A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.
A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.
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DOI：
10.1186/s13195-017-0318-y
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发表时间：
2017-12-08
期刊：
影响因子：
--
通讯作者：
SCarlet RoAD Investigators
中科院分区：
文献类型：
--
作者：
Ostrowitzki S;Lasser RA;Dorflinger E;Scheltens P;Barkhof F;Nikolcheva T;Ashford E;Retout S;Hofmann C;Delmar P;Klein G;Andjelkovic M;Dubois B;Boada M;Blennow K;Santarelli L;Fontoura P;SCarlet RoAD Investigators
Gantenerumab是一种全人源单克隆抗体，可结合聚集的β淀粉样蛋白（Aβ），并通过Fc受体介导的吞噬作用清除Aβ斑块。在SCarlet RoAD试验中，我们评估了gantenerumab在前驱阿尔茨海默病（AD）中的疗效和安全性。在这项随机、双盲、安慰剂对照的III期研究中，我们对gantenerumab进行了为期2年的研究。患者随机接受gantenerumab 105 mg或225 mg或安慰剂皮下注射，每4周一次。主要终点是临床痴呆评定总分（CDR-SB）评分从基线至第104周的变化。我们评估了脑脊液生物标志物（所有患者）和淀粉样蛋白正电子发射断层扫描（子研究）的治疗效果。一旦50%的患者完成2年治疗，则进行无效分析。在接受至少一剂的患者中评估安全性。在筛选的3089例患者中，797例接受了随机化。研究因无效而提前停止;停止给药;研究揭盲。未观察到组间主要（安慰剂、gantenerumab 105 mg和gantenerumab 225 mg的最小二乘均值[95% CI] CDR-SB较基线的变化分别为1.60 [1.28，1.91]、1.69 [1.37，2.01]和1.73 [1.42，2.04]）或次要临床终点的差异。一般无症状淀粉样蛋白相关影像学异常的发生率以剂量和APOE ε4基因型依赖性方式增加。探索性分析表明，药物对临床和生物标志物终点的影响具有剂量依赖性。该研究因无效而提前停止，但在选定临床和生物标志物终点的探索性分析中观察到的剂量依赖性效应表明，可能需要更高剂量的gantenerumab才能实现临床疗效。ClinicalTrials.gov，NCT01224106。2010年10月14日注册。本文的在线版本（doi：10.1186/s13195-017-0318-y）包含补充材料，可供授权用户使用。
Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer’s disease (AD). In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. ClinicalTrials.gov, NCT01224106. Registered on October 14, 2010. The online version of this article (doi:10.1186/s13195-017-0318-y) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
影响因子：
48
作者：
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通讯作者：
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DOI：
10.1056/nejmoa1304839
发表时间：
2014-01-23
期刊：
The New England journal of medicine
影响因子：
--
作者：
Salloway S;Sperling R;Fox NC;Blennow K;Klunk W;Raskind M;Sabbagh M;Honig LS;Porsteinsson AP;Ferris S;Reichert M;Ketter N;Nejadnik B;Guenzler V;Miloslavsky M;Wang D;Lu Y;Lull J;Tudor IC;Liu E;Grundman M;Yuen E;Black R;Brashear HR;Bapineuzumab 301 and 302 Clinical Trial Investigators
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影响因子：
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影响因子：
10.6
作者：
Freeborough, PA;Fox, NC
通讯作者：
Fox, NC