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.
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.
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DOI：
10.1016/j.clinthera.2010.06.019
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发表时间：
2010-07
影响因子：
3.2
通讯作者：
Satlin A
中科院分区：
文献类型：
--
作者：
Farlow MR;Salloway S;Tariot PN;Yardley J;Moline ML;Wang Q;Brand-Schieber E;Zou H;Hsu T;Satlin A
据报道，目前批准的阿尔茨海默病（AD）治疗方法可提供症状性益处，但未证实对临床进展有影响。我们假设，随着时间的推移，初始治疗效果的丧失可以通过高剂量的胆碱酯酶抑制剂来减轻。本研究的目的是确定中度至重度AD患者将多奈哌齐从10 mg/d增加到23 mg/d的有效性和耐受性。这项随机双盲研究于2007年6月6日至2009年3月27日在亚洲、欧洲、澳大利亚、北美、南非和南美的219个地点进行。年龄在45 - 90岁之间，可能患有AD，精神状态检查评分0 - 20分（中度至重度损害），并且在研究开始前接受多奈哌齐10mg每日一次≥12周的患者符合条件。患者（n = 1467）被随机分配接受高剂量多奈哌齐（23mg每日一次）或标准剂量多奈哌齐（10mg每日一次），持续24周。主要的有效性测量是认知和整体功能的变化，在第24周使用严重损伤电池（SIB；认知）和临床医生基于访谈的变化印象加上护理者输入量表（CIBIC+；整体功能评分）的最小二乘平均基线变化（LSM [SE] Δ）分数（最后一次观察结果）进行评估。采用自发患者/护理人员报告和开放式提问对治疗中出现的不良事件（teae）进行评估；临床实验室检测（血液学、生物化学和由中心实验室分析的尿液分析）；12导心电图;身体和神经系统检查，包括生命体征测量。疗效分析纳入1371例患者（平均年龄73.8岁，女性62.8%，白人73.5%，体重34.0-138.7 kg）。981例患者中有296例（30.2%）退出多奈哌齐23mg /d组；486例患者中有87例（17.9%）退出多奈哌齐10mg /d组。研究结束时（第24周），多奈哌齐23 mg/d组SIB评分的LSM （SE） Δ显著高于多奈哌齐10 mg/d组（分别为+2.6 [0.58]vs +0.4[0.66]；差异为2.2;P < 0.001）。CIBIC+评分两组间差异无统计学意义（4.23 [1.07]vs 4.29[1.07]）。事后分析显示，多奈哌齐23 mg/d组晚期AD患者的SIB评分和CIBIC+治疗效果的LSM Δ高于10 mg/d组晚期AD患者（SIB, +1.6 [0.78] vs - 1.5[0.88]，分别[P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]）。服用多奈哌齐23 mg/d的963例患者中有710例（73.7%）出现teae，服用多奈哌齐10 mg/d的471例患者中有300例（63.7%）出现teae。多奈哌齐23mg /d组，分别有297例（30.8%）、332例（34.5%）和81例（8.4%）患者报告轻度、中度和重度teae；多奈哌齐10 mg/d组，这些比例分别为147（31.2%）、119（25.3%）和34（7.2%）。23 mg/d剂量组报告的3种最常见的严重不良事件是恶心（9例[0.9%]vs 1例[0.2%]）、头晕（7例[0.7%]vs 1例[0.2%]）和呕吐（6例[0.6%]vs 0例）。最常报道的teae被认为可能与23mg /d剂量治疗相关，包括恶心（59例[6.1%]vs 9例[1.9%]）、呕吐（48例[5.0%]vs 4例[0.8%]）和腹泻（31例[3.2%]vs 7例[1.5%]）。在研究期间或研究停止30天内报告了13例死亡（23 mg/d， 8例患者[0.8%];10 mg/d， 5例患者[1.1%]）；所有这些都被认为与研究药物无关。在这项研究中，在中度至重度AD患者中，与多奈哌齐10mg /d相比，多奈哌齐23mg /d在认知方面有更大的益处。整体功能的治疗间差异在总体人群中并不显著。多奈哌齐23mg /d似乎对晚期AD患者的整体功能评估有好处，但这一观察结果需要进一步的研究来证实。
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. 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. 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 ≥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] Δ) 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. 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) Δ 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 Δ 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. 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.
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影响因子：
11
作者：
Bohnen, NI;Kaufer, DI;Moore, RY
通讯作者：
Moore, RY
影响因子：
4.2
作者：
Pappas, BA;Bayley, PJ;Thal, LJ
通讯作者：
Thal, LJ
影响因子：
2.4
作者：
Homma, Akira;Imai, Yukimichi;Ohbayashi, Toshio
通讯作者：
Ohbayashi, Toshio
DOI：
10.1111/j.1532-5415.2004.52303.x
发表时间：
2004-07-01
影响因子：
6.3
作者：
Galasko, D;Kershaw, PR;Tariot, PN
通讯作者：
Tariot, PN
影响因子：
10.6
作者：
ALEXOPOULOS, GS;ABRAMS, RC;SHAMOIAN, CA
通讯作者：
SHAMOIAN, CA