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Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease.

ABSTRACT: Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated.At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores.Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.ClinicalTrials.gov identifier: NCT00478205.

SUBMITTER: Ferris SH

PROVIDER: S-EPMC3226311 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease.

Ferris Steven H SH Schmitt Frederick A FA Saxton Judith J Richardson Sharon S Mackell Joan J Sun Yijun Y Xu Yikang Y

Alzheimer's research & therapy 20110620 3

<h4>Introduction</h4>Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we perform ...[more]

PMID: 21689411

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Project description:BackgroundDonepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d.MethodSafety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed.ResultsThe safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%).DiscussionThe 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those observed in studies with a dose increase from 5 to 10 mg/d.ConclusionThe good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD.

Project description:Donepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer's disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD.Patients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs.915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ± 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs.Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study.This study shows that long-term treatment with donepezil 23 mg/day is associated with no new safety signals. The elevated incidence of AEs in patients increasing the dose of donepezil from 10 mg/day to 23 mg/day was limited to the initial weeks of the study.

Project description:IntroductionThe US Food and Drug Administration approved a 23 mg daily dose of donepezil for treatment of moderate to severe Alzheimer's disease (AD) based on outcomes from a large trial comparing the 23 mg/day dose with the standard 10 mg/day dose. Results from this study indicated that after 24 weeks, donepezil 23 mg/day provided significant cognitive benefits over donepezil 10 mg/day, measured using the Severe Impairment Battery (SIB). In the analyses reported herein, we further characterize the range of cognitive domains impacted by treatment with donepezil 23 mg/day.MethodsA post hoc analysis was conducted using data from a 24-week, randomized, double-blind trial comparing donepezil 23 mg/day versus 10 mg/day in 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20). Changes from baseline to week 24 in the nine SIB domain scores were analyzed in the intent-to-treat (ITT) population (baseline MMSE 0 to 20), in patients with more severe baseline AD (MMSE 0 to 16), and in severity strata based on baseline MMSE scores (0 to 5, 6 to 10, 11 to 15, 16 to 20).ResultsIn the ITT population, changes in six of the nine SIB domains favored donepezil 23 mg/day over donepezil 10 mg/day. LS mean treatment differences were significant for the language, visuospatial ability, and construction domains. In the more advanced cohort of patients (MMSE 0 to 16 at baseline), LS mean treatment differences were statistically significant favoring donepezil 23 mg/day in five of the nine domains: language, memory, visuospatial ability, attention, and construction. Descriptive analysis of LS mean changes in SIB domain scores in the four baseline severity strata showed variable patterns of response; overall, cognitive benefits of donepezil 23 mg/day were greatest in patients with MMSE scores of 0 to 15.ConclusionsThese results suggest that donepezil 23 mg/day provides benefits over 10 mg/day across a range of cognitive domains. The magnitude of benefit and domains impacted varied depending on the stage of AD; significant benefits with higher dose donepezil were most apparent at more advanced stages of AD and were most prominent in the language domain.

Project description:Treatment of Alzheimer's disease with acetylcholinesterase inhibitors can result in symptomatic benefits, but patients often show variable responses. The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23?mg/d or 10?mg/d and to identify factors potentially influencing response.A post hoc analysis was conducted using data from a large, 24-week, randomized, double-blind, international study enrolling patients with moderate to severe Alzheimer's disease (baseline Mini-Mental State Examination [MMSE], 0-20) (NCT 00478205). Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24. Univariate and multivariate analyses were also performed.Donepezil 23?mg/d provided statistically significant incremental cognitive benefits over donepezil 10?mg/d irrespective of baseline functional severity, measured by scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living-severe version (P?<?0.05). When patients were categorized by baseline cognitive severity (MMSE score), significant benefits of donepezil 23?mg/d over 10?mg/d were seen in both subgroups when based on MMSE scores of 0-9 versus 10-20 (P?<?0.02 and P?<?0.01, respectively), and in the more severe subgroup when based on MMSE scores of 0-16 versus 17-20 (P?<?0.0001 and P?>?0.05). Statistically significant incremental cognitive benefits of donepezil 23?mg/d over 10?mg/d were also observed regardless of age, gender, weight, or prestudy donepezil 10?mg/d treatment duration (P?<?0.05). In the multivariate analysis, the only significant interaction was between treatment and baseline MMSE score.The cognitive benefits of donepezil 23?mg/d over 10?mg/d were achieved regardless of the patient's age, gender, weight, duration of prior donepezil 10?mg/d, and functional severity. The influence of baseline cognitive severity on response seemed to be dependent on the level of impairment, with cognitive benefits of donepezil 23?mg/d over 10?mg/d most apparent in those patients at a more advanced stage of disease. These data may be useful in helping practicing physicians make informed decisions for their patients with advanced Alzheimer's disease.

Project description:AimThe Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB - the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity.MethodsA post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini-Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated.ResultsAssessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24.ConclusionsIn this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD.

Project description:BackgroundOur previous studies showed that GV1001 has various protective effects against β-amyloid and other stressors. Based on these findings, we hypothesized that GV1001 might have beneficial effects in patients with Alzheimer's disease (AD).MethodsA phase 2, double-blind, parallel-group, placebo-controlled, 6-month randomized clinical trial was performed to evaluate the safety and efficacy of subcutaneously administered GV1001. Between September 2017 and September 2019, 13 centers in South Korea recruited participants. A total of 106 patients were screened, and 96 patients with moderate-to-severe AD were randomized 1:1:1 to the placebo (group 1, n = 31), GV1001 0.56 mg (group 2, n = 33), and 1.12 mg (group 3, n = 32) groups. GV1001 was administered every week for 4 weeks (4 times), followed by every 2 weeks until week 24 (10 times). The primary endpoint was the change in the Severe Impairment Battery (SIB) score from baseline to week 24. The key secondary efficacy endpoints were the change in the Clinical Dementia Rating Sum of Box (CDR-SOB), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, and Global Deterioration Scale scores. The safety endpoints were also assessed based on adverse events, laboratory test results, vital signs, and other observations related to safety.ResultsGroup 3 showed less decrease in the SIB score at 12 and 24 weeks compared with group 1 (P < 0.05). These were not significantly observed in group 2. Among the secondary endpoints, only the NPI score showed significantly better improvement in group 2 than in group 3 at week 12; however, there were no other significant differences between the groups. Although the ADCS-ADL and CDR-SOB scores showed a pattern similar to SIB scores, a statistically significant result was not found. Adverse events were similar across all three groups.ConclusionsThe results indicate that GV1001 1.12 mg met the primary endpoint of a statistically significant difference. GV1001 was well tolerated without safety concerns. This study warrants a larger clinical trial.Trial registrationClinicalTrials.gov NCT03184467 . Registered on June 12, 2017.

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Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease.

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Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease.

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