At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease.

BACKGROUND: Consensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer's disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit. OBJECTIVES: To estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI). DESIGN: Retrospective anchor- and distribution-based analyses of data from the ADC-008 (NCT00000173) study were used to estimate thresholds for meaningful within-patient change on the target measures. SETTING: Analyses were conducted using data from ADC-008 a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study among participants with the amnestic subtype of MCI, which was conducted by the Alzheimer's Disease Cooperative Study (ADCS) between March 1999 and January 2004 in the United States and Canada. PARTICIPANTS: Analyses were based on 769 eligible participants who completed the baseline assessment from 69 ADCS sites in the United States and Canada. MEASUREMENTS: The target outcome measures for this analysis included the CDR-SB, the ADAS-Cog, and the MMSE. The anchor measures for this analysis included the Global Deterioration Scale and the MCI-Clinical Global Impression of Change. RESULTS: Focusing on the 12-month time point, within-patient increases of 1-2.5 points in the CDR-SB and increases of 2-5 points on the 11-item ADAS-Cog and 13-item ADAS-Cog, on average, reflect minimal-to-moderate levels of deterioration, respectively. CONCLUSIONS: These thresholds may be useful to aid the interpretation of Alzheimer's disease clinical trial data by illustrating meaningful within-patient progression over the course of a clinical trial via supplementary progressor analyses, which may in turn be informative for treatment decisions. Estimates generated via these methods are specifically intended to evaluate within-patient change and are not intended to assess the magnitude and meaningfulness of differences between group-level changes over time.

Chinese Version of the Baylor Profound Mental Status Examination: A Brief Staging Measure for Patients with Severe Alzheimer's Disease.

BACKGROUND: A specialized instrument for assessing the cognition of patients with severe Alzheimer's disease (AD) is needed in China. OBJECTIVES: To validate the Chinese version of the Baylor Profound Mental Status Examination (BPMSE-Ch). DESIGN: The BPMSE is a simplified scale which has proved to be a reliable and valid tool for evaluating patients with moderate to severe AD, it is worthwhile to extend the use of it to Chinese patients with AD. SETTING: Patients were assessed from the Memory Clinic Outpatient. PARTICIPANTS: All participants were diagnosed as having probable AD by assessment. MEASUREMENTS: The BPMSE was translated into Chinese and back translated. The BPMSE-Ch was administered to 102 AD patients with a Mini-Mental State Examination (MMSE) score below 17. We assessed the internal consistency, reliability, and construct validity between the BPMSE-Ch and MMSE, Severe Impairment Battery (SIB), Global Deterioration Scale (GDS-1), Geriatric Depression Scale(GDS-2), Instrumental Activities of Daily Living (IADL), Physical Self-Maintenance Scale (PSMS), Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). RESULTS: The BPMSE-Ch showed good internal consistency (α = 0.87); inter-rater and test-retest reliability were both excellent, ranging from 0.91 to 0.99. The construct validity of the measure was also supported by significant correlations with MMSE, SIB. Moreover, as expected, the BMPSE-Ch had a lower floor effect than the MMSE, but a ceiling effect existed for patients with MMSE scores above 11. CONCLUSIONS: The BPMSE-Ch is a reliable and valid tool for evaluating cognitive function in Chinese patients with severe AD.

Korean version of the Baylor Profound Mental Status Examination: a brief staging measure for patients with severe Alzheimer's disease.

BACKGROUND: The Baylor Profound Mental Status Examination (BPMSE) was modeled to provide a brief patient-derived rating scale for staging and tracking patients with severe stages of Alzheimer's disease (AD). METHODS: The BPMSE was administered to 91 patients with probable AD (Korean version of the MMSE less than 16) according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. The patients were also evaluated using the Korean version of the Severe Impairment Battery (SIB-Ko), Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), Barthel Activities of Daily Living (B-ADL), the Korean version of the Instrumental Activities of Daily Living (K-IADL), the Korean version of the Neuropsychiatric Inventory (K-NPI) and the Functional Assessment Staging (FAST). RESULTS: There were significant correlations between the BPMSE- Ko and K-MMSE scores (r = 0.66, p < 0.001) and between the BPMSE-Ko and SIB-Ko scores (r = 0.83, p < 0.001). The BPMSE-Ko correlated with the CDR, GDS, B-ADL, K-IADL, K-NPI and FAST scores (p < 0.001). The BPMSE-Ko scores continued to decline even after the K-MMSE reached values near 0. CONCLUSIONS: The BPMSE-Ko is a time efficient and useful tool to measure cognitive function in patients with severe AD.

Importance of subtle amnestic and nonamnestic deficits in mild cognitive impairment: prognosis and conversion to dementia.

BACKGROUND/AIMS: To evaluate baseline characteristics and conversion to dementia in mild cognitive impairment (MCI) subtypes. METHODS: We prospectively evaluated conversion to dementia in 106 patients with amnestic MCI (A-MCI) as defined by Petersen's operationalized criteria on a paragraph recall task, amnestic-subthreshold MCI (AS-MCI) as defined by impairment on the ADAS-cog delayed word list recall with normal paragraph recall, nonamnestic MCI (NA-MCI) defined by a nonmemory domain, and in 27 patients with subjective memory loss who had no deficit on formal neuropsychological testing. RESULTS: For all MCI subtypes, the 4-year conversion to dementia was 56% (14% annually) and to AD was 46% (11% annually). Conversion to AD in the A-MCI (56%) was similar to the rate in AS-MCI (50%). Conversion to AD in the A-MCI and AS-MCI combined was 56% (14% annually). Conversion to dementia in the NA-MCI was 52% (13% annually) and the majority converted to AD (62%). CONCLUSIONS: All MCI subtypes are at risk of converting to AD if the groups are carefully defined by an abnormal psychometric domain. All subtypes except subjective memory loss converted to AD at higher than expected rates. Both the A-MCI and AS-MCI subtypes had a similarly high rate of conversion to AD. The deficit on a word list recall task may develop before an abnormality on delayed paragraph recall is evident, at least in some subjects.

Realistic expectations for treatment success in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive degenerative disease that warrants active management to delay or slow progression of its symptoms. The symptoms of AD encompass behavior and daily function as well as cognition, so clinicians should take a global view in the assessment of treatment success. Because there is currently no cure for AD, one cannot expect an initial cognitive improvement observed in the first few months of therapy to be sustained indefinitely. However, one should expect that the patient who is treated early and persistently with medication for AD will show less evidence of behavioral, functional, and cognitive deterioration over a period of time than one would expect in the absence of pharmacotherapy. Thus, treatment success includes not only short-term improvement of symptoms but also less decline over the long term. Determination of treatment success therefore also requires awareness of the typical progression of untreated AD. In this article we review the natural history of AD and evidence for the effectiveness of the treatments indicated for AD: donepezil, galantamine, rivastigmine, and memantine.

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group.

BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus). RESULTS: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. CONCLUSION: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease.

The family medical history: assessing patient understanding of diabetes mellitus.

In this preliminary study, we attempted to determine whether diabetic subjects with a positive family medical history for diabetes have a better understanding of their own disease (ie., of its course, treatment, and genetic characteristics) than diabetic subjects without diabetes in their histories. We interviewed 50 diabetic subjects and scored their responses to determine their understanding of diabetes in general and in their own cases in particular. The data were analyzed using the Student's t test and chi-square analysis. Overall, patients with positive histories did not have significantly higher understanding than patients with negative histories. However, if patients had extensive exposure to the affected relative, or if tht relative was a spouse or a parent, the patients' understanding was significantly higher (P less than 0.05). Educational level, age, and duration of diabetes did not affect patients' understanding. The data suggest that the family medical history can be a valuable teaching model, once we redefine it so as to reconcile patient concepts about illness with physician concepts of disease.

A method for estimating progression rates in Alzheimer disease.

BACKGROUND: The ability to predict progression of disease in patients with Alzheimer disease (AD) would aid clinicians, improve the validation of biomarkers, and contribute to alternative study designs for AD therapies. OBJECTIVE: To test a calculated rate of initial decline prior to the first physician visit (preprogression rate) for its ability to predict progression during subsequent follow-up. METHODS: We calculated preprogression rates for 298 patients with probable or possible AD (using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations (NINCDS-ADRDA) with a formula using expected Mini-Mental State Examination (MMSE) scores, scores at presentation, and a standardized estimate of duration. The patients are being followed up longitudinally in our Alzheimer Disease Research Center. The time to clinically meaningful deterioration, defined as an MMSE score drop of 5 or more points, was compared for patients stratified as slow, intermediate, and rapid progressors based on the preprogression rate. Cox regression analysis was used to examine the contribution of demographic variables (age, sex, ethnicity, and level of education), initial MMSE scores, estimated symptom duration, and the calculated preprogression rate to the time it took to reach the end point across the groups. RESULTS: Both initial MMSE (hazard ratio, 0.95 (0.002); z = 4.19; P<.001) and the calculated preprogression rate (hazard ratio, 1.06 (0.019); z = 3.16; P =.002) were significant in determining time to clinically meaningful decline during longitudinal follow-up (Cox regression analysis). Slow, intermediate, and rapid progressors (based on preprogression rates) experienced significantly different time intervals to clinically meaningful deterioration, with the slow progressors taking the longest time, the intermediate progressors in the middle, and the rapid progressors reaching the end point first (log rank chi(2)(1) = 9.81, P =.002). CONCLUSION: An easily calculable rate of early disease progression can classify patients as rapid, intermediate, or slow progressors with good predictive value, even at initial presentation.

Establishing the limits of the Mini-Mental State. Examination of 'subtests'.

It has been suggested that the Mini-Mental State examination can be used to examine a patient's cognitive profile. We therefore examined the validity of Mini-Mental State subtests and individual items. The memory item, attention-concentration items, and constructional item had satisfactory sensitivity-specificity and correlated significantly with scores on neuropsychological tests. In contrast, four of the five Mini-Mental State language items had very low sensitivity, and three of five failed to correlate with neuropsychological test scores. These findings establish limits with regard to the ability of the Mini-Mental State to generate a cognitive profile. Our data also provide information regarding validity, difficulty level, and optimal cutoff scores for widely used mental status tasks.

Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease.

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.

The influence of handedness on the clinical presentation and neuropsychology of Alzheimer disease.

BACKGROUND: Research on the influence of handedness on the clinical presentation and neuropsychology of Alzheimer disease (AD) is scarce. OBJECTIVE: To compare clinical presentation and neuropsychological test performance of right- and left-handed patients with AD. DESIGN: We hypothesized that left-handedness would be associated with younger onset, more rapid progression, and possibly cognitive hemispheric asymmetry. After determining handedness with the Edinburgh Inventory for Handedness for 922 patients with AD, 18 left-handed patients were compared with 18 right-handed patients matched individually on Mini-Mental State Examination scores, education, and age. We compared clinical characteristics (eg, age of onset), estimated rate of initial cognitive decline, language and visuospatial test performances, and patterns of cognitive and motor asymmetries for the 2 groups. SETTING: Alzheimer's Disease Research Center at Baylor College of Medicine, Houston, Tex. MAIN OUTCOME MEASURES: Results of the Wechsler Adult Intelligence Scale-Revised verbal and performance IQ tests, the Western Aphasia Battery sequential commands subtest, the Boston Naming Test, the Halstead-Reitan Finger-Tapping Test, and the calculated Rate of Initial Progression. RESULTS: We found that left-handed patients had younger ages of onset but unexpectedly lower estimated rates of initial cognitive decline, and their results on language tests did not differ from those of right-handed patients. Regarding asymmetry, left-handed patients were more likely than right-handers to obtain lower verbal IQ than performance IQ scores and to exhibit faster finger-tapping speeds with their nondominant hand, but group differences did not attain statistical significance. There were disproportionately few left-handed patients with AD compared with population norms. CONCLUSIONS: Left-handed patients with AD do not differ from right-handed patients in the severity or pattern of neuropsychological deficits. Left-handedness or some factor associated with it may contribute to the early appearance of cognitive deficits during the development of Alzheimer disease, but may temper the subsequent rate of progression of deficits.

Neuropsychological functioning in cortical-basal ganglionic degeneration: Differentiation from Alzheimer's disease.

Patients with cortical-basal ganglionic degeneration (CBGD) display prominent rigidity and apraxia, exhibit an asymmetric onset of symptoms, and may show other symptoms including abnormal saccadic eye movements, the "alien limb" sign, limb dystonia, and myoclonus. We compared the neuropsychological test performances of 21 CBGD patients with 21 Alzheimer's disease (AD) patients displaying no extrapyramidal symptoms and with 12 ADA patients who did show such symptoms. Groups were matched for age, educational level, and overall severity of dementia. Since the cognitive deficit was mild in most CBGD patients, most AD patients included in this study were also only mildly demented. The CBGD patients performed significantly better than the AD patients on test of immediate and delayed recall of verbal material; whereas the AD patients (with or without extrapyramidal symptoms) performed better on tests of praxis, finger tapping speed, and motor programming. The CBGD and AD groups all displayed prominent deficits on tests of sustained attention/mental control and verbal fluency, and exhibited mild deficits on confrontation naming. The CBGD patients endorsed significantly more depressive symptoms on the Geriatric Depression Scale.

Incidence and prevalence of dementia in a multiethnic cohort of municipal retirees.

BACKGROUND: Multiethnic population-based studies of dementia are lacking in the literature; therefore, we conducted a study to determine the incidence and prevalence of dementia among, black, white, and Hispanic municipal retirees age 50 and older. METHODS: In 1991, city of Houston municipal workers who retired between 1980 and 1984 received in-home screening for cognitive impairment using the Mini-Mental State Examination and were referred for comprehensive neurologic evaluation if indicated. Families of deceased retirees were interviewed, medical records were reviewed, and death certificates were obtained to determine case status of the retiree. Study participation was 90%. RESULTS: Crude prevalence of dementia, among retirees age 60 and older, was 2.65 per 100 population. Age-adjusted to the 1970 US population, age 60 to 80, the prevalence was 1.85 per 100 population. Age-adjusted prevalence of dementia was similar among Hispanic and black men, 4.75 and 4.80 respectively, and lowest among white men, 2.42 per 100 population. Forty-three percent of the prevalent cases (30% of the incidence cases) were not previously diagnosed. The cumulative incidence of dementia calculated to age 80 was 39% for Hispanic men, 28% for black men, and 14% for white men. Fifty-five percent of the incidence cases were diagnosed as having ischemic vascular dementia (IVD), 20% as having probable or possible Alzheimer's dementia (AD), and 25% as having unspecified dementia. CONCLUSIONS: Risk of dementia by age 80 was more pronounced for Hispanic and black men compared with white men. IVD was the predominant cause of dementia among both black and white men. Grouping Hispanics with whites may mask differences when studying dementia.

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

The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.

A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients.

OBJECTIVE: To examine the effects of donepezil compared with placebo on the preservation of function in patients with AD over a 1-year period. METHODS: This was a prospective, 54-week, double-blind, placebo-controlled, survival to endpoint study. Patients were required to have at entry: a diagnosis of probable AD (National Institute of Neurological and Communicative Disorders and Stroke criteria); Mini-Mental State Examination score of 12 to 20; Clinical Dementia Rating of 1 or 2; modified Hachinski ischemia score < or =4; and capability of performing 8 of 10 instrumental activities of daily living and 5 of 6 basic activities of daily living. Patients (n = 431) were randomized to placebo or donepezil (5 mg/day for 28 days, 10 mg/day thereafter). Outcome measures were the AD Functional Assessment and Change Scale, the Mini-Mental State Examination, and Clinical Dementia Rating scale. At each visit, investigators determined whether predefined criteria for clinically evident decline in functional status had been met. Patients who met the endpoint criteria were discontinued per protocol. RESULTS: Donepezil extended the median time to clinically evident functional decline by 5 months versus placebo. The probability of patients treated with donepezil remaining in the study with no clinically evident functional loss was 51% at 48 weeks, compared with 35% for placebo. The Kaplan-Meier survival curves for the two treatment groups were different (p = 0.002, log-rank test). CONCLUSIONS: Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.

Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To define and investigate key issues in the management of dementia and to make literature-based treatment recommendations. METHODS: The authors searched the literature for four clinical questions: 1) Does pharmacotherapy for cognitive symptoms improve outcomes in patients with dementia? 2) Does pharmacotherapy for noncognitive symptoms improve outcomes in patients with dementia? 3) Do educational interventions improve outcomes in patients and/or caregivers? 4) Do other nonpharmacologic interventions improve outcomes in patients and/or caregivers? RESULTS: Cholinesterase inhibitors benefit patients with AD (Standard), although the average benefit appears small; vitamin E likely delays the time to clinical worsening (Guideline); selegiline, other antioxidants, anti-inflammatories, and estrogen require further study. Antipsychotics are effective for agitation or psychosis in patients with dementia where environmental manipulation fails (Standard), and antidepressants are effective in depressed patients with dementia (Guideline). Educational programs should be offered to family caregivers to improve caregiver satisfaction and to delay the time to nursing home placement (Guideline). Staff of long-term care facilities should also be educated about AD to minimize the unnecessary use of antipsychotic medications (Guideline). Behavior modification, scheduled toileting, and prompted voiding reduce urinary incontinence (Standard). Functional independence can be increased by graded assistance, skills practice, and positive reinforcement (Guideline).

Clinical benefits of a new piperidine-class AChE inhibitor.

Alzheimer's disease (AD) is associated with a deficiency of acetylcholine (ACh) in the forebrain that correlates with brain pathology and cognitive dysfunction. The most promising approach to enhancing central ACh neurotransmission has been the utilization of agents that inhibit cholinesterases which block its catabolism. Initially, the success of this strategy was limited by subtherapeutic levels of acetylcholinesterase (AChE) inhibition, tolerability problems and toxicity of the first agents. Donepezil HCI represents a new chemical class of AChE inhibitors, the piperidines. In clinical trials, donepezil has been shown to improve significantly cognition and global function in patients with mild to moderately severe AD, and has demonstrated an excellent tolerability and safety profile. These benefits, as well as a simple, once-daily dosing regimen, make donepezil a viable therapeutic option for AD patients.

Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: final analysis of a US multicentre open-label study.

This multicentre, open-label study evaluated the long-term efficacy and safety of donepezil in the treatment of patients with mild to moderately severe Alzheimer's disease (AD). The 133 patients who entered the study had previously completed a 14-week randomized, double-blind, placebo-controlled study with donepezil. In this open-label study, patients were treated initially with 3 mg per day donepezil, which could be increased to 5, 7 and 10 mg per day in a step-wise fashion. Patients attended the clinic for assessments at 3-week intervals for the first 12 weeks, then subsequently at 12-week intervals for up to 240 weeks (254 cumulative weeks). Efficacy was assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinical Dementia Rating-Sum of the Boxes scale (CDR-SB), and data were compared with those predicted for historical untreated AD patients. During the first 6-9 months of the study, mean ADAS-cog and CDR-SB scores showed evidence of clinical improvement from baseline. After this time scores gradually deteriorated. Overall the decline was less than that estimated if this cohort of patients had not been treated. The most common adverse events were related to the nervous and digestive systems, and were generally mild and transient, resolving without the need for dose modifications. There was no evidence of hepatotoxicity. In conclusion, these data demonstrate that donepezil is a well-tolerated, realistic symptomatic treatment for AD over a period of up to 4.9 years. An interim report of the first 98 weeks of the study has been published previously.