Kishnani Priya S, Sommer Barbara R, Handen Benjamin L, Seltzer Benjamin, Capone George T, Spiridigliozzi Gail A, Heller James H, Richardson Sharon, McRae Thomas
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Am J Med Genet A. 2009 Aug;149A(8):1641-54. doi: 10.1002/ajmg.a.32953.
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 < or = 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.
我们研究的目的是评估多奈哌齐对患有唐氏综合征（DS）但无阿尔茨海默病（AD）证据的年轻成年人的疗效和安全性。我们进行了一项为期12周的随机、双盲、安慰剂对照研究，并进行了为期12周的开放标签扩展研究。干预措施为对年龄在18 - 35岁、患有DS但无AD的年轻成年人使用多奈哌齐（5 - 10毫克/天）。主要测量指标是严重损伤量表（SIB）测试，次要测量指标是文兰适应性行为量表（VABS）、儿童河梅德行为记忆测试以及语言基本能力临床评估第三版。基线时，123名受试者被随机分配接受多奈哌齐或安慰剂治疗。在双盲阶段，两组的SIB评分均较基线有显著改善，组间差异无统计学意义。在开放标签阶段，原多奈哌齐组的SIB评分保持稳定；原安慰剂组显示出与双盲阶段相似的改善。在双盲阶段，多奈哌齐组的VABS评分有所提高，而安慰剂组则未提高（观察病例，P = 0.03；末次观察结转，P = 0.07）。使用五种反应定义中的三种进行事后反应者分析，多奈哌齐有显著意义（P≤0.045）。不良事件发生率与AD研究相当。在这项针对DS的药物的首次大规模、多中心试验中，多奈哌齐似乎是安全的。由于明显的学习/练习和天花板效应，主要测量指标的疗效解释受到限制。事后分析结果表明，多奈哌齐对部分但并非所有受试者有效，这与DS的表型变异性一致。需要进一步的研究来证实多奈哌齐在该人群中的潜在益处。
