Evolution and Future of Stroke Trials

benefit, and is completed efficiently and expeditiously.Particularly, a trial population should include the patient population that is most affected by the disease, in terms of race, ethnicity, sex and age.Because many environmental, genetic and psychological factors can affect outcome and recurrence in individual patients, demonstrating efficacy of a therapy requires a reasonable balance of these important confounding factors between treatment and non-treatment groups, best achieved by randomization in clinical trials.Preclinical stroke models try to address these confounders by using genetically similar animals in tightly controlled laboratory environment.The National Institute of Neurologic Disorders and Stroke (NINDS) Stroke Pre-Clinical Assessment Network (SPAN) for testing potential acute stroke treatments in mice has tried to better model human variability by including male and female animals of various ages and genetic strains (hypertensive mice), and by conducting experiments in multiple laboratory environments, better mirroring the multi-center approach to clinical stroke trials.8 Hopefully, better design of preclinical trials may improve the pipeline of future therapies to be tested in patients with stroke. Advances in Stroke TrialsAdvances in the design of randomized trials have accompanied and accelerated advances in proven stroke therapies.Some of the early innovations in the design and analyses of randomized stroke trials have included double-blinding in the 1963 trial of plasmin for acute ischemic stroke, 4 factorial design testing two medications alone or together in the secondary-prevention Canadian Aspirin Trial, 3 the incorporation of the modified Rankin Score as the primary outcome measure in many acute stroke trials with categorical, ordinal, and sliding dichotomy statistical methodologies, 9 step-forward randomization to minimize time to treatment in the NINDS t-PA Stroke Trials of recombinant tissue plasminogen activator (rt-PA), 10 and pooled analyses of the initial rt-PA trials in 2004.11 Major advances in stroke clinical trials over the past 10+ years include national and global clinical trial infrastructures; 12,13 advances in trial design such as adaptive trials (DAWN: DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo, 14 DEFUSE 3: Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3, 15,44 ENRICH: The Early Minimally Invasive Removal of Intracerebral Hemorrhage, 16 MOST: Multi-Arm Optimization of Stroke Therapy, 17 registry-based trials (AcT: Intravenous tenecteplase compared with tissue plasminogen activator for acute ischemic stroke in Canada), 18 stepped-wedge cluster trials (INTERACT 3: The Third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial), 19 pre-hospital acute trials (e.g.FAST-MAG: The Field Administration of Stroke Therapy-Magnesium, 20 RACE-CAT: Transfer to the Closest Local Stroke Center vs Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory, 21 and RIGHT-2: Prehospital Transdermal Glyceryl trinitrate in Patients with Presumed Ultra-acute Stroke Trial), 22 pragmatic trials (SATURN: Statins in Intracerebral Hemorrhage Trial -https://classic.clinicaltrials.gov/ct2/show/NCT03936361,Early versus Late initiation of direct oral Anticoagulants in post-ischemic stroke patients with atrial fibrillation-ELAN) 23 ; minimization of time from stroke onset to randomization in acute trials using mobile stroke units (BEST MSU (Mobile Stroke Unit) 24 , Berlin, Germany MSU