Abstract
Objective: To investigate the efficacy and safety of donepezil in patients with moderate to severe AD (standardized Mini-Mental State Examination [sMMSE] scores of 5 to 17; Functional Assessment Staging score ≤6 at baseline).
Methods: Two-hundred ninety patients were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil 5 mg/day for the first 28 days and 10 mg/day thereafter as per the clinician’s judgment (n = 144) or placebo (n = 146). The primary outcome measure was the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+).
Results: Patients’ mean age was 73.6 years (range 48 to 92 years). Baseline demographics were similar between the treatment groups. Least squares (LS) mean ± SE sMMSE scores at baseline were 11.7 ± 0.35 for the donepezil group and 12.0 ± 0.34 for the placebo group. Patients receiving donepezil showed benefits on the CIBIC+, compared with placebo, at all visits up to week 24 (p < 0.001) and at week 24 last observation carried forward (LOCF) (p < 0.0001). All other secondary measures (including sMMSE, Severe Impairment Battery, Disability Assessment for Dementia, Functional Rating Scale, and Neuropsychiatric Inventory) showed significant differences between the groups in favor of donepezil at week 24 LOCF. Eighty-four percent of donepezil- and 86% of placebo-treated patients completed the trial. Adverse events (AE) were experienced by 83% of donepezil- and 80% of placebo-treated patients, the majority of which were rated mild in severity; 8% of donepezil- and 6% of placebo-treated patients discontinued because of AE. Laboratory and vital sign abnormalities were similar between the treatment groups.
Conclusion: These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with very good tolerability.
There are currently no approved treatments for the more advanced stages of AD. This represents an important gap in treatment, given the prevalence estimates of moderate to severe AD. In the Canadian Study of Health and Aging (CSHA), 46% of patients with dementia in the community were graded as mild severity, whereas 54% were classified as moderate or severe.1 In the institutional sample in the CSHA, only 11% were mild and 89% were moderate or severe. The assessment of treatment benefits in patients with moderate to severe AD is warranted, particularly to address the prominent functional losses and behavioral symptoms that occur in these stages.
In the 1970s, postmortem examinations of the brains of patients with largely end-stage AD reported markedly reduced activity of central cholinergic markers.2 These cholinergic deficits were reported to correlate with cognitive deficits and disease severity in AD.3 The cholinergic deficiency has also been linked to neuropsychiatric symptoms of AD,4-6⇓⇓ where medial frontal and limbic cholinergic deficits have been identified.7,8⇓ Cholinomimetic therapies may then improve both cognitive and noncognitive AD symptoms.
Donepezil is a reversible and highly centrally selective inhibitor of acetylcholinesterase (AChE) that has been shown to significantly improve cognition and maintain patient function in placebo-controlled trials of 6-month9,10⇓ to 1-year11,12⇓ duration in mild to moderate AD. The current study is the first placebo-controlled clinical trial of donepezil in patients with moderate to severe AD. It was undertaken to investigate donepezil’s efficacy on global function, cognition, activities of daily living (ADL), and behavior as well as its safety.
Methods.
Study design.
This trial was a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in patients with moderate to severe AD. It included 32 sites: 22 in Canada, 6 in Australia, and 4 in France. An initial screening visit was performed within 4 weeks of the baseline visit. At baseline, eligible patients were randomized in a 50/50 split using a computerized randomization schedule to 24 weeks of once-daily doses of either placebo or donepezil. Blinding was established with identical film-coated tablets within a blister-packaged card. The initial blister pack was for either 5 mg/day of donepezil or placebo for 28 days, following which the investigator could increase the dose of study drug or placebo equivalent to 10 mg/day to improve efficacy. The study medication could be reduced to 5 mg/day or placebo equivalent at any time during the study to improve tolerability as required, although 10 mg/day was the intended dose of study drug. At each study visit, the medication card from the previous treatment period was returned to the investigator, and percent compliance was calculated by dividing the number of doses taken by the number of days of the treatment period.
Before screening, written informed consent was obtained from both patients and their responsible caregivers or legal guardians. If the patient was not capable of providing informed consent, written consent was obtained from the patient’s representative and verbal assent was received from the patient. Caregivers could participate as collateral informants for the study if they had an estimated minimum contact of 8 hours three times a week. They were required to accompany the patient to each visit and complete several of the assessments both at home and at clinic visits. The study was conducted according to the Declaration of Helsinki.13 The protocol and its amendments were submitted to and approved by institutional review boards.
Patients.
All patients met criteria for either “clinically probable” or “clinically possible” AD according to the National Institute of Neurological and Communication Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria,14 with a screening standardized Mini-Mental State Examination (sMMSE)15 score of 5 to 17 inclusive and a Functional Assessment Staging Test (FAST)16 score of ≤6 at baseline. Patients residing in the community or in assisted living settings were allowed to participate; however, those requiring total nursing care were excluded. All patients were either ambulatory or ambulatory when aided with a walker or cane (not confined to a wheelchair). A CT or MRI scan within the previous 24 months had to be consistent with AD without any other significant comorbid pathologies.
Patients with concomitant illnesses such as controlled type I or type II diabetes mellitus, stable treated thyroid disease, and controlled hypertension (sitting diastolic blood pressure <95 mm Hg) were included. From a cardiac standpoint, patients could also be included if they had either a right bundle branch block (complete or partial) or a pacemaker. Patients were excluded if there was evidence of any cause for their dementia other than AD or if there was a complicating delirium, depression, or other concurrent diagnosis that might interfere with their participation in the study. Patients with other primary neurologic or psychiatric diagnoses were not allowed. Patients with a known or suspected history of drug or alcohol misuse in the prior 10 years were excluded, as were individuals with a known hypersensitivity to AChE inhibitors (AChEI). Also excluded were patients with clinically significant obstructive airway disease or asthma, hematologic or oncologic disorders within the last 2 years, B12 or folate deficiency, and active gastrointestinal, renal, hepatic, endocrine, or cardiovascular system disease.
Most concomitant medications were allowed except those with notable cholinomimetic or anticholinergic effects and investigational drugs. Daily treatments for behavioral abnormalities with loxapine, haloperidol, risperidone, zolpidem, oxazepam, and lorazepam were allowed provided that patients were on a stable dose of these drugs for a minimum of 4 weeks before the baseline visit and were to remain on the same dose for 4 weeks after the start of study medication. Patients not receiving psychoactive medications at entry were permitted to receive such therapy after a minimum of 4 weeks after the start of study medication. Rates of use of concomitant psychoactive medications during the study were calculated using the following three categories: treatment-emergent use, continued use, and cessation of use.
Outcome measures.
Efficacy.
The primary efficacy measure for the study was the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+).17 This semistructured interview, performed first with the caregiver and then with the patient, provided a global assessment of change at weeks 4, 8, 12, 18, and 24. The CIBIC+ version in this study was developed and validated by the Alzheimer’s Disease Study Cooperative Group.18 At baseline, the Clinician’s Interview-Based Impression of Severity (CIBIS) was used to rate the severity of disease on a 7-point scale. Subsequent to baseline, the CIBIC+ change scores were rated on a 7-point Likert-like Scale (LS), where 4 represented no change compared with baseline, 1 markedly improved, and 7 markedly worsened.
The secondary efficacy measures included two cognitive scales: the sMMSE,15 which has a 30-point range, and the Severe Impairment Battery (SIB),19 a 51-item scale with scores ranging from 0 to 100. Functional assessments included the Disability Assessment for Dementia (DAD),20 a 10-domain, 40-item instrument that measures instrumental and basic ADL, as well as the modified Instrumental Activities of Daily Living Scale (IADL+) and Physical Self-Maintenance Scale (PSMS+).21 The Neuropsychiatric Inventory (NPI),22 a 12-item, caregiver-rated instrument, was used to evaluate behavioral and neuropsychiatric symptoms including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy, disinhibition, irritability, aberrant motor behavior, night-time behavior, and appetite/eating disorders. The Functional Rating Scale (FRS),23 an eight-domain, multidimensional instrument with a 40-point sum of the boxes’ maximum score, was used to evaluate global functioning.
Other assessments included the Caregiver Stress Scale (CSS),24 the Health-Related Quality of Life of Caregivers (SF-36) questionnaire,25 and the Canadian Utilization of Services Tracking (CAUST) questionnaire.26 The CSS is a modified version of the 20-part, multiple-item scale by Pearlin et al.24 to assess caregiver stress. The SF-36 is an extensively validated quality-of-life scale that was self-rated by caregivers, and the CAUST is an assessment of health-care resource utilization and work productivity developed in Canada and modified for use in the other participating countries. The results of these other assessments in this trial will be discussed in a future article.
Safety.
Safety was evaluated by means of medical history, physical examinations, vital signs, clinical laboratory tests, and EKG as well as monitoring of adverse events (AE) throughout the study. Serious AE was defined as any AE that was life threatening or resulted in death, hospitalization, prolongation of hospitalization, or significant disability. The motoric domain of the Unified PD Rating Scale (UPDRS)27 was performed to evaluate the effects of donepezil on paratonia, rigidity, cogwheeling, and impairment of postural reflexes.
Statistical analysis.
Based on treatment effect sizes from a previous donepezil study in mild to moderate AD,9 a sample size of 96 patients in each treatment arm (192 in total) was estimated for α = 0.05 with 80% power to detect a 0.4 mean difference in CIBIC+ with an SD of 0.98. Accounting for higher rates of potential patient withdrawals in this more advanced AD population, 240 patients were to be included in the study in Canada. To facilitate recruitment, additional sites were later added in Australia and France to compensate for the anticipated drop in patient enrollment after the market launch of donepezil in Canada. This led to an actual sample size of 290.
The primary analysis of efficacy was based on the change from baseline score on the CIBIC+ at week 24 in the intent-to-treat population, using a last-observation-carried-forward (LOCF) analysis where there were missing values. The intent-to-treat population consisted of all randomized patients who took at least one dose of study medication and provided both a baseline assessment and at least one postbaseline efficacy assessment. Secondary analyses were carried out using an observed case analysis at each visit.
Efficacy variables at baseline were summarized using analysis-of-variance models with effects for center and treatment. All continuous variables with baseline assessment were analyzed at each time point and at week 24 LOCF. Analysis-of-covariance methods, with effects for treatment, center, and baseline, were used to assess treatment differences at each postbaseline visit. All statistical tests were two sided, and p values of ≤0.05 were considered significant. The Cochran–Mantel–Haenszel test, stratified by center, was used to assess the CIBIC+ as a categorical variable at week 24 LOCF.
The safety population consisted of all randomized patients who had taken at least one dose of study medication or for whom it was unknown whether they had taken any study medication but for whom there were postrandomization data. For the safety analysis, all observed AE were reported, regardless of suspected causal relationship to the study drug. These included adverse drug reactions, illnesses with symptom onset during the study or exacerbations of pre-existing illnesses, as well as objective test findings that resulted in a change in the study drug dosage. Rates for AE, laboratory abnormalities, and EKG changes were summarized. All statistical analyses were performed using SAS version 6.12 software (SAS Institute, Cary, NC).
Results.
Table 1 presents the demographic and baseline values for the study populations. There was no imbalance in demographic characteristics including age, sex, or race. The majority of patients were community dwelling (donepezil 87%, placebo 88%), and the remainder were in assisted living situations (donepezil 13%, placebo 12%). There were no significant differences between the treatment groups in the baseline scores on the CIBIS, sMMSE, SIB, DAD, IADL+, PSMS+, NPI, and FRS (table 1).
Patient demographic and baseline characteristics by treatment
The completion rates for the study were 84% in the donepezil group and 86% in placebo-treated patients (figure 1). The most common reasons for discontinuation were AE (8% donepezil, 6% placebo) and withdrawal of consent (3% donepezil, 5% placebo). There were 82% of donepezil- and 85% of placebo-treated patients who attained a maximum daily dosage of 10 mg of donepezil/placebo equivalent. Of these, 10% of donepezil patients and 5% of placebo patients subsequently had their daily dose lowered to 5 mg/day for tolerability. The mean compliance rate in both treatment groups was 98% at week 24.
Figure 1. Flow diagram of patient progress through the trial, including screening, randomization, and timing of assessments.
All patients had at least one comorbid medical condition at baseline. Similar profiles of other comorbid conditions were observed between the treatment groups, with the exception of arthropathies and related disorders, for which there was a higher incidence in the donepezil-treated group. Concomitant medications were used by nearly all patients (donepezil 97%, placebo 95%). Concomitant psychoactive medications were taken by 33% of donepezil-treated patients at baseline compared with 24% of placebo patients. During the study, this 9% difference was sustained between the treatment groups. The patterns of psychoactive medication use are presented in table 2. The most commonly used of the psychoactive medications were hypnotics, sedatives, and anxiolytics.
Psychoactive medication use during the trial
Efficacy.
Primary efficacy measure.
There were significant drug–placebo differences in the CIBIC+ scores at all visits (mean treatment difference = 0.54 at week 24 LOCF). As seen in figure 2, mean LS scores were above baseline severity for the donepezil-treated group until week 24, whereas the scores of the placebo-treated group declined throughout the study. At week 24 LOCF, 63% of donepezil- and 42% of placebo-treated patients were rated as improved or no change (p < 0.0001).
Figure 2. Clinician’s Interview-Based Impression of Change with caregiver input. Least squares (LS) mean ± SE scores for donepezil- and placebo-treated patients through 24 weeks of treatment. LOCF = last observation carried forward.
Secondary efficacy measures.
There were mean improvements in cognition, on both the sMMSE and the SIB, in the donepezil-treated group with mean differences from placebo that were significant at all visits throughout the trial (week 24 LOCF mean treatment difference = 1.79 on the sMMSE and 5.62 on the SIB; figure 3). However, the placebo decline on the SIB suggests a greater sensitivity to detect change in this population than the sMMSE.
Figure 3. Cognition. Least squares (LS) mean ± SE change from baseline scores for donepezil- and placebo-treated patients through 24 weeks of treatment, as measured using the standardized Mini-Mental State Examination (sMMSE) and Severe Impairment Battery (SIB). LOCF = last observation carried forward.
On the functional measures, including the DAD, IADL+, and PSMS+, there were significant differences in favor of donepezil treatment compared with placebo at week 24 LOCF. On the DAD, the donepezil-treated group remained stable throughout the study with a mean decline of only 0.74 point compared with the 8.98-point decline in the placebo group at week 24 LOCF (p < 0.0001; mean treatment difference = 8.23; figure 4). Subanalysis of the DAD (basic ADL only or instrumental ADL only) as well as the components of initiation, planning and organization, and effective performance for all ADL showed differences between the groups in favor of donepezil-treated patients at week 24 LOCF (p < 0.002). Similarly, the results of the IADL+ and PSMS+ showed less mean decline in the donepezil-treated group than placebo (week 24 LOCF mean treatment difference = 6.83 on the IADL+ [p < 0.0001] and 1.32 on the PSMS+ [p = 0.0015]).
Figure 4. Disability Assessment for Dementia (DAD). Least squares (LS) mean ± SE change from baseline scores for donepezil- and placebo-treated patients through 24 weeks of treatment. LOCF = last observation carried forward.
Behavioral and neuropsychiatric symptoms improved from baseline with donepezil by 4.6 points on the NPI total score at week 24 LOCF. There were fluctuations in the mean NPI total scores in the placebo group, with a decline of 1 point at week 24 LOCF (figure 5). The mean differences in NPI total scores were significant at weeks 4 and 24 and at week 24 LOCF (treatment difference 5.64). The outcome of patients using psychoactive medications at baseline (n = 47, donepezil; n = 35, placebo) was compared with that of those not using these medications (n = 97, donepezil; n = 111, placebo). For nonusers of psychoactive medications at baseline, there were significant differences between the two treatment groups in favor of donepezil on NPI total scores at all visits and at week 24 LOCF. In patients who were receiving psychoactive medications at baseline (table 2), differences between the groups favored donepezil on NPI total scores at weeks 4, 18, and 24 and at week 24 LOCF but were not significant. Individual NPI item analysis at week 24 LOCF showed an advantage for donepezil treatment compared with placebo on all items for the full intent-to-treat population, with significant differences between the groups for depression/dysphoria, anxiety, and apathy.
Figure 5. Neuropsychiatric Inventory (NPI). Least squares (LS) mean ± SE change from baseline scores for donepezil- and placebo-treated patients through 24 weeks of treatment. LOCF = last observation carried forward.
The FRS also showed a stabilization of global functioning in the donepezil-treated group, with a mean decline of 0.38 sum of the boxes compared with the 1.66 sum of boxes decline in the placebo group at week 24 LOCF (mean treatment difference = 1.28; p = 0.0002). For each visit from week 8 onward, there were significant differences for donepezil treatment compared with placebo.
Safety.
Eighty-three percent of donepezil- and 80% of placebo-treated patients experienced at least one AE during the course of the trial, of whom 8% of donepezil- and 6% of placebo-treated patients withdrew because of AE. The majority of AE (68%) were rated as mild in severity and in general were similar between treatment groups. AE rated moderate (26%) or severe (6%) were also similarly distributed between the groups. Table 3 shows the most common AE occurring in ≥5% of patients receiving donepezil.
Adverse events occurring in ≥5% of patients receiving donepezil
Weight loss was reported as an AE in 10 (7%) donepezil- and 6 (4%) placebo-treated patients. However, during actual weight measurements at each clinic visit, weight loss (defined as a decrease of ≥7% of baseline body weight at any time during the trial) was experienced by 10 (7%) donepezil- and 12 (8%) placebo-treated patients.
A total of 35 patients (13% donepezil and 12% placebo) experienced serious AE. In the donepezil-treated group, all of the serious AE were considered unrelated to donepezil by the investigator. There was a single death in the donepezil-treated group from a myocardial infarction that was considered to be unrelated to the treatment.
In this study, mean ± SE baseline UPDRS motor scores were 4.20 ± 0.66 for donepezil-treated patients and 4.18 ± 0.63 for placebo-treated patients. Mean changes from baseline at week 24 LOCF were 0.33 ± 0.75 for donepezil- and 2.04 ± 0.72 for placebo-treated patients (p = 0.062), where an increase in score represents an increase in extrapyramidal motor disturbance. Results of the subpopulations of patients with and without symptoms at baseline were similar to those of the total study population.
In general, there were no clinically meaningful differences between donepezil and placebo in the rates of laboratory or EKG abnormalities. Clinically meaningful bradycardia (defined as <60 beats/min and a reduction from baseline of at least 20% at any assessment during the trial, determined by auscultation) was experienced by 10% of donepezil-treated patients and 7% of those who received placebo. Bradycardia was reported as an AE in 1.4% of patients receiving donepezil (all were rated as mild) and in no patients receiving placebo. Vital signs generally remained normal during the course of the study and were similar for the two treatment groups.
Discussion.
There is evidence that cholinergic markers, particularly choline acetyltransferase (ChAT) as well as AChE, do not fall significantly until later AD stages.28 In addition, in earlier stages of AD, ChAT and vesicular acetylcholine transporter are reported to be relatively preserved.29 These observations suggest that donepezil could be beneficial for the symptomatic management of more advanced AD stages than those previously investigated.
Previous randomized, placebo-controlled clinical trials of donepezil and other AChEI in AD included patients with mild to moderate AD (baseline MMSE scores of 10 to 26).9,10,30,31⇓⇓⇓ In the registration studies of donepezil, patients had a mean ± SD MMSE score of 19.4 ± 4.7, and 75% of patients were staged at entry with Clinical Dementia Rating score of 1.9,32⇓ All patients in these studies were community dwelling, and those with prominent behavioral symptoms were generally excluded. The current trial studied patients with moderate to severe AD. The study sample included community-dwelling patients as well as patients in assisted living settings who still had measurable functional ability. The mean baseline scores on the sMMSE and DAD reflect this more advanced study population. Furthermore, the NPI total scores at baseline indicate higher levels of behavioral symptoms than in previous randomized, controlled trials of AChEI.33 This allowed an assessment of symptomatic benefits of donepezil on behavior in this study.
In selecting outcome measures for this study, it was imperative that the primary outcome be clinically meaningful. There were reservations about the perceived clinical relevance of a small but significant change on a cognitive outcome measure at this stage of disease, to the exclusion of the noncognitive symptoms. The CIBIC+ was then selected for its clinical relevance and for its structure, which allows for input from the caregiver and assessment of the patient. Its validation and short-term reliability, as well as demonstrated sensitivity to change, have previously been established in an AD population similar to the one used here.18 The secondary outcome measures, with the exception of the sMMSE, were all selected for their utility in this AD severity, where it was not anticipated that a floor effect would be encountered. The study results supported this expectation.
We found consistent benefits for donepezil across the full range of primary and secondary outcome measures, including global function, cognition, behavior, and ADL. The significant differences in favor of donepezil, at each visit on the CIBIC+, suggest that a clinical response to AChEI may be more readily evident in this severity of AD compared with milder disease. The converging benefits across all measures in the study indicate that this is a treatment effect and not a result of instrumentation and measurement.
Both the sMMSE and the SIB were used to assess cognition in this study. The SIB showed a significant sensitivity to change, allowing the measurement of both a decline from baseline in the placebo group (3.6 points) and an improvement from baseline in the donepezil group (2.1 points). These results contrast with the sMMSE, for which a floor effect was encountered in the placebo group, arguing against its utility as an outcome measure in clinical trials of more advanced AD.34 These data reinforce that there are measurable changes in cognition in the later stages of AD that can be a suitable outcome measure in future trials.
There was a stabilization in function with donepezil treatment in this study. Previously, it has been shown on the DAD that patients with moderate AD decline more rapidly than those with mild AD and that the baseline severity is important in predicting the subsequent rate of change.35 In the current study, the placebo decline is even larger than those recorded in mild to moderate AD study groups.35,36⇓ The finding that donepezil-treated patients maintained their baseline ADL becomes even more significant in the light of this placebo decline. Furthermore, it is likely, given the patterns of functional loss by this stage of disease, that patients will not recover lost functions on the DAD, making stabilization of function the best possible functional outcome. Such benefits were observed across both instrumental and basic ADL.
Previous trials of patients with mild to moderate AD have indicated that AChEI therapy may provide some relief from behavioral disturbances associated with AD.4,33,37⇓⇓ In this study, the donepezil-treated group showed significant improvement in the total NPI score. In addition, a trend across all items on the NPI favored donepezil, with significant benefits on apathy, depression, and anxiety. These findings reinforce the likelihood that cholinergic deficiencies do underlie some of the neuropsychiatric manifestations of AD and that donepezil treatment can be beneficial.
The safety data from this study indicate that the good tolerability profile observed with donepezil in patients with mild to moderate AD9,10⇓ is retained with progression of the disease into the moderate to severe stages. There was no induction or worsening of parkinsonism and no clinically meaningful weight loss or bradycardia with donepezil treatment. There was a higher incidence of arthralgias in the donepezil arm of the study; however, this group had higher rates of arthropathies and related disorders at entry into the study.
These study results in moderate to severe AD also have potentially important implications for future research. Moderate to severe AD may be a disease stage at which the metrics of the instruments used can readily capture therapeutic benefits. For proof of principle studies, it may be possible to use smaller sample sizes to test new treatments than is the case in milder AD.37 This could allow an improvement in the efficiency of phase II and III studies; however, there are ethical considerations that will also need to be faced in this context, for example, issues of informed consent and risks/benefits of the putative treatment.
Together with a good tolerability profile, resulting in few discontinuations, these data suggest that the benefits of donepezil extend into the moderate to severe stages of AD. A confirmatory study is currently being undertaken in patients with severe AD.
Appendix
Donepezil MSAD Study Investigators Group: P.-J. Albarède (Hôpital la Grave-Casselardit, Toulouse, France); D. Ames (Royal Melbourne Hospital, Parkville, VIC, Australia); R.J. Ancill (St. Vincent’s Hospital, Vancouver, BC, Canada); S. Atallah (Résidence de Montvenoux, Tarare, France); P. Bailey (Saint John, NB, Canada); S.E. Black (Sunnybrook Health Science Center, Toronto, ON, Canada); M.J. Borrie (Parkwood Hospital, London, ON, Canada); K. Boundy (Queen Elizabeth Hospital, Woodville, SA, Australia); R. Clarnette (Osborne Park Hospital, Stirling, WA, Australia); S. Cohen (Seniors’ Health Center, North York, ON, Canada); D.G. Darby (Austin and Repatriation Hospital, Heidelberg, VIC, Australia); M. Ewer (Adelaide Clinic, Gilberton, SA, Australia); K. Farcnik (Toronto Hospital Western Division, ON, Canada); R.D. Helme (National Ageing Research Institute, Parkville, VIC, Australia); D. Hogan (Health Sciences Center, Calgary, AB, Canada); A. Kertesz (St. Joseph’s Health Center, London, ON, Canada); C. Masters (Mental Health Research Institute, Parkville, VIC, Australia); J. Maupetit (CHG Hôpital Garderose, Libourne, France); P. McCracken (Glenrose Rehabilitation Hospital, Edmonton, AB, Canada); E. Mohr (Pacific Neuroscience Institute, Victoria, BC, Canada); D.W. Molloy (Hamilton Health Sciences Corporation, ON, Canada); M. Mordasini (Center Hospitalier de Ravenel, Mirecourt, France); A. Moscovitch (Canadian Sleep Institute, Calgary, AB, Canada); C. Patterson (Chedoke McMaster Hospital, Hamilton, ON, Canada); N. Pillay (M.C. Neurology Clinical Trials, Winnipeg, MB, Canada; currently at Peter Lougheed Hospital, Calgary, AB, Canada); K. Rabheru (London Psychiatric Hospital, ON, Canada); A. Rajput (Royal University Hospital, Saskatoon, SK, Canada); F. Rousseau (Hôpital Clinic Roy-Rousseau, Beauport, QC, Canada); D. Tessier (Institut Universitaire de Gérratrie de Sherbrooke, QC, Canada); F. Veloso (Pasqua Hospital, Regina, SK, Canada); and J. Willmer (Ottawa, ON, Canada).
Acknowledgments
Supported by Pfizer, Inc. (New York, NY) and Eisai, Inc. (Teaneck, NJ).
Acknowledgment
The authors thank Quintiles Inc. (Montreal, QC, Canada) for assisting in this research and PPS International Communications (Worthing, UK) for assisting in the development of this manuscript.
Footnotes
-
*See the Appendix on page 619 for a complete list of the members of the Donepezil MSAD Study Investigators Group.
- Received November 20, 2000.
- Accepted April 15, 2001.
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