Atri Alireza, Frölich Lutz, Ballard Clive, Tariot Pierre N, Molinuevo José Luis, Boneva Neli, Windfeld Kristian, Raket Lars L, Cummings Jeffrey L
Ray Dolby Brain Health Center, California Pacific Medical Center, San Francisco.
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
JAMA. 2018 Jan 9;319(2):130-142. doi: 10.1001/jama.2017.20373.
New therapeutic approaches for Alzheimer disease (AD) are needed.
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.
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).
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.
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.
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.
clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.
阿尔茨海默病（AD）需要新的治疗方法。
评估选择性5-羟色胺-6受体拮抗剂依达拉奉对轻至中度AD进行症状治疗是否有效。
设计、地点和参与者：三项随机临床试验，纳入了2525名年龄在50岁及以上的轻至中度AD患者（研究1：119个地点的933名患者；研究2：158个地点的858名患者；研究3：126个地点的734名患者）。这三项为期24周的研究于2013年10月至2017年1月进行；2017年1月12日进行最终随访。
在胆碱酯酶抑制剂治疗（研究1和2中为多奈哌齐；研究3中为多奈哌齐、卡巴拉汀或加兰他敏）基础上加用依达拉奉（10、30或60mg/天）或安慰剂。
所有三项研究的主要终点：采用阿尔茨海默病评估量表（ADAS-Cog）的11项认知子量表测量，从基线到24周认知总分的变化（范围为0 - 70；分数越低表明损害越小）；关键次要终点：阿尔茨海默病协作研究 - 临床总体印象变化量表和23项日常生活活动量表得分。剂量组疗效要求在主要终点以及1个或更多关键次要终点上比安慰剂有显著益处。记录安全数据和不良事件情况。
在三项试验中随机分组的2525名患者中（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），2254名（89%）完成了研究。在研究1中，60mg剂量依达拉奉组从基线到24周ADAS-Cog总分的平均变化为0.37，30mg剂量组为0.61，安慰剂组为0.41（60mg剂量组与安慰剂组的调整平均差值为0.05 [95%CI，-0.88至0.98]，30mg剂量组为0.33 [95%CI，-0.59至1.26]）。在研究2中，30mg剂量依达拉奉组从基线到24周ADAS-Cog总分的平均变化为1.01，10mg剂量组为0.53，安慰剂组为0.56（30mg剂量组与安慰剂组的调整平均差值为0.63 [95%CI，-0.38至1.65]；鉴于门控测试策略以及30mg剂量时的无效结果，未对10mg剂量进行统计学比较）。在研究3中，60mg剂量依达拉奉组从基线到24周ADAS-Cog总分的平均变化为0.38，安慰剂组为0.82（与安慰剂组的调整平均差值为-0.55 [95%CI，-1.45至0.36]）。依达拉奉组55.4%至69.7%的参与者出现治疗中出现的不良事件，而安慰剂组为56.7%至61.4%。
在轻至中度AD患者中，与安慰剂相比，使用依达拉奉在24周治疗期间并未改善认知。这些发现不支持使用依达拉奉治疗AD。
clinicaltrials.gov标识符：NCT01955161、NCT02006641和NCT02006654。
