Bernard Katy, Gouttefangeas Sylvie, Bretin Sylvie, Galtier Stéphanie, Robert Philippe, Holthoff-Detto Vjera, Cummings Jeffrey, Pueyo Maria
Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France.
CoBTeK IA lab, Memory Center, Université Côte d'azur, Nice, France.
Alzheimers Dement (N Y). 2019 Jun 24;5:231-240. doi: 10.1016/j.trci.2019.04.002. eCollection 2019.
S47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors that may emerge as a favorable candidate for the symptomatic treatment of cognitive and depressive disorders in patients suffering from Alzheimer's disease (AD) of mild to moderate severity and with depressive symptoms.
For this double-blind, placebo-controlled 24-week phase II trial, 520 outpatients aged between 55 and 85 years, with probable AD at mild to moderate stages (a Mini-Mental State Examination score of 24-15 inclusive) and exhibiting depressive symptoms (Cornell Scale for Depression in Dementia [CSDD] ≥ 8) were recruited in twelve countries and randomized to 3 doses of S47445 (5-15-50 mg) or placebo. The primary end point was the change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score at week 24. Secondary measures included the Disability Assessment for Dementia, Mini-Mental State Examination, ADAS-Cog 13-item, CSDD, Clinical Global Impression of Change (Alzheimer's Disease Cooperative Study-CGIC), Neuropsychiatric Inventory (NPI), and safety criteria.
Baseline characteristics were comparable between the 4 groups. After 24 weeks, no statistically significant treatment difference was demonstrated between S47445 (5, 15 or 50 mg/d) and placebo on cognition (ADAS-Cog), function (Disability Assessment for Dementia), or depressive symptoms (CSDD). An improvement on neuropsychiatric symptoms assessed by NPI was evidenced at the lower dose 5 mg/d (Δ -2.55, = .023, post hoc analysis) compared to placebo. CSDD and total NPI scores improved in all groups including placebo. There were no specific and/or unexpected safety signals observed with any of the S47445 doses.
S47445 administered for 24 weeks was safe and well tolerated by patients with mild to moderate AD; the compound did not show significant benefits over placebo on cognition, function, or depressive symptoms.
S47445是一种新型的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体正变构调节剂，可能成为治疗轻度至中度阿尔茨海默病（AD）且伴有抑郁症状患者认知和抑郁障碍症状的理想候选药物。
在这项为期24周的双盲、安慰剂对照II期试验中，12个国家招募了520名年龄在55至85岁之间、轻度至中度阶段可能患有AD（简易精神状态检查表评分在24至15分之间）且有抑郁症状（痴呆抑郁症状康奈尔量表[CSDD]≥8）的门诊患者，并随机分为3种剂量的S47445（5 - 15 - 50毫克）或安慰剂组。主要终点是第24周时11项阿尔茨海默病评估量表认知子量表（ADAS - Cog）总分相对于基线的变化。次要指标包括痴呆残疾评估、简易精神状态检查表、13项ADAS - Cog、CSDD、临床总体印象变化（阿尔茨海默病协作研究 - CGIC）、神经精神科问卷（NPI）和安全性标准。
4组之间的基线特征具有可比性。24周后，S47445（5、15或50毫克/天）与安慰剂在认知（ADAS - Cog）、功能（痴呆残疾评估）或抑郁症状（CSDD）方面未显示出统计学上的显著治疗差异。与安慰剂相比，较低剂量5毫克/天的S47445通过NPI评估的神经精神症状有改善（Δ -2.55，P = 0.023，事后分析）。包括安慰剂组在内的所有组中，CSDD和NPI总分均有所改善。使用任何剂量的S47445均未观察到特定和/或意外的安全信号。
对于轻度至中度AD患者，服用24周的S47445是安全且耐受性良好的；该化合物在认知、功能或抑郁症状方面未显示出比安慰剂有显著益处。
