Maher-Edwards Gareth, Watson Carolyn, Ascher John, Barnett Carly, Boswell Diane, Davies John, Fernandez Manuel, Kurz Alexander, Zanetti Orazio, Safirstein Beth, Schronen Juan Paul, Zvartau-Hind Marina, Gold Michael
Neurosciences, GlaxoSmithKline, Uxbridge, Middlesex, UK.
Neurosciences, GlaxoSmithKline, Research Triangle Park, NC, USA.
Alzheimers Dement (N Y). 2015 May 7;1(1):23-36. doi: 10.1016/j.trci.2015.04.001. eCollection 2015 Jun.
Two previous studies of SB742457, a 5-hydroxytryptamine (5-HT) receptor antagonist, suggested the efficacy of improvements in cognition and global outcome in Alzheimer's disease (AD).
Two randomized, placebo-controlled trials investigated SB742457 15 and 35 mg daily in subjects with mild-to-moderate AD (Mini-Mental Health State Examination [MMSE] 10-26). Study 1 (n = 576) investigated SB742457 and donepezil (5-10 mg daily) as monotherapy for 6 months. Study 2 (n = 684) investigated SB742457 in subjects who were maintained on donepezil. Coprimary endpoints at 24 weeks assessed cognition (AD Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global outcome (Study 1: Clinician Interview-Based Impression of Change Plus Caregiver Input [CIBIC+]; Study 2: Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Safety was assessed throughout.
Both studies failed to achieve formal statistical significance for their primary objectives. Study 1: SB742457 monotherapy was not statistically significantly different from placebo on any endpoint. Donepezil improved CIBIC+ but not ADAS-Cog. Study 2: SB742457 35 mg showed statistically significant differences relative to placebo for ADAS-cog (weeks 12, 24, and 48, but not week 36), ADCS-ADL (weeks 12-36, but not week 48), and CDR-SB (week 12 only).
Neither study met the overall criteria for success, but as an adjunct to donepezil, SB742457 was associated with sustained improvements for up to 48 weeks in cognition and ADL, compared with donepezil alone.Clinical Trial Registration: Clinicaltrials.gov: Study 1 NCT00708552; Study 2 NCT00710684.
先前两项关于5-羟色胺（5-HT）受体拮抗剂SB742457的研究表明，其对改善阿尔茨海默病（AD）的认知和整体预后有效。
两项随机、安慰剂对照试验对轻度至中度AD患者（简易精神状态检查表[MMSE]评分为10 - 26）每日服用15毫克和35毫克SB742457进行了研究。研究1（n = 576）将SB742457和多奈哌齐（每日5 - 10毫克）作为单一疗法进行了6个月的研究。研究2（n = 684）在维持服用多奈哌齐的患者中对SB742457进行了研究。24周时的共同主要终点评估了认知（AD评估量表 - 认知分量表[ADAS - Cog]）和整体预后（研究1：基于临床医生访谈的变化印象加护理人员意见[CIBIC +]；研究2：临床痴呆评定量表 - 方框总和[CDR - SB]）。对安全性进行了全程评估。
两项研究的主要目标均未达到正式的统计学显著性。研究1：SB742457单一疗法在任何终点上与安慰剂相比均无统计学显著差异。多奈哌齐改善了CIBIC +，但未改善ADAS - Cog。研究2：35毫克SB742457在ADAS - cog（第12、24和48周，但第36周未显示）、ADCS - ADL（第12 - 36周，但第48周未显示）和CDR - SB（仅第12周）方面与安慰剂相比有统计学显著差异。
两项研究均未达到成功的总体标准，但作为多奈哌齐的辅助药物，与单独使用多奈哌齐相比，SB742457与长达48周的认知和ADL持续改善相关。临床试验注册：Clinicaltrials.gov：研究1 NCT00708552；研究2 NCT00710684。
