Identifying stroke therapeutics from preclinical models: A protocol for a novel application of network meta-analysis

Introduction: Globally, stroke is the second leading cause of death. Despite the burden of illness and death, few acute interventions are available to patients with ischemic stroke. Over 1,000 potential neuroprotective therapeutics have been evaluated in preclinical models. It is important to use robust evidence synthesis methods to appropriately assess which therapies should be translated to the clinical setting for evaluation in human studies. This protocol details planned methods to conduct a systematic review to identify and appraise eligible studies and to use a network meta-analysis to synthesize available evidence to answer the following questions: 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 alteplase in (i) reducing cerebral infarction size, and (ii) improving neurobehavioural outcomes? Methods: We will search Ovid Medline and Embase for articles on the effects of combination therapies with alteplase. Controlled comparison studies of preclinical in vivo models of experimentally induced focal ischemia testing the efficacy of therapies with alteplase versus alteplase alone will be identified. Outcomes to be extracted include infarct size (primary outcome) and neurobehavioural measures. Risk of bias and construct validity will be assessed using tools appropriate for preclinical studies. Here we describe steps undertaken to perform preclinical network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. This will be a novel use of this evidence synthesis approach in stroke medicine to assess pre-clinical therapeutics. Combining all evidence to simultaneously compare mutliple therapuetics tested preclinically may provide a rationale for the clinical translation of therapeutics for patients with ischemic stroke.  Dissemination: Review findings will be submitted to a peer-reviewed journal and presented at relevant scientific meetings to promote knowledge transfer. Registration: PROSPERO number to be submitted following peer review

Systematic Review and Meta-analysis: Important Tools in Understanding Drug Development for Stroke

Animal models of ischaemic stroke have become an integral part of the preclinical pipeline for identifying novel neuroprotective drug targets and drugs. As the process serves as a filter, researchers do not expect complete concordance between the experimental animal and human clinical trial data. However, the paucity of clear examples of translation of promising animal results into drugs that work in a clinical setting has raised concerns about the utility of this translational paradigm. Preclinical systematic reviews have been used in response to these concerns to identify weaknesses in animal studies and provide empirical evidence supporting improvements to the design and conduct of preclinical animal experiments. We propose that further strategic development and application of data analysis methods can help continue this process of improvement and help identify the most promising therapeutic targets and drugs. These next steps in systematic review aim to tighten the focus of preclinical research, streamline the drug development process, and minimise research waste