Current Alzheimer's disease clinical trials: methods and placebo outcomes.
Current Alzheimer's disease clinical trials: methods and placebo outcomes.
复制标题
DOI：
10.1016/j.jalz.2009.07.038
复制
发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Sano M
中科院分区：
文献类型：
--
作者：
Schneider LS;Sano M
治疗阿尔茨海默病(AD)的第二阶段和第三阶段药物开发通常需要长达18个月的随机、安慰剂对照临床试验。然而，18个月的试验还没有显示出对测试药物有利的统计上的显著结果。我们通过评估安慰剂组来检查这些试验的特征和潜在的假设。我们在Clinicaltrials.gov注册表中搜索为期至少18个月的随机、安慰剂对照的AD临床试验，并从安慰剂组中提取人口统计学、临床和试验特征以及主要结果的变化。我们从报告、摘要、出版物和赞助商那里获得了更多信息。在已确定的23项试验中，11项已完成并有基线数据可用；9项有后续数据可用；17项为III期。一般纳入标准非常相似，除了最低简易精神状态检查(MMSE)评分从12到20。第三阶段试验的样本量从402到1684，II期的样本量从80到400。胆碱酯酶抑制剂的使用率从53%到100%，美金胺的使用率从13.5%到78%。AD评估量表-认知量表(ADAS-COG)是所有试验的共同主要结果；日常生活活动、全球严重程度或全球变化评级是其他共同主要结果。载脂蛋白Eε4基因携带者在58%~67%之间，平均基线ADASCOG在17.8~24.2之间。安慰剂组的ADAS-COG在18个月期间恶化的范围从4.34到9.10，标准差从8.17到9.39，在18个月期间增加。纳入标准基本上类似于早期6个月和12个月的试验，在这些试验中，不允许使用胆碱酯酶抑制剂，平均ADAS-COG变化率也是如此。然而，在ADAS-COG安慰剂组中，不断增加的变异性和相对较小的总体变化，例如，大约25%的患者病情恶化不超过1个百分点，可能会使一种适度有效的药物更不可能得到可靠的认可，特别是当该药物可能只起作用于缓解功能下降而不是改善功能的时候。通过汇集个别试验数据，这些观察将得到加强，药物赞助商应该参与这种努力。
Eighteen-month-long randomized, placebo-controlled clinical trials are common for phase II and phase III drug development for Alzheimer's disease (AD). Yet, no 18-month trial has shown statistically significant outcomes favoring the test drug. We examined characteristics and underlying assumptions of these trials by assessing the placebo groups. We searched the clinicaltrials.gov registry for randomized, placebo-controlled clinical trials for AD of at least 18-month duration and extracted demographic, clinical, and trials characteristics, and change in main outcomes from the placebo groups. We obtained additional information from presentations, abstracts, publications, and sponsors. Of 23 trials identified, 11 were completed and had baseline data available; nine had follow-up data available; 17 were phase III. General inclusion criteria were very similar except that minimum Mini-Mental State Examination (MMSE) scores varied from 12 to 20. Sample sizes ranged from 402 to 1,684 for phase III trials and 80 to 400 for phase II. Cholinesterase inhibitor use was from 53% to 100%, and memantine use was from 13.5% to 78%. The AD Assessment Scale-cognitive (ADAS-cog) was the co-primary outcome in all trials; and activities of daily living, global severity, or global change ratings were the other co-primaries. APOE ε4 genotype carriers ranged from 58% to 67%; mean baseline ADAS-cog was 17.8 to 24.2. ADAS-cog worsening in the placebo groups during 18 months ranged from 4.34 to 9.10, with standard deviations from 8.17 to 9.39, increasing during 18 months. Inclusion criteria are essentially similar to earlier 6-month and 12-month trials in which cholinesterase inhibitors were not allowed, as were mean ADAS-cog rates of change. Yet increasing variability and relatively little change overall in the ADAS-cog placebo groups, eg, about 25% of patients do not worsen by more than 1 point, might make it more unlikely than previously assumed that a modestly effective drug can be reliably recognized, especially when the drug might work only to attenuate decline in function and not to improve function. These observations would be strengthened by pooling individual trials data, and pharmaceutical sponsors should participate in such efforts.
登录
查看更多内容
影响因子：
158.5
作者：
Petersen, RC;Thomas, RG;Thal, LJ
通讯作者：
Thal, LJ
影响因子：
--
作者：
Harrison, John;Psychol, C.;Grundman, Michael
通讯作者：
Grundman, Michael
影响因子：
9.9
作者：
MCKHANN, G;DRACHMAN, D;STADLAN, EM
通讯作者：
STADLAN, EM
影响因子：
4.8
作者：
FOLSTEIN, MF;FOLSTEIN, SE;MCHUGH, PR
通讯作者：
MCHUGH, PR
DOI：
10.1016/j.jalz.2006.04.003
发表时间：
2006-07-01
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Mohs, Richard C;Kawas, Claudia;Carrillo, Maria C
通讯作者：
Carrillo, Maria C