1 Research Service, Edward Hines Jr. Veterans Affairs Hospital, Hines, IL, USA.
2 Loyola University Chicago Health Sciences Division, Maywood, IL, USA.
J Cereb Blood Flow Metab. 2018 Aug;38(8):1327-1338. doi: 10.1177/0271678X17730994. Epub 2017 Sep 27.
Many preclinical treatment strategies for stroke have failed when tested in human trials. Although the reasons for these translation failures are multifactorial, one potential concern is the statistical analysis of the preclinical data. One way to rigorously evaluate new therapies is to use an intention-to-treat analysis in preclinical studies. Therefore, in this study, we set out to evaluate the treatment efficacy of a potential clinically relevant therapeutic agent for stroke, i.e., anti-Nogo-A immunotherapy, using an intention-to-treat analysis. Adult rats were trained on the skilled forelimb reaching task and subsequently underwent an ischemic stroke. Nine weeks later, the rats either received intracerebroventricular anti-Nogo-A antibody, control antibody, or no treatment. Skilled reaching performance was assessed by a non-linear model using both an intention-to-treat and per-protocol analysis. Following testing, dendritic complexity was evaluated in the contralesional and perilesional sensorimotor cortex. Both intention-to-treat and per-protocol analysis showed that anti-Nogo-A immunotherapy resulted in statistically significant improved recovery on the skilled forelimb reaching task, although treatment effect was less (though statistically significant) in the intention-to-treat group. Improved functional performance was not shown to be associated with dendritic changes. In conclusion, this study provides evidence for the importance of using intention-to-treat paradigms in testing preclinical therapeutic strategies.
许多针对中风的临床前治疗策略在临床试验中都失败了。尽管这些转化失败的原因是多方面的，但一个潜在的问题是临床前数据的统计分析。一种严格评估新疗法的方法是在临床前研究中使用意向治疗分析。因此，在这项研究中，我们着手使用意向治疗分析来评估一种潜在的与临床相关的中风治疗药物，即抗 Nogo-A 免疫疗法的治疗效果。成年大鼠接受熟练的前肢抓握任务训练，随后进行缺血性中风。9 周后，大鼠接受脑室注射抗 Nogo-A 抗体、对照抗体或不治疗。使用意向治疗和方案分析的非线性模型评估熟练的抓握表现。测试后，在对侧和病灶周围感觉运动皮层评估树突复杂性。意向治疗和方案分析均表明，抗 Nogo-A 免疫疗法可显著改善熟练前肢抓握任务的恢复，但意向治疗组的治疗效果（尽管有统计学意义）较低。改善的功能表现与树突变化无关。总之，这项研究为在测试临床前治疗策略时使用意向治疗范式提供了证据。
