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Designing clinical trials for bridging cerebroprotection in the era of mechanical thrombectomy: are we missing the point?
    1. 1Diagnostic Imaging, University of Calgary, Calgary, Alberta, Canada
    2. 2Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
    3. 3Clinical Neurosciences, Foothills Medical Centre, Calgary, Alberta, Canada
    1. Correspondence to Dr Mayank Goyal, Seaman Family MR Research Centre, Foothills Medical Centre, 1403 - 29th St. NW, Calgary, Alberta T2N 2T9, Canada; mgoyal2412{at}

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    Cerebroprotectants are therapies that aim to diminish or prevent ischemic tissue damage in acute ischemic stroke. Numerous cerebroprotectants for human acute ischemic stroke have been investigated, many of which have pleiotropic effects that target both tissue damage mechanisms occurring before recanalization (eg, early infarct growth) and after recanalization (eg, reperfusion injury, blood–brain barrier breakdown).1 2 While the exact contribution of these various mechanisms to the ‘overall burden’ of the ischemic tissue damage is currently not clear yet, early infarct growth before recanalization is one of the mechanisms that seem to impact patient outcomes most profoundly.3

    Therefore, bridging cerebroprotectants (ie, therapies aimed at stopping or slowing down infarct growth until definitive reperfusion is achieved) are a particularly promising adjunctive ischemic stroke treatment in addition to endovascular treatment (EVT). A wealth of animal literature has repeatedly shown that many compounds have bridging cerebroprotectant properties. A prototypic compound, nerinetide, is effective in non-human primate models of ischemic stroke due to large vessel occlusion4,4–6

    Three randomized clinical trials have evaluated the efficacy of nerinetide in large vessel occlusion ischemic stroke undergoing EVT: ESCAPE-NA1 (Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke), ESCAPE-NEXT (Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis), and FRONTIER (Field Randomization of Nerinetide (NA-1) Therapy in Early Responders) trials. The results of these trials were conflicting, with ESCAPE-NA1 showing improved outcomes with nerinetide in the no-alteplase stratum only,7 ESCAPE-NEXT showing no treatment effect, and FRONTIER showing improved outcomes with nerinetide in the entire modified intention to treat sample, which was even more pronounced in patients with confirmed ischemic stroke and subsequent vessel recanalization. A preliminary pooled analysis of the trials suggests a possible higher benefit of nerinetide in patients that were enrolled …

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    • Contributors All authors contributed to the conception and design of the work. JMO drafted the manuscript and figures. All authors contributed to critical revision of the manuscript and figure. All authors gave approval of the version to be published and agree to be accountable for all aspects of the work.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

    • Competing interests MG and MDH are principal investigators of the ESCAPE-NA1 and ESCAPE-NEXT trials.

    • Provenance and peer review Not commissioned; externally peer reviewed.