Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (P.D.L., J.L., K.A.N.).
Department of Neurology (P.D.L.), Keck School of Medicine of USC, Los Angeles, CA.
Stroke. 2022 May;53(5):1802-1812. doi: 10.1161/STROKEAHA.121.038047. Epub 2022 Mar 31.
Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.
脑缺血和再灌注引发了脑内的细胞事件，导致神经功能障碍。研究这些细胞事件为开发新的治疗方法提供了充分的靶点。尽管做了大量的工作，但没有一种治疗方法转化为成功的中风治疗。除了其他问题，如不完全的机制知识和临床试验设计的错误，导致以前转化失败的一个关键因素可能是临床前评估中科学严谨性不足：非盲法结局评估；未随机分组；样本量不合适；以及在年轻雄性动物中进行的临床前评估忽略了相关的生物学变量，如年龄、性别和相关的合并症。有前途的结果很少在多个实验室中得到复制。我们试图通过在 6 个独立的研究实验室中对候选治疗方法进行严格评估来解决其中的一些问题。中风临床前评估网络（SPAN）采用最先进的实验设计，以测试以下假设：严格的临床前评估可以成功减少或消除在选择用于临床试验评估的治疗方法时常见的偏倚源。SPAN 是一项随机、安慰剂对照、盲法、多实验室试验，采用多臂多阶段方案，选择一种或多种有希望在人类中风临床试验中取得成功的潜在中风治疗方法。SPAN 的第一阶段实施了程序标准化和实验严谨性。所有参与的研究实验室都按照一个共同的方案进行大脑中动脉闭塞手术，并迅速在计划的 4 个阶段中的第 1 个阶段招募了 913 只小鼠，方案的执行率非常高，数据完成情况显著，实验对象的损失率低。SPAN 第 1 阶段成功地实施了治疗掩蔽、随机分组、预随机分组纳入/排除标准和盲法评估，以排除偏倚。我们的数据表明，减少已知偏倚源的大型、多实验室临床前评估工作是可行和实用的。随后的 SPAN 阶段将使用老年动物和患有合并症的动物评估候选治疗方法在未来中风临床试验中的潜在成功。
