The DONE SYMPLE Trial is a Phase III, multicenter, prospective, randomized, open-label trial with blinded endpoint assessment (PROBE design), evaluating the safety and efficacy of endovascular therapy (EVT) in patients with acute ischemic stroke (AIS) due to anterior circulation large vessel occlusion (LVO) treated between 6 to 72 hours from last known well. The key innovation is the use of non-contrast computed tomography (NCCT) with automated software analysis as the sole selection modality, replacing advanced imaging requirements such as CT perfusion or MRI diffusion-perfusion mismatch.
The trial addresses critical gaps in access to reperfusion therapy by enabling stroke triage and selection using standard NCCT imaging combined with artificial intelligence tools, thereby facilitating inclusion of centers without advanced imaging infrastructure. The selection criteria are based on automated estimation of ischemic core volume (≤70 cc) and evidence of LVO detection, derived from FDA-cleared deep learning algorithms and structured image analysis (e.g., ASPECTS quantification and vessel segmentation).
A total of 500 patients will be randomized 1:1 to either (1) standard medical therapy or (2) EVT plus standard medical therapy. Randomization will be stratified by baseline stroke severity (NIH Stroke Scale), time from symptom onset, core infarct volume, and enrolling site. EVT will be performed using CE-marked or FDA-cleared thrombectomy devices following standard institutional practice.
The primary endpoint is global disability at 90 days, assessed using the utility-weighted modified Rankin Scale (dw-mRS). Secondary efficacy analyses include mRS ordinal shift, dichotomized mRS (0-2), NIHSS change, and angiographic endpoints such as reperfusion success (TICI ≥2b) and first-pass effect (TICI 2c-3 on first attempt). Safety outcomes include symptomatic intracranial hemorrhage (sICH) per Heidelberg criteria, infarct growth on serial imaging, and all-cause mortality.
The statistical framework employs a Bayesian Gaussian model stratified by time-to-treatment intervals (6-24, 24-48, and 48-72 hours). The adaptive enrichment design enables interim analyses after enrollment milestones (n=200, 275, 350, 425) to evaluate futility, efficacy, or harm. The final sample size accounts for 10% potential LVO detection misclassification by automated software and 5% anticipated loss to follow-up.
Imaging is adjudicated centrally by a blinded core laboratory, ensuring uniform quantification of infarct volume and recanalization metrics. Functional outcomes are assessed by trained evaluators blinded to treatment allocation. Trial conduct is overseen by an independent data monitoring committee and a clinical events committee to adjudicate adverse events and outcomes.
By leveraging accessible imaging with automated tools, the DONE SYMPLE Trial aims to demonstrate that safe and effective EVT can be extended to patients beyond 24 hours and in settings without advanced imaging. If positive, the findings will inform future guideline updates and support broader implementation of thrombectomy in underserved populations globally.
