GlaxoSmithKline, Uxbridge, Middlesex, UK.
Curr Alzheimer Res. 2010 Aug;7(5):374-85. doi: 10.2174/156720510791383831.
This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of the 5-HT6 receptor antagonist, SB-742457, in subjects with mild-to-moderate probable Alzheimer's disease (AD).
Participating subjects had a Mini-Mental State Examination (MMSE) score of 12 to 26 after a 4-week, single-blind, placebo run-in phase, and were randomized (2:1:1:2) to receive placebo, SB-742457 5 mg, 15 mg, or 35 mg once daily for 24 weeks. Coprimary efficacy endpoints were the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) score and change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score at Week 24, in the intent-to-treat (ITT) population. A model-based design provided 90% power to detect a linear trend in treatment response across increasing doses and > or =90% power to compare SB-742457 35 mg with placebo.
371 subjects were randomized. In the ITT population (n=357), linear trend analysis at Week 24 suggested a dose response for CIBIC+ with a mean slope of -0.05 points/5-mg dose increase (95% confidence interval [CI]: -0.09, -0.01; p=0.016). The dose response slope for change from baseline in ADAS-Cog was -0.22 points/5-mg dose increase (95% CI: -0.45, 0.01; p=0.059). The adjusted mean treatment difference from placebo at Week 24 for SB-742457 35 mg (-0.31) was significant on CIBIC+ (95% CI: -0.62, -0.00; p=0.047) but non-significant on ADAS-Cog (-1.28 [95% CI: -2.96, 0.40]; p=0.135). Adverse events occurred in 24-37% in the SB-742457 groups vs 29% for placebo; 11-16% discontinued SB-742457 vs 15% for placebo.
SB-742457 was generally safe and well tolerated and may be efficacious in AD.
这项随机、双盲、安慰剂对照研究旨在探讨 5-HT6 受体拮抗剂 SB-742457 对轻度至中度可能患有阿尔茨海默病（AD）的受试者的疗效和耐受性。
参与研究的受试者在为期 4 周的单盲安慰剂导入期后，进行 Mini-Mental State Examination（MMSE）评分，得分在 12 至 26 之间，随后按照 2:1:1:2 的比例随机（2:1:1:2）接受安慰剂、SB-742457 5mg、15mg 或 35mg 每日一次，共 24 周。主要疗效终点为意向治疗（ITT）人群中治疗 24 周时临床医生访谈基于照顾者输入的变化印象量表（CIBIC+）评分和阿尔茨海默病评估量表认知子量表（ADAS-Cog）评分的变化。基于模型的设计具有 90%的效能，可检测到递增剂量下治疗反应的线性趋势，且具有 >90%的效能，可比较 SB-742457 35mg 与安慰剂。
共有 371 名受试者被随机分组。在 ITT 人群（n=357）中，24 周时线性趋势分析提示 CIBIC+的剂量反应呈下降趋势，平均斜率为每增加 5mg 剂量减少 0.05 分（95%置信区间[CI]：-0.09，-0.01；p=0.016）。ADAS-Cog 评分从基线的变化斜率为每增加 5mg 剂量减少 0.22 分（95%CI：-0.45，0.01；p=0.059）。SB-742457 35mg 治疗与安慰剂相比，24 周时的调整平均治疗差异为-0.31（95%CI：-0.62，-0.00；p=0.047），CIBIC+显著（95%CI：-0.62，-0.00；p=0.047），但 ADAS-Cog 不显著（-1.28 [95%CI：-2.96，0.40]；p=0.135）。SB-742457 组的不良事件发生率为 24%-37%，安慰剂组为 29%；SB-742457 组 11%-16%的患者因不良事件停药，安慰剂组为 15%。
SB-742457 通常安全且耐受良好，在 AD 中可能有效。
