treatment in patients
with AD.
Design Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind,
placebo-controlled clinical trials: a 15-week study (12 weeks of treatment
followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment
followed by a 6-week placebo washout).
Interventions All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks,
after which an increase to 10 mg/d was encouraged.
Measures Primary efficacy measures were the Alzheimer's Disease Assessment Scale–cognitive
subscale and the Clinical Dementia Rating–Sum of the Boxes.
Results After the shorter 3-week placebo washout, donepezil-associated benefits
remained above original baseline values for an additional 24 weeks of open-label
treatment. Benefits on Alzheimer's Disease Assessment Scale–cognitive
subscale scores for patients who received 10 mg/d in the double-blind study
were evident compared with the other groups for 108 weeks of open-label treatment.
In contrast, donepezil-associated benefits were lost after the 6-week placebo
washout, and scores decreased below original baseline values for all patient
groups. Although scores improved relative to the new open-label study baseline
scores after drug use was restarted, patients remained below original baseline
values. The most common adverse events were associated with the nervous and
digestive systems and were generally mild and transient; 17% of patient discontinuations
were associated with adverse events.
Conclusions Donepezil is an effective and safe drug for the long-term symptomatic
treatment of mild to moderately severe AD for up to 144 weeks (2.8 years),
and sustained treatment may confer some advantages.
INTRODUCTION
TO DATE, the most successful agents developed for the treatment of Alzheimer
disease (AD) are the acetylcholinesterase inhibitors,1, 2, 3, 4
of which donepezil hydrochloride is currently the most widely used. The clinical
benefits of donepezil treatment have been demonstrated in 4 clinical trials,3, 5, 6, 7 in which
significant improvements in cognition and global function have been observed
in studies of up to 24 weeks' duration. However, the optimal time for continuing
donepezil treatment beyond 24 weeks to maintain benefits remains an important
clinical question.
Results of an open-label phase 2 extension trial8
suggest that donepezil-associated benefits can be maintained for up to 1 year,
but these results might have underestimated the true effect of donepezil treatment
for 2 reasons. First, during the 12 weeks of the initial double-blind study,
most patients were treated with donepezil, 1 and 3 mg/d; these dosages are
now known to be subtherapeutic. Second, because of previous protocol restrictions,
most patients did not receive the most beneficial dosage of donepezil (10
mg/d) until 60 weeks after initiation of open-label treatment.8
Long-term use of donepezil is also supported by a favorable safety profile.
Preclinical trials have shown that donepezil preferentially inhibits brain
acetylcholinesterase, with little effect on cholinesterase of cardiac or smooth
intestinal muscles.5 This observation provides
a possible explanation for the few peripheral adverse events (AEs) reported
with the use of donepezil.9 Preclinical toxicology
investigations have shown that donepezil is not associated with hepatotoxicity
or unexpected toxic reactions.5 These impressions
have been confirmed in phase 2 trials10 and
3 clinical trials,3, 6, 7
in which donepezil has shown no dose-limiting hepatotoxicity.
To further assess the long-term efficacy and safety of donepezil administration,
this phase 3, open-label extension study evaluated treatment of patients with
effective dosages of donepezil (5 or 10 mg/d) from day 1 for up to 144 weeks.
It is recognized that open-label studies are not optimal; however, given that
there are practical and ethical difficulties in maintaining patients with
AD in long-term, placebo-controlled trials, this study provides important
evidence for the sustained efficacy of donepezil treatment.
PATIENTS AND METHODS
PATIENTS
Men and women aged 50 years and older who had successfully completed
1 of 2 US phase 3, double-blind clinical trials3, 6
were eligible for this extension study. Patients were required by the double-blind
study protocol to have an established diagnosis of AD, as defined by Diagnostic and Statistical Manual of Mental Disorders, Revised
Third Edition,11 category 290.00 or
290.10 and by National Institute of Neurological and Communicative Disorders
and Stroke–Alzheimer's Disease and Related Disorders Association guidelines.12 Patients were also required to have mild to moderately
severe AD at baseline of the double-blind trials, as defined by Mini-Mental
State Examination13 scores of 10 to 26 and
Clinical Dementia Rating (CDR)14 scores of
1 (mild) or 2 (moderate). Patients were otherwise generally healthy and ambulatory
or ambulatory aided. Women were surgically sterile or at least 2 years past
menopause.
Patients were excluded if they had evidence of other psychiatric or
neurological disease, other serious diseases that were not clinically stable,
type 1 or type 2 diabetes mellitus, alcoholism or drug misuse, a history of
a hematologic or oncologic disorder in the past 2 years, or known sensitivity
to acetylcholinesterase inhibitors. Most concomitant medications were allowed,
except investigational agents, cholinomimetic agents, and cholinergic antagonists.
Patients were excluded from this open-label study if they had withdrawn prematurely
from the initial double-blind studies.
This trial was conducted in compliance with the US Code of Federal Regulations
and the principles stated in the Declaration of Helsinki.15
STUDY DESIGN
This multicenter, open-label extension study was a continuation of 2
US phase 3, randomized, double-blind, placebo-controlled, clinical trials:
a 15-week study (study 301) comprising 12 weeks of treatment followed by a
3-week placebo washout3 and a 30-week study
(study 302) comprising 24 weeks of treatment followed by a 6-week placebo
washout.6 Study duration was 152 weeks: 144
weeks of treatment followed by an intended 8-week placebo washout. When donepezil
became commercially available, it was decided to allow all remaining patients
to continue therapy for a further 12 weeks, at which point the study was closed.
Thus, many patients left the study after several months to obtain donepezil
by prescription, and the final placebo washout period and subsequent evaluation
were not routinely performed.
At the start of the extension trial, all patients received single daily
doses of 5 mg of donepezil for the first 6 weeks, irrespective of the daily
dosage received during the initial double-blind studies. The dosage of donepezil
could be increased to single daily doses of 10 mg after the week 6 visit based
on the decision of the clinician and the overall drug tolerability of the
patient. Up to week 120, the dosage of donepezil could be reduced or increased
to 5 or 10 mg/d at the discretion of the investigator. Between weeks 120 and
144 (end of study), no dosage adjustments were permitted.
Safety and efficacy evaluations were undertaken at termination of the
double-blind study, after the placebo washout (cumulative week 15 or 30),
at weeks 6 and 12 of the open-label study, and at 12-week intervals thereafter.
Patients had to remain 80% compliant with the donepezil regimen to continue
in the open-label study.
EFFICACY EVALUATION
The primary efficacy measures were the Alzheimer's Disease Assessment
Scale–cognitive subscale (ADAS-Cog),16
an extensively validated scale for the assessment of cognitive performance,
and the CDR–Sum of the Boxes (CDR-SB),14
a global measure of dementia severity. The baseline for all efficacy measures
was the original baseline from study 301 or 302.
SAFETY EVALUATIONS
Safety was assessed by physical examination (including vital signs),
clinical laboratory tests (including hematologic analysis, clinical chemistry
analysis, and urinalysis), electrocardiography, monitoring of AEs, and evaluation
of general health and well-being. The baseline for all safety evaluations
was the week 0 visit of study 303, which, with few exceptions, was the termination
visit of study 301 (week 15) or study 302 (week 30).
All AEs, reported or observed, were recorded at each office visit and
classified in terms of severity, date of onset, duration, and investigator's
rating of relation to drug. Events were grouped by body system and assigned
preferred terms using the modified Coding Symbols for Thesaurus
of Adverse Reaction Terms (COSTART) dictionary.17
Medications were coded using a modified World Health Organization preferred
drug name dictionary.18
DATA ANALYSIS
The primary analysis of efficacy and safety included all patients who
received at least the first dose of study drug and provided at least 1 postbaseline
assessment. In the open-label phase, mean total scores (on the ADAS-Cog, CDR-SB,
and Mini-Mental State Examination) for observed cases at each office visit
were used to calculate mean changes from baseline scores. Standard errors
and 95% confidence intervals were also calculated to assess the separation
between the groups. Because of the open-label study design, using no comparator
placebo group, no statistical analyses were performed. A subanalysis of the
data was performed (mean and mean change from baseline) after stratifying
patients into groups based on the original double-blind treatment received.
For the safety analysis, AEs were defined as an AE that started with
or after administration of the first dose of study medication or a preexisting
condition that was exacerbated after initiation of treatment. Similarly, abnormal
laboratory values were defined as values that were within reference ranges
before but outside reference ranges after administration of the first dose
or preexisting abnormalities that deteriorated after the start of treatment.
Adverse events and abnormal laboratory values were also included if they occurred
within 30 days of discontinuing treatment.
RESULTS
PATIENT CHARACTERISTICS AND DISPOSITION
A total of 763 patients enrolled in this extension study (398 [85%]
of 468 patients from study 301 and 365 [77%] of 473 from study 302 (Figure 1). Demographic characteristics (age,
sex, and race), Mini-Mental State Examination scores, and CDR scores collected
at baseline in the double-blind studies were similar for both patient cohorts.
Overall, 96% of patients were taking concomitant medications; at least 20%
of patients took analgesics (54%), systemic antibacterials (43%), vitamins
(37%), psycholeptics (36%), and anti-inflammatory compounds (26%). Overall,
76% of patients were still receiving donepezil after 48 weeks of open-label
treatment, and 49% were still being treated with donepezil after 2 years (week
108; a high number of withdrawals took place at this stage due to donepezil's
commercial availability, leading to prescriptive use of the drug) (Figure 1). The most common reasons for study
discontinuation were study closure on commercialization of donepezil (46%),
AEs (17%), and request of patient or investigator (13%).
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Figure 1. Enrollment and completion of patients
through the double-blind and open-label phases of the study. In the open-label
phase, patients were encouraged to take 10 mg of donepezil daily, and more
than 90% did so.
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DOSAGE INCREASES
By week 12 of the open-label trial, the dosage of donepezil had been
increased from 5 mg/d to 10 mg/d for most patients (88%). After this point,
the percentage of patients receiving 10 mg/d varied between 92% and 97% for
the remainder of the study.
EFFICACY
ADAS-Cog Scores
During the double-blind studies (studies 301 and 302), all donepezil-treated
groups demonstrated statistically significant clinical benefits compared with
placebo-treated patients during the study and at the end point.3, 6
At entry into the extension study, patients had completed a placebo
washout of 3 or 6 weeks. During the 3-week washout (study 301), patients taking
donepezil did not experience a complete loss of treatment benefit before initiation
of open-label treatment.3 Consequently, the
effects of donepezil treatment on cognitive performance were still apparent
at the start of the open-label trial (cumulative week 15) (Figure 2).
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Figure 2. Mean change in Alzheimer's Disease
Assessment Scale–cognitive subscale (ADAS-Cog) scores from baseline
in the study 301 cohort stratified by treatment originally received in the
double-blind study. The double-blind study includes only patients enrolled
in the open-label study. In the open-label study, more than 90% of patients
received 10 mg of donepezil daily; the remainder received 5 mg of donepezil
daily.
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In contrast, during the longer, 6-week placebo washout (study 302),
donepezil-associated benefits were lost, with mean change in ADAS-Cog scores
from baseline for both active treatment groups declining to a level similar
to the mean change in the score for the placebo group.6
Thus, at the start of the open-label trial (cumulative week 30), the mean
change in ADAS-Cog scores from baseline for this patient cohort had declined
to below the initial baseline scores reported from study 302 by +3.06 points
for the 5- and 10-mg doses averaged (Figure
3). The mean change in ADAS-Cog scores from baseline did not improve
to the original baseline values of the double-blind study at any time throughout
the open-label extension study. However, improvements were observed relative
to the new baseline of the open-label study, and these improvements were maintained
for a further 24 weeks (cumulative week 54).
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Figure 3. Mean change in Alzheimer's Disease
Assessment Scale–cognitive subscale (ADAS-Cog) scores from baseline
in the study 302 cohort stratified by treatment originally received in the
double-blind study. The double-blind study includes only patients enrolled
in the open-label study. In the open-label study, more than 90% of patients
received 10 mg of donepezil daily; the remainder received 5 mg of donepezil
daily.
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When patients from study 301 were examined based on the treatment they
received during the original double-blind trial, a differential response was
observed (Figure 2). The mean change
in ADAS-Cog scores from baseline for patients originally randomized to receive
5 mg of donepezil daily and placebo began to decline to below baseline values
from week 12 of the open-label study (cumulative week 27). In contrast, patients
who had initially received 10 mg of donepezil daily continued to show improvement
compared with baseline for 24 weeks, declining to below baseline values by
week 36 of the open-label study (cumulative week 51) but showing less decline
compared with the other groups until week 108 (cumulative week 123). Because
the effects of donepezil therapy were completely washed out in the study 302
cohort, and all patients were starting below their original baseline value,
there was no differential response observed with respect to the treatment
patients received in the double-blind phase (Figure 3).
Changes in ADAS-Cog scores after 1, 2, and 3 years of donepezil treatment
by treatment received in the double-blind studies are shown in Table 1. Patients who originally received placebo in the double-blind
studies showed a larger decline in ADAS-Cog scores after 1, 2, and 3 years
of donepezil treatment than did those who had taken donepezil from the beginning
of the double-blind studies, presumably because of the delayed start of treatment.
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Comparison of the Cumulative Mean Change in ADAS-Cog Scores From Baseline*
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CDR-SB Scores
After the 3-week placebo washout, the mean change in CDR-SB scores from
baseline for patients originally in study 301 were at or improved with respect
to the original baseline, irrespective of the treatment received during the
double-blind study.3 Once patients began open-label
therapy, their scores remained improved compared with baseline scores for
24 weeks (cumulative week 39), after which time scores gradually declined
(data not shown).
After the 6-week placebo washout, the mean change in CDR-SB scores from
baseline for all of the study 302 double-blind treatment groups had declined
to below the original baseline values.6 However,
once patients began open-label therapy, their scores remained at, or close
to, the new baseline value (week 0 of the extension study, cumulative week
30) for 12 weeks (cumulative week 42) (data not shown).
SAFETY
Adverse events were generally mild and transient, resolving without
the need for dose modifications; the most common AEs were associated with
the nervous and digestive systems. Overall, 92% of patients experienced at
least 1 AE; AEs occurring in 10% or more of patients were urinary tract infection
(23%), accident (20%), pain (19%), agitation (19%), diarrhea (14%), insomnia
(13%), depression (12%), headache (10%), and nausea (10%). Only 3 of these
events were considered by the investigator to be related to donepezil treatment
in most patients: diarrhea (62% considered possibly or definitely related),
nausea (65%), and headache (62%). Selected AEs (those that occurred more frequently
with donepezil use than with placebo use in previous double-blind, placebo-controlled
trials3, 6, 7) occurred
predominantly during the first 24 weeks of treatment. Two hundred fourteen
patients (28%) experienced a serious AE; 203 patients (27%) experienced nonfatal
serious AEs, none of which were considered possibly related to donepezil treatment
in more than 1% of patients who experienced the serious AE. The incidence
of discontinuations related to AEs was low (128 patients [17%]).
There were 37 deaths (5% of patients) during the study or within 4 weeks
of discontinuation or completion of the study; cancer (10 patients) and progression
of AD (5 patients) were the most common causes of death. For 33 patients,
death was considered to be unrelated to donepezil treatment. The role of donepezil
treatment could not be ruled out by the investigator in the other 4 deaths
(2 myocardial infarctions and 2 unknown causes). Death due to myocardial infarction
or other causes has not been associated with donepezil treatment in any previous
studies.
No clinically significant, donepezil-related changes were apparent in
the results of the clinical laboratory tests, physical examinations, or electrocardiograms.
By radial pulse rate, bradycardia (defined as a heart rate  50 bpm) was
observed in 138 patients (18%) at some point during the study, although only
9 patients (1%) were reported by the investigator as having bradycardia as
an AE. Of these 9 events, 7 were judged to be possibly related to use of the
study medication, with 4 resulting in withdrawal from the study and 2 being
considered serious AEs. The earliest occurrence of bradycardia as an AE was
noted at week 12, with most cases recorded after week 26.
Use of concomitant medications increased during the study from 7% in
weeks 0 to 6 to 22% in weeks 85 to 120. Two therapeutic classes, antidepressants
and psycholeptics, showed a progressive increase in use through weeks 49 to
84.
COMMENT
In this open-label extension study, when patients were examined with
respect to original double-blind study group (study 301 or 302), differences
in response were observed. After the 6-week placebo washout, the benefits
of 24 weeks of treatment with donepezil on cognition and global function were
completely lost in the study 302 cohort. Scores on the ADAS-Cog and CDR-SB
at the start of the extension trial had declined to below the original baseline
values, and although cognitive and functional benefits of donepezil treatment
were observed for these patients during open-label treatment, they did not
improve to their original baseline levels. These data suggest that interrupting
donepezil treatment for as long as 6 weeks might result in patients not returning
to the levels of cognition and global function that they had attained before
interruption, taking into account the deterioration expected with the passage
of time.
Patients from study 301 underwent a shorter, 3-week placebo washout
and, as a consequence, the donepezil-associated benefits observed during the
double-blind period were not completely lost. The efficacy scores for these
patients remained improved from baseline at the end of placebo washout. Patients
who received 10 mg of donepezil daily during the double-blind period showed
the largest and most sustained response during the open-label period. Mean
ADAS-Cog scores remained at or improved with respect to baseline for almost
a year (51 weeks) of treatment (mean change from baseline score at week 51,
+0.57), exceeding the time above baseline observed for the placebo or 5 mg/d
groups (mean change from baseline scores at week 51, +1.92 and +1.93, respectively).
This is supported by better outcomes found on all measures for 10 mg/d (after
4-6 weeks at 5 mg/d) vs 5 mg/d in all previous studies.3, 6, 7, 10
The results of this study suggest that patients who receive 10 mg of donepezil
daily without interruption achieve the best long-term outcome.
Furthermore, the results suggest that if initiation of treatment is
delayed, patients might not have the opportunity to attain maximal benefits
because of more advanced disease. In study 301, although patients treated
with placebo for 3 months before starting donepezil treatment had a similar
initial treatment response as those who received donepezil, 10 mg/d, for 3
months, they were unable to achieve the same level of cognitive function because
they were starting from a lower baseline level.
Donepezil has been shown to have an excellent safety and tolerability
profile in patients with AD,3, 6
including those with a variety of comorbid conditions and taking concomitant
medications.19, 20 In this study,
donepezil was well tolerated during long-term treatment, with approximately
half of the original patient cohort still receiving donepezil after 2 years.
This is an excellent result considering not only the unrelenting progression
of the disease but also that 46% of patients withdrew to receive donepezil
by prescription when it became commercially available. Although 92% of patients
experienced at least 1 AE, this slightly higher incidence than in the preceding
placebo-controlled trials3, 6 was
likely related to the long study duration. The incidence of AEs resulting
in discontinuations was low (17%) and was comparable to the rates reported
in shorter-term clinical trials.3, 6, 7
During the extension trial, use of concomitant medications, in particular
psycholeptics and antidepressants, increased. This observation is consistent
with the progressive changes in cognitive and behavioral symptoms observed
in patients with AD.
In conclusion, the results of this extension trial strongly suggest
that donepezil is an effective agent for long-term treatment of mild to moderately
severe AD based on clinical data up to 144 weeks (2.8 years). At the very
least, conservative interpretations suggest that patients taking 10 mg of
donepezil daily, with uninterrupted treatment, can expect to perform better
than baseline after 1 year. The data from this study suggest that patients
do best when taking 10 mg of donepezil daily and when the dosage is maintained
at that level without interruption. Donepezil treatment effects that are lost
after prolonged discontinuation are not fully recovered when drug treatment
is restarted.
AUTHOR INFORMATION
Accepted for publication November 10, 2000.
This study was supported by Eisai Inc, Teaneck, NJ, and Eisai Co Ltd,
Tokyo, Japan.
We thank PPS International Communications, Worthing, England, for assistance
in the development of the manuscript.
Donepezil Study Group Investigators
Bruce Albala, CNS Bioservices, Pleasantville, NY; Milton Alter, Lankenau
Hospital, Wynnewood, Pa; Jeffrey T. Apter, Woodlands Professional Building,
Princeton, NJ; Barry Baumel, NeuroMedical Research Associates, Tamarac, Fla;
Gary Booker, Louisiana State University Medical Center, Shreveport; Walter
Brown, Clinical Studies Ltd, East Providence, RI; Christopher Clark, University
of Pennsylvania Medical Center, Philadelphia; Stanley Cohan, Georgetown University
Medical Center, Washington, DC; James Dexter, University of Missouri, Columbia;
Martin R. Farlow, Indiana University School of Medicine, Indianapolis; Mildred
Farmer, Clinical Studies, Florida, St Petersburg; John P. Feighner, Feighner
Research Institute, San Diego, Calif; Steven Ferris, New York University Medical
Center, New York; David G. Folks, University of Nebraska Medical Center, Omaha;
David G. Gorman, Lovelace Science Resources Inc, Albuquerque, NM; George Hanna,
Fontaine Research Park, Charlottesville, Va; Jon F. Heiser, Pharmacology Research
Institute, Newport Beach, Calif; Richard Hubbard, Southwest Institute of Clinical
Research, Rancho Mirage, Calif; Claire Jurkowski, Hampton Hospital, West Hampton,
NJ; F. Cleveland Kinney, University of Alabama–Birmingham; K. Ranga
Krishnan, Duke University Medical Center, Durham, NC; Richard Margolin, Vanderbilt
University Medical Center, Nashville, Tenn; James McCarthy, Clinical Studies,
Cape Cod, South Yarmouth, Mass; Henry Nasrallah, Ohio State University, Columbus;
Rodney J. Pelchat, Thomas Jefferson Medical College, Philadelphia; Carl H.
Sadowsky, West Palm Beach Neurology Group, West Palm Beach, Fla; Mary Sano,
Columbia University, New York, NY; Frederick W. Schaerf, Medical Studies,
Florida, Fort Myers; Lon Schneider, University of Southern California School
of Medicine, Los Angeles; Benjamin Seltzer, Tulane Medical School, New Orleans,
La; Alan Siegal, Hamden, Conn; Stuart R. Stark, The Neurology Center, Alexandria,
Va; Abbey Strauss, Clinical Studies, Boynton Beach, Fla; Larry Tune, Wesley
Woods Geriatric Hospital, Atlanta, Ga; Thomas Walshe, Advanced Treatment Strategies
Inc, Arlington, Mass; James Webster, Northwestern Memorial Hospital, Chicago,
Ill; Myron Weiner, University of Texas, Dallas; and Troy Williams, Clinical
Studies, Arizona, Peoria.
From the Department of Neurology, Baylor College of Medicine, Houston,
Tex (Dr Doody); University Hospitals of Cleveland and the Department of Neurology,
Case Western Reserve University, Cleveland, Ohio (Dr Geldmacher); the Departments
of Neurology and Cognitive Science, Johns Hopkins University School of Medicine,
Baltimore, Md (Dr Gordon); and Biometrics (Mr Perdomo) and Clinical Research
(Dr Pratt), Eisai Inc, Teaneck, NJ. A complete list of the Donepezil Study
Group investigators appears on page 429. Dr Doody has received research support,
consulting fees, and honoraria from Eisai Inc and Pfizer. Dr Geldmacher has
received consulting fees and honoraria from Eisai Inc and research support,
consulting fees, and honoraria from Pfizer, and he holds minority stock interest
in Pfizer. Dr Gordon has received research support, consulting fees, and speaker
fees from Eisai Inc and Pfizer. Drs Perdomo and Pratt are full-time employess
of Eisai Inc.
Corresponding author and reprints: Rachelle S. Doody, MD, PhD, Department
of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston,
TX 77030-3498.
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