Importance New therapeutic approaches for Alzheimer disease (AD) are needed. Objective To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Design, Setting, and Participants Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Interventions Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Main Outcomes and Measures Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Results Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, −0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, −0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, −0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, −0.55 [95% CI, −1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. Conclusions and Relevance In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. Trial Registration clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654

中文翻译：

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艾达哌啶作为胆碱酯酶抑制剂的辅助药物对阿尔茨海默病患者认知变化的影响

重要性 需要新的阿尔茨海默病 (AD) 治疗方法。目的 评估选择性 5-羟色胺-6 受体拮抗剂伊达洛匹定对轻中度 AD 的对症治疗是否有效。设计、设置和参与者 三项随机临床试验，包括 2525 名 50 岁或以上患有轻度至中度 AD 的患者（研究 1：n = 933 名患者在 119 个地点；研究 2：n = 858 在 158 个地点；和研究 3： n = 734 在 126 个站点）。为期 24 周的研究于 2013 年 10 月至 2017 年 1 月进行；2017 年 1 月 12 日的最终随访。 干预 胆碱酯酶抑制剂治疗（研究 1 和 2 中的多奈哌齐；研究 3 中的多奈哌齐、利凡斯的明或加兰他敏）中加入艾达哌啶（10、30 或 60 毫克/天）或安慰剂。主要结果和测量 所有 3 项研究的主要终点：通过阿尔茨海默病评估量表 (ADAS-Cog) 的 11 项认知分量表测量的从基线到 24 周的认知总分的变化（范围，0-70；分数越低表示损伤越小）；关键的次要终点：阿尔茨海默病合作研究——临床总体变化印象量表和 23 项日常生活活动量表评分。剂量组疗效需要在主要终点和 1 个或多个关键次要终点方面优于安慰剂。记录安全数据和不良事件概况。结果 在 3 项试验中随机分配的 2525 名患者（平均年龄 74 岁；平均基线 ADAS-Cog 总分 26；62% 至 65% 的参与者为女性）中，2254 名 (89%) 完成了研究。在研究 1 中，ADAS-Cog 总分在基线和 24 周之间的平均变化为 0。60 毫克剂量的伊达洛匹定组为 37，30 毫克剂量组为 0.61，安慰剂组为 0.41（与安慰剂的调整平均差异，60 毫克剂量为 0.05 [95% CI，-0.88 至 0.98]组和 0.33 [95% CI，-0.59 至 1.26]（对于 30-mg 剂量组）。在研究 2 中，ADAS-Cog 总分在基线和 24 周之间的平均变化对于 30-mg 伊达洛匹定组为 1.01，对于 10-mg 剂量组为 0.53，对于安慰剂组为 0.56（调整后的平均差异与安慰剂，30 毫克剂量组为 0.63 [95% CI，-0.38 至 1.65]；考虑到门控测试策略和 30 毫克剂量的无效结果，未对 10 毫克剂量进行统计比较）。在研究 3 中，基线和 24 周之间 ADAS-Cog 总分的平均变化对于 60 毫克剂量的伊达洛匹定组为 0.38 和 0。安慰剂组为 82（与安慰剂相比调整后的平均差异，-0.55 [95% CI，-1.45 至 0.36]）。伊达洛匹定组中 55.4% 至 69.7% 的参与者发生了治疗中出现的不良事件，而安慰剂组中的参与者则为 56.7% 至 61.4%。结论和相关性 在轻度至中度 AD 患者中，与安慰剂相比，使用伊达洛匹定在 24 周的治疗中并未改善认知能力。这些发现不支持使用伊达洛匹定治疗 AD。试验注册 Clinicaltrials.gov 标识符：NCT01955161、NCT02006641 和 NCT02006654 结论和相关性 在轻度至中度 AD 患者中，与安慰剂相比，使用伊达洛匹定在 24 周的治疗中并未改善认知能力。这些发现不支持使用伊达洛匹定治疗 AD。试验注册 Clinicaltrials.gov 标识符：NCT01955161、NCT02006641 和 NCT02006654 结论和相关性 在轻度至中度 AD 患者中，与安慰剂相比，使用伊达洛匹定在 24 周的治疗中并未改善认知能力。这些发现不支持使用伊达洛匹定治疗 AD。试验注册 Clinicaltrials.gov 标识符：NCT01955161、NCT02006641 和 NCT02006654