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Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study.

Abstract

BACKGROUND

Currently approved Alzheimer's disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor.

OBJECTIVE

The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD.

METHODS

This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for > or =12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatment-emergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements.

RESULTS

The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0-138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Delta in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Delta in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs -1.5 [0.88], respectively [P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication.

CONCLUSIONS

In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205.

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  • Authors+Show Affiliations

    ,

    Department of Neurology, Indiana University School of Medicine, Indianapolis, 46202, USA. mfarlow@iupui.edu

    , , , , , , , ,

    Source

    Clinical therapeutics 32:7 2010 Jul pg 1234-51

    MeSH

    Aged
    Aged, 80 and over
    Alzheimer Disease
    Cholinesterase Inhibitors
    Cognition
    Donepezil
    Dose-Response Relationship, Drug
    Double-Blind Method
    Female
    Humans
    Indans
    Male
    Middle Aged
    Piperidines
    Severity of Illness Index

    Pub Type(s)

    Comparative Study
    Journal Article
    Multicenter Study
    Randomized Controlled Trial
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    20678673

    Citation

    Farlow, Martin R., et al. "Effectiveness and Tolerability of High-dose (23 Mg/d) Versus Standard-dose (10 Mg/d) Donepezil in Moderate to Severe Alzheimer's Disease: a 24-week, Randomized, Double-blind Study." Clinical Therapeutics, vol. 32, no. 7, 2010, pp. 1234-51.
    Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clin Ther. 2010;32(7):1234-51.
    Farlow, M. R., Salloway, S., Tariot, P. N., Yardley, J., Moline, M. L., Wang, Q., ... Satlin, A. (2010). Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clinical Therapeutics, 32(7), pp. 1234-51. doi:10.1016/j.clinthera.2010.06.019.
    Farlow MR, et al. Effectiveness and Tolerability of High-dose (23 Mg/d) Versus Standard-dose (10 Mg/d) Donepezil in Moderate to Severe Alzheimer's Disease: a 24-week, Randomized, Double-blind Study. Clin Ther. 2010;32(7):1234-51. PubMed PMID: 20678673.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. AU - Farlow,Martin R, AU - Salloway,Stephen, AU - Tariot,Pierre N, AU - Yardley,Jane, AU - Moline,Margaret L, AU - Wang,Qin, AU - Brand-Schieber,Elimor, AU - Zou,Heng, AU - Hsu,Timothy, AU - Satlin,Andrew, PY - 2010/06/03/accepted PY - 2010/8/4/entrez PY - 2010/8/4/pubmed PY - 2010/12/14/medline SP - 1234 EP - 51 JF - Clinical therapeutics JO - Clin Ther VL - 32 IS - 7 N2 - BACKGROUND: Currently approved Alzheimer's disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor. OBJECTIVE: The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD. METHODS: This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for > or =12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatment-emergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements. RESULTS: The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0-138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Delta in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Delta in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs -1.5 [0.88], respectively [P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication. CONCLUSIONS: In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/20678673/Effectiveness_and_tolerability_of_high_dose__23_mg/d__versus_standard_dose__10_mg/d__donepezil_in_moderate_to_severe_Alzheimer's_disease:_A_24_week_randomized_double_blind_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(10)00224-9 DB - PRIME DP - Unbound Medicine ER -