Proof-of-Concept Randomized Trial of the Monoclonal Antibody GSK249320 Versus Placebo in Stroke Patients.
Proof-of-Concept Randomized Trial of the Monoclonal Antibody GSK249320 Versus Placebo in Stroke Patients.
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DOI：
10.1161/strokeaha.116.014517
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发表时间：
2017-03
期刊：
影响因子：
8.3
通讯作者：
Thompson TR
中科院分区：
文献类型：
--
作者：
Cramer SC;Enney LA;Russell CK;Simeoni M;Thompson TR
文本中提供了补充数字内容。一类中风后恢复性治疗集中于通过阻断基于髓鞘的抑制性蛋白如髓鞘相关糖蛋白来促进轴突生长。本研究的目的是扩展GSK 249320（一种针对髓鞘相关糖蛋白的Fc区失活的人源化单克隆抗体）的临床前和临床研究结果，以探索对卒中后运动结局的影响。在这项IIb期双盲、随机、安慰剂对照研究中，30个中心的缺血性卒中24 - 72小时前和步态障碍患者随机接受2次GSK 249320或安慰剂IV输注。主要结局指标是从基线到第90天步态速度的变化。2013年5月至2014年7月期间，共134例受试者接受了随机化。两组在基线时总体匹配良好。在预先规定的中期分析时停止研究，因为治疗差异符合预定义的无效标准截止值; GSK 249320组第90天的步态速度变化为0.55±0.46（平均值±SD），安慰剂组为0.56±0.50。次要终点包括上肢功能一致。GSK 249320的2次IV输注耐受性良好。未检测到抗GSK 249320的中和抗体。GSK 249320在中风后72小时内，与安慰剂相比，步态速度没有改善。可能的原因包括将研究结果转化为人类的挑战，以及没有直接证据表明该疗法达到了生物靶点。该抗体耐受性良好，免疫原性低，这一发现可能有助于未来的研究，旨在使用单克隆抗体来改变特定生物学途径中的活性，以改善卒中的恢复。URL：http://www.clinicaltrials.gov。唯一标识符：NCT 01808261。
Supplemental Digital Content is available in the text. One class of poststroke restorative therapy focuses on promoting axon outgrowth by blocking myelin-based inhibitory proteins such as myelin-associated glycoprotein. The purpose of the current study was to extend preclinical and clinical findings of GSK249320, a humanized monoclonal antibody to myelin-associated glycoprotein with disabled Fc region, to explore effects on motor outcomes poststroke. In this phase IIb double-blind, randomized, placebo-controlled study, patients at 30 centers with ischemic stroke 24 to 72 hours prior and gait deficits were randomized to 2 IV infusions of GSK249320 or placebo. Primary outcome measure was change in gait velocity from baseline to day 90. A total of 134 subjects were randomized between May 2013 and July 2014. The 2 groups were overall well matched at baseline. The study was stopped at the prespecified interim analysis because the treatment difference met the predefined futility criteria cutoff; change in gait velocity to day 90 was 0.55±0.46 (mean±SD) in the GSK249320 group and 0.56±0.50 for placebo. Secondary end points including upper extremity function were concordant. The 2 IV infusions of GSK249320 were well tolerated. No neutralizing antibodies to GSK249320 were detected. GSK249320, within 72 hours of stroke, demonstrated no improvement on gait velocity compared with placebo. Possible reasons include challenges translating findings into humans and no direct evidence that the therapy reached the biological target. The antibody was well tolerated and showed low immunogenicity, findings potentially useful to future studies aiming to use a monoclonal antibody to modify activity in specific biological pathways to improve recovery from stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01808261.