Sharon Richardson

Efficacy of donepezil in mild cognitive impairment A randomized placebo-controlled trial

Objective: To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI). Methods: A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician’s Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations. Results: Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient. Conclusion: Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.

Donepezil preserves cognition and global function in patients with severe Alzheimer disease

Objective: To evaluate the efficacy and safety of donepezil for severe Alzheimer disease (AD). Methods: Patients with severe AD (Mini-Mental State Examination [MMSE] scores 1 to 12 and Functional Assessment Staging [FAST] scores ≥6) were enrolled in this multinational, double-blind, placebo-controlled trial at 98 sites. Patients were randomized to donepezil 10 mg daily or placebo for 24 weeks. Primary endpoints were the Severe Impairment Battery (SIB) and Clinicians Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resource Utilization for Severe Alzheimer Disease Patients (RUSP). Efficacy analyses were performed in the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF). Safety assessments were performed for patients receiving ≥1 dose of donepezil or placebo. Results: Patients were randomized to donepezil (n = 176) or placebo (n = 167). Donepezil was superior to placebo on SIB score change from baseline to endpoint (least squares mean difference 5.32; p = 0.0001). CIBIC-Plus and MMSE scores favored donepezil at endpoint (p = 0.0473 and p = 0.0267). Donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP. Adverse events reported were consistent with the known cholinergic effects of donepezil and with the safety profile in patients with mild to moderate AD. Conclusion: Patients with severe AD demonstrated greater efficacy compared to placebo on measures of cognition and global function.

Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10–17

The objective of this 10‐week, randomized, double‐blind, placebo‐controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5–10 mg/day) in children (aged 10–17 years) with DS of mild‐to‐moderate severity. The primary measures were the Vineland‐II Adaptive Behavior Scales (VABS‐II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS‐II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject‐performance‐based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double‐blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v‐scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between‐group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated.

The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome

The objective of our study was to assess the efficacy and safety of donepezil in young adults with Down syndrome (DS) but no evidence of Alzheimer disease (AD). A 12‐week, randomized, double‐blind, placebo‐controlled study with a 12‐week, open‐label extension was conducted. The intervention consisted of donepezil (5–10 mg/day) in young adults (aged 18–35 years) with DS, but no AD. The primary measure was the Severe Impairment Battery (SIB) test and secondary measures were the Vineland Adaptive Behavior Scales (VABS), the Rivermead Behavioral Memory Test for Children, and the Clinical Evaluation of Language Fundamentals, Third Edition. At baseline, 123 subjects were randomly assigned treatment with donepezil or placebo. During the double‐blind phase, SIB scores improved significantly from baseline in both groups, with no significant between‐group differences. During the open‐label phase, SIB scores in the original donepezil group remained stable; the original placebo group showed an improvement similar to that seen in the double‐blind phase. VABS scores improved for donepezil, but not placebo, during the double‐blind phase (observed cases, P = 0.03; last observation carried forward, P = 0.07). Post hoc responder analyses were significant for donepezil using three of five response definitions (P ≤ 0.045). Adverse event rates were comparable to AD studies. In this first large‐scale, multicenter trial of a pharmacological agent for DS, donepezil appears safe. Efficacy interpretation was limited for the primary measure due to apparent learning/practice and ceiling effects. Outcomes in post hoc analyses suggested efficacy in some, but not all subjects, consistent with phenotypic variability of DS. Additional studies are required to confirm potential benefits of donepezil in this population.

Assessing Therapeutic Efficacy in a Progressive Disease A Study of Donepezil in Alzheimer's Disease

AbstractObjective: To determine the value of continued donepezil treatment in patients with Alzheimer’s disease for whom clinical benefit was initially judged to be uncertain. Methods: The study consisted of three phases: (i) a 12- to 24-week, pre-randomisation, open-label donepezil-treatment phase; (ii) a 12-week, randomised, double-blind, placebo-controlled phase; and (iii) a 12-week, single-blind (i.e. patient-blind) donepezil-treatment phase. Patients with mild to moderate Alzheimer’s disease received open-label treatment with donepezil (5 mg/day for 4 weeks, then 10 mg/day for the remainder of the phase) for 12–24 weeks. Patients who exhibited a decline or no change from baseline on the Mini-Mental State Examination (MMSE) and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were randomised into the double-blind phase in which patients received 12 weeks of treatment with donepezil (10 mg/day) or placebo. At the end of the double-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil, in a 12-week single-blind phase. Patients were assessed at the start of the double-blind phase and at weeks 6 and 12 of this phase, and at the end of the single-blind phase. Results: Six hundred and nineteen patients completed the open-label phase; 69% showed clear clinical benefit and 31% showed uncertain benefit. 202 patients were randomised to continued donepezil treatment (n = 99) or placebo (n = 103). Differences in favour of continued donepezil versus placebo were observed in cognition and behaviour. In addition, there was a non-significant trend favouring donepezil in activities of daily living (ADL) [week 12 observed case mean treatment differences: MMSE, 1.13 (p = 0.02); Alzheimer’s Disease Assessment Scale - cognitive subscale, 0.57 (p = 0.5); the Neuropsychiatric Inventory, −3.16 (p = 0.02); Disability Assessment for Dementia scale, 3.67 (p = 0.1)]. Conclusion: Most patients showed clear clinical benefit during initial donepezil treatment. Among patients for whom clinical benefit was uncertain, improvement in cognition and behaviour were observed for those who continued donepezil treatment compared with the group switched to placebo. Initial decline or stabilisation does not necessarily indicate a lack of efficacy in Alzheimer’s disease, and the decision to discontinue treatment should be based on an evaluation of all domains (cognition, behaviour and ADL) and performed at several timepoints.

Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease

To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimers disease (AD) and to explore relationships between donepezils effects on apathy and other Neuropsychiatric Inventory (NPI)–measured behavioural symptoms.

Effect of donepezil on cognition in severe Alzheimer's disease: a pooled data analysis.

To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total scores from baseline to week 24 was 6.22 (p < 0.0001, Cohens d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6-9 stratum (LS mean difference, 7.60; p < 0.0001, Cohens d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohens d, 0.17-0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.

A brief instrument to assess treatment response in the patient with advanced Alzheimer disease.

The availability of effective treatments for severe Alzheimer disease (AD) has accentuated the need for brief, simple tools to evaluate treatment response in busy clinical settings for patients with advanced dementia. To develop such a tool, data on 875 patients from 4 double-blind–randomized studies of donepezil in severe AD [Mini-Mental State Examination (MMSE) 0 to 12 inclusive] were pooled and analyzed to identify Severe Impairment Battery (SIB) items, which are sensitive to change over time. Eight of the 51 SIB items were chosen based on effect sizes and relative ease of administration. The resulting SIB-8 was then applied to a validation data set (not used to generate the short form) to characterize its usefulness. The items, Month, Months of Year, Write Name, Sentence, Fluency, Confrontational Naming–Spoon, Using Spoon–Photograph, and Digit Span, were sensitive to change with treatment (P<0.0001) and easy to administer. Baseline SIB-8 scores were correlated with baseline MMSE and full-scale SIB scores, and provided a good distribution of scores in patients at the lower end of the MMSE. The SIB-8 is a brief (≤3 min) assessment for patients with severe AD that is sensitive to change and able to detect treatment response.

Disease-modifying approaches to Alzheimer’s disease: Challenges and opportunities—Lessons from donepezil therapy

The era of disease modification as a therapeutic option for Alzheimers disease (AD) is upon us. With dozens of novel drugs in development, there is more need than ever to develop biomarkers that distinguish normal aging from AD and AD from other dementias, track changes over time as disease progresses, and respond to interventions. Future trials will need to weight biomarker outcomes equal to cognitive outcomes especially when the biomarkers are linked to specific mechanisms, such as changes to beta amyloid (Aβ) deposition or brain volume. Since the advent of donepezil as a treatment for AD, new mechanisms of action of this molecule have been discovered. In this perspective, we review trial design and discuss the use of biomarkers by using lessons learned from previous trials conducted with cholinergic therapy.

Efficacy and Safety of Donepezil in Patients With Alzheimer's Disease in Assisted Living Facilities

The aim of this 12-week, open-label study was to determine the safety and efficacy of donepezil in participants with Alzheimer’s disease (AD) residing in assisted living facilities (ALFs). Participants received 5 mg donepezil daily for 6 weeks followed by 10 mg daily for 6 weeks. Primary and secondary outcomes were change from baseline in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory 8 (NPI-8) scores, respectively. Safety was assessed by adverse events (AEs) and laboratory tests. Of the 97 participants, 76 completed the study. Mean MMSE score (18.7 at baseline) improved 1.8 points (P < .0001) at study end. Total NPI-8 score improved 1.8 points (P = .043). The most frequent AEs were nausea and diarrhea. Donepezil improved cognition and behavior and was safe and well tolerated. The results suggest a need for proactive screening and diagnosis of AD and support the value of treatment and use of donepezil in participants residing in ALFs.