Grant: Knowledge Synthesis Grant

<html> <body> <p> <strong>Background</strong> Despite decades of preclinical and clinical research, stroke continues to kill 6 million people every year globally¹. By 2006 there were <strong><em>at least 1,026 preclinical (i.e. in vitro and in vivo) experimental treatments</em></strong> <strong><em>for acute stroke</em></strong> with published data, and 114 preclinical therapies had been brought to clinical trial². <strong><em>Only one treatment with a preclinical basis</em></strong>, tissue plasminogen activator (tPA), has been successfully translated to the clinic for ischemic stroke³. Establishing which experimental treatment can minimize the morbidity and mortality associated with acute stroke in preclinical models is of paramount importance. However, given multiple therapies and mechanisms of action, it is difficult to assess which therapies should proceed to clinical trial.</p> <p>Preclinical systematic reviews have served as a method to transparently evaluate experimental therapies for more than decade^4,5. Previous preclinical systematic reviews have considered treatments in isolation using pair-wise meta-analyses, which limits the ability to evaluate the comparative effectiveness across treatments. Recently, network meta-analysis (NMA) has been used in comparative effectiveness research to study the relative benefits and harms of multiple interventions in humans^6,7. Such analyses allow the comparison of many interventions based on all &lsquo;direct&rsquo; and &lsquo;indirect&rsquo; information. <strong><em>No previous preclinical systematic review has used a NMA approach</em></strong><em>.</em> Such an approach has the potential to establish a more rigorous framework for decisions to embark on clinical trials while reducing risks to human trial participants and costs of preclinical translation^3,4,8. Comparison of preclinical stroke therapeutics represents an excellent case study for such work.</p> <p> <strong>Question Addressed</strong> </p> <p> <strong>Primary Objective</strong> We will perform a systematic review with NMA to address the following question: <em>In preclinical in vivo models of focal ischemic stroke, what are the relative benefits of competing therapies tested in combination with the gold standard treatment tPA</em><em>⁹</em> <em>(40 therapies pre-2010</em><em>¹⁰</em><em>) for</em> <br> <u>Primary Outcome</u> <br> (1) reducing infarct size?<br> <u>Secondary Outcomes</u> <br> (2) improving neurobehavioural outcomes?<br> (3) reducing mortality?</p> <p> <strong>Secondary Objectives</strong> We will:<br> A) assess the risk of bias and completeness of reporting of the included studies;<br> B) explore what novel considerations for statistical adjustments are necessary for NMA of preclinical studies (e.g. method of ischemic induction, timing of treatment, species, sex, and comorbidities);<br> C) evaluate the challenges of applying NMA to preclinical studies (these might include heterogeneity, consistency and similarity assumptions; availability of key study covariates).<br> </p> <p> <strong>Methods</strong> This review will evaluate the benefits and harms of therapies for acute stroke in preclinical models. The review will use established methods for systematic reviews and NMA described in detail in this proposal. We will conduct a search and collect data from eligible preclinical studies that test therapies for stroke. We will utilize sensitivity analyses to establish the robustness of the findings and identify the challenges in preclinical study reporting that limit the application of NMA.<br> </p> <p> <strong>Team Expertise</strong> Our team includes scientists, physicians, and trainees with expertise in knowledge synthesis and translation, including NMA, as well as extensive knowledge of preclinical stroke models. We will employ an integrated knowledge translation approach¹¹ and share findings with our knowledge users.</p> </body> </html>