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首页> 外文期刊>Lancet Neurology >Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial.
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Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial.

机译：tarenflurbil在轻度至中度阿尔茨海默氏病中的疗效和安全性：一项随机的II期临床试验。

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BACKGROUND: The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD. METHODS: 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316). FINDINGS: A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effectsize 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg tarenflurbil group for months 12-24 (all p<0.05). INTERPRETATION: 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures ofdaily activities and global function in patients with mild AD. FUNDING: Myriad Pharmaceuticals.
机译：背景：淀粉样蛋白-β肽Abeta（42）与阿尔茨海默氏病（AD）的发病机制有关。我们旨在测试tarenflurbil（一种选择性的Abeta（42）降低剂（SALA））对轻度至中度AD患者认知和功能的影响。方法：210名生活在社区中的患者，他们的迷你精神状态检查（MMSE）得分为15-26，被随机分配为每天两次接受Tarenflurbil（400 mg [n = 69]或800 mg [n = 70]）在第二阶段，多中心，双盲研究中，使用安慰剂（n = 71）治疗12个月。主要疗效结果是AD评估量表认知子量表（ADAS-cog），阿尔茨海默氏病合作研究活动的日常生活量表（ADCS-ADL）和临床痴呆症分级总和（CDR-sb）。在为期12个月的延长治疗阶段中，接受了Tarenflurbil的患者继续接受相同剂量，并且接受安慰剂的患者被随机分配为Tarenflurbil，每日两次800毫克或400毫克。主要疗效分析是通过意向治疗进行的。该试验已在加拿大卫生部（084527）和英国药品和保健产品监管局（20365/0001 / A 69316）中注册。结果：一项预先进行的相互作用分析显示，轻度AD（基线MMSE 20-26）和中度AD（基线MMSE 15-19）的患者对ADAS-cog和ADCS-ADL中的tarenflurbil的反应不同（p> or = 0.10）。 ;因此，这些组分别进行了分析。 800毫克tarenflurbil组的轻度AD患者的日常生活活动下降率低于安慰剂组（ADCS-ADL斜率差异每年3.98 [95％CI 0.33至7.62]点，影响大小[安慰剂下降率的降低] 46.4％，Cohen d 0.45; p = 0.033）和每年的全局功能（CDR-sb差异-0.80 [-1.57至-0.03]点），效应量35.7％，Cohen d 0.42; p = 0.042 ）;认知下降的减慢没有显着差异（ADAS-cog差异每年-1.36 [-4.07至1.36]点，影响33.7％，Cohen d 0.20; p = 0.327）。在中度AD患者中，每天两次800 mg tarenflurbil对ADCS-ADL和ADAS-cog无明显影响，而对CDR-sb则有负面影响（-52％，Cohen d -1.08; p = 0.003）。最常见的不良事件为腹泻（分别在800 mg，400 mg和安慰剂组中分别有7、9和5位患者），恶心（7、7和4位患者中）和头晕（在5、9位中） ，以及四名患者）。在800毫克tarenflurbil组中持续24个月的轻度AD患者的所有三个主要结局的下降率均低于安慰剂组0-12个月和tarenflurbil组12-24个月的患者（所有p <0.001），并且比安慰剂组0-12个月和800 mg tarenflurbil组12-24个月的患者有更好的结局（所有p <0.05）。解释：每天两次800毫克tarenflurbil具有良好的耐受性，长达24个月的治疗，有证据表明轻度AD患者的每日活动和总体功能指标与剂量有关。资金来源：无数制药公司。

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