Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials.
Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials.
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DOI：
10.1001/jamaneurol.2022.2909
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发表时间：
2022-11-01
期刊：
影响因子：
29
通讯作者：
Doody, Rachelle S.
中科院分区：
文献类型：
--
作者：
Ostrowitzki, Susanne;Bittner, Tobias;Sink, Kaycee M.;Mackey, Howard;Rabe, Christina;Honig, Lawrence S.;Cassetta, Emanuele;Woodward, Michael;Boada, Merce;van Dyck, Christopher H.;Grimmer, Timo;Selkoe, Dennis J.;Schneider, Andres;Blondeau, Kathleen;Hu, Nan;Quartino, Angelica;Clayton, David;Dolton, Michael;Dang, Yifan;Ostaszewski, Beth;Sanabria-Bohorquez, Sandra M.;Rabbia, Michael;Toth, Balazs;Eichenlaub, Udo;Smith, Jillian;Honigberg, Lee A.;Doody, Rachelle S.
抗淀粉样蛋白抗体 crenezumab 对早期阿尔茨海默病 (AD) 患者安全有效吗？在预先计划的中期分析表明 CREAD 不太可能达到主要终点后，crenezumab CREAD（813 名受试者）和 CREAD2（806 名受试者）的随机临床试验提前终止。 Crenezumab 每 4 周静脉注射 60 mg/kg，持续长达 100 周，耐受性良好，但不会减少临床衰退，也不会影响 AD 相关生物标志物。 Crenezumab 具有良好的耐受性，但并未减少早期 AD 参与者的临床衰退或改变疾病相关的生物标志物。这些随机临床试验评估了 crenezumab 与安慰剂在早期阿尔茨海默病患者中的安全性和有效性。阿尔茨海默病 (AD) 是一种以大脑中 β-淀粉样斑块和 τ 缠结为特征的神经退行性疾病，代表着未满足的医疗需求，目前尚无完全批准的治疗方法来改变疾病进展。旨在研究 crenezumab（一种针对 β-淀粉样蛋白寡聚体的人源化单克隆免疫球蛋白 G4 抗体）在前驱至轻度（早期）AD 患者中的安全性和有效性。两项 3 期多中心随机双盲安慰剂对照平行组 Crenezumab 在早期 AD 受试者中的疗效和安全性研究（CREAD 和 CREAD2）分别于 2016 年和 2017 年启动，旨在评估 crenezumab 在早期 AD 受试者中的疗效和安全性。 CREAD（30 个国家的 194 个中心）和 CREAD2（27 个国家的 209 个中心）是全球多中心研究。 CREAD 和 CREAD2 分别筛选了 3736 名和 3664 名参与者。 CREAD 和 CREAD2 分别筛选了 3736 名和 3664 名参与者。这两项试验均招募了 50 至 85 岁的早期 AD 患者。患有某些合并症和脑梗死证据或磁共振成像显示超过 4 处微出血或软脑膜含铁血黄素沉着症区域的参与者被排除在外。分别排除 2923 名和 2858 名参与者后，CREAD 中的 813 名参与者和 CREAD2 中的 806 名参与者以 1:1 的比例随机分配至安慰剂或 crenezumab。最终分析中，CREAD 中安慰剂组有 409 名参与者，crenezumab 组有 404 名参与者，CREAD2 中安慰剂组有 399 名参与者，crenezumab 组有 407 名参与者。数据分析分别截至 2019 年 1 月和 2019 年 8 月。参与者每 4 周接受安慰剂或 60 mg/kg crenezumab 静脉注射，持续长达 100 周。主要结局是临床痴呆评分-框总和 (CDR-SB) 评分从基线到第 105 周的变化。 CREAD 中有 813 名参与者（平均 [SD] 年龄，70.7 [8.2] 岁；483 名女性和 330 名男性），CREAD2 中有 806 名参与者（平均 [SD] 年龄，70.9 [7.7] 岁；456 名女性和 350 名男性）。两组之间的基线特征是平衡的。 CREAD 研究第 105 周时，CDR-SB 评分（安慰剂减去 crenezumab）相对于基线的平均变化的组间差异为 -0.17（95% CI，-0.86 至 0.53；P = .63）（88 例安慰剂；86 例 crenezumab）。与之前的试验相比，没有发现新的安全信号，淀粉样蛋白相关的水肿成像异常罕见、轻微且短暂。没有观察到 AD 生物标志物发生有意义的变化。两项研究均在预先计划的中期分析表明 CREAD 不太可能达到主要终点后终止。 Crenezumab 具有良好的耐受性，但并未减少早期 AD 参与者的临床衰退。 ClinicalTrials.gov 标识符：CREAD、NCT02670083； CREAD2，NCT03114657
Is the antiamyloid antibody crenezumab safe and efficacious in people with early Alzheimer disease (AD)? The randomized clinical trials of crenezumab CREAD (813 participants) and CREAD2 (806 participants) were discontinued early following a preplanned interim analysis indicating CREAD was unlikely to meet the primary end point. Crenezumab, 60 mg/kg delivered intravenously every 4 weeks for up to 100 weeks, was well tolerated but did not reduce clinical decline nor affect AD-relevant biomarkers. Crenezumab was well tolerated but did not reduce clinical decline or change disease-relevant biomarkers in participants with early AD. These randomized clinical trials evaluate the safety and efficacy of crenezumab vs placebo in individuals with early Alzheimer disease. Alzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression. To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD. Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively. Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks. The primary outcome was change from baseline to week 105 in Clinical Dementia Rating–Sum of Boxes (CDR-SB) score. There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was −0.17 (95% CI, −0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point. Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD. ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657
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影响因子：
11.2
作者：
Yang, Ting;Dang, Yifan;Selkoe, Dennis J.
通讯作者：
Selkoe, Dennis J.
DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
DOI：
10.1186/s13195-018-0424-5
发表时间：
2018-09-19
期刊：
Alzheimer's research & therapy
影响因子：
--
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
通讯作者：
Paul R
影响因子：
9
作者：
Yoshida, Kenta;Moein, Anita;Quartino, Angelica
通讯作者：
Quartino, Angelica
影响因子：
3.5
作者：
Herdman, M.;Gudex, C.;Lloyd, A.;Janssen, M. F.;Kind, P.;Parkin, D.;Bonsel, G.;Badia, X.
通讯作者：
Badia, X.