Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer's disease (BLAZE).
Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer's disease (BLAZE).
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DOI：
10.1186/s13195-018-0424-5
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发表时间：
2018-09-19
期刊：
影响因子：
--
通讯作者：
Paul R
中科院分区：
文献类型：
--
作者：
Salloway S;Honigberg LA;Cho W;Ward M;Friesenhahn M;Brunstein F;Quartino A;Clayton D;Mortensen D;Bittner T;Ho C;Rabe C;Schauer SP;Wildsmith KR;Fuji RN;Suliman S;Reiman EM;Chen K;Paul R
我们研究了crenezumab(一种人源化抗淀粉样蛋白- β （a β)免疫球蛋白（Ig）G4单克隆抗体）对轻至中度阿尔茨海默病（AD）患者淀粉样蛋白病理、神经变性和疾病进展的生物标志物的影响。这项双盲、安慰剂对照、随机II期研究纳入了轻度至中度AD患者，MMSE评分为18-26分。在研究的第一部分中，患者按2:1随机分配，每2周（q2w）接受低剂量皮下（SC） 300 mg crenezumab或安慰剂治疗68周；在第二部分中，患者按2:1随机分配，每4周（q4w）接受高剂量静脉注射（IV） 15mg /kg crenezumab或安慰剂，持续68周。主要终点是通过florbetapir正电子发射断层扫描（PET）在修改意向治疗人群中评估从基线到第69周淀粉样蛋白负荷的变化。次要终点是从基线到第69周脑脊液（CSF）生物标志物和氟脱氧葡萄糖PET的变化，以及从基线到第73周阿尔茨海默病评估量表认知亚量表（ADAS-Cog12）和临床痴呆评分盒子总和（CDR-SB）的12点变化。对接受至少一剂研究治疗的患者进行安全性评估。2011年8月至2012年9月，91例患者入组并随机分组(低剂量SC队列：crenezumab （n = 26）或安慰剂（n = 13）；高剂量IV队列：crenezumab （n = 36）或安慰剂（n = 16）)。使用预先指定的小脑参考区域计算florbetapir PET的标准摄取值比（SUVRs），未达到主要终点。使用皮质下白质参考区进行的探索性分析显示，在高剂量IV队列中，斑块淀粉样蛋白积累缓慢的趋势不显著。在这两个队列中，观察到CSF a β(1-42)水平较基线有显著的平均升高。在高剂量IV组的轻度（MMSE 20-26）亚组中，ADAS-Cog12和CDR-SB获益的趋势不显著。未见水肿/积液引起淀粉样蛋白相关影像学异常。未达到主要终点。探索性发现提示潜在的Aβ靶点与crenezumab结合，并可能减缓斑块淀粉样蛋白的积累。研究高剂量crenezumab对淀粉样蛋白负荷和疾病进展的影响正在进行中。ClinicalTrials.gov NCT01397578。于2011年7月18日注册。本文的在线版本（10.1186/s13195-018-0424-5）包含补充资料，可供授权用户使用。
We investigated the effect of crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD). This double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18–26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment. From August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n = 26) or placebo (n = 13); high-dose IV cohort: crenezumab (n = 36) or placebo (n = 16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF Aβ(1–42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20–26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed. The primary endpoint was not met. Exploratory findings suggest potential Aβ target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing. ClinicalTrials.gov, NCT01397578. Registered on 18 July 2011. The online version of this article (10.1186/s13195-018-0424-5) contains supplementary material, which is available to authorized users.
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影响因子：
2.1
作者：
Sano M;Raman R;Emond J;Thomas RG;Petersen R;Schneider LS;Aisen PS
通讯作者：
Aisen PS
DOI：
10.1016/j.dadm.2016.02.006
发表时间：
2016
期刊：
Alzheimer's & dementia (Amsterdam, Netherlands)
影响因子：
--
作者：
Siemers E;Holdridge KC;Sundell KL;Liu-Seifert H
通讯作者：
Liu-Seifert H
DOI：
10.1186/s13195-017-0318-y
发表时间：
2017-12-08
期刊：
Alzheimer's research & therapy
影响因子：
--
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
通讯作者：
SCarlet RoAD Investigators
影响因子：
14
作者：
Fleisher, Adam S.;Joshi, Abhinay D.;Mintun, Mark A.
通讯作者：
Mintun, Mark A.
影响因子：
5.7
作者：
Fonov V;Evans AC;Botteron K;Almli CR;McKinstry RC;Collins DL;Brain Development Cooperative Group
通讯作者：
Brain Development Cooperative Group