Overview
The DONE SYMPLE Investigator-initiated phase III prospective, randomized, open-label, blinded endpoint-controlled clinical trial.
This clinical trial is a global clinical study testing whether a procedure called endovascular therapy, which removes blood clots from blocked brain arteries, can safely benefit more stroke patients when used up to 72 hours after symptoms begin. Endovacular Therapy is already proven to improve recovery in patients treated within 6 hours, but only when advanced imaging like Computed Tomography (CT) perfusion or Magnetic Resonance Imaging (MRI) is available to guide treatment. Unfortunately, many hospitals, specially in underserved areas, do not have access to this type of imaging.
This trial will investigate whether a basic brain scan called non-contrast CT, which is widely available in hospitals around the world, can be used instead. Special software will automatically analyze the CT scan to help doctors decide if a patient has enough brain tissue left to save with Endovascular Therapy. If this simpler approach works, it could expand access to lifesaving stroke care for more people globally.
The study will enroll 500 adult stroke patients, ages 18 to 80, with a large vessel blockage in the brain's anterior circulation, moderate to severe stroke symptoms, and who are between 6 and 72 hours from when they were last known to be well. All participants will undergo CT imaging analyzed by the automated software. If the scan shows a small core of already damaged brain tissue and a larger area of threatened but still viable brain, the patient will qualify.
Participants will be randomly assigned to receive either standard medical therapy alone or medical therapy plus Endovasculat Therapy which involves inserting a catheter through a blood vessel to reach the brain and using a device to remove the clot. This procedure is performed by trained stroke or neurointerventional specialists. The study is "open-label," meaning patients and doctors know which treatment is given, but the assessment of patient recovery will be done by independent reviewers who do not know the group assignments.
The primary goal is to determine if patients who receive Endovascular Therapy have better recovery at 90 days, measured by a scale called the modified Rankin Scale, which assesses how much disability a patient has after a stroke. The trial will also look at safety (especially brain bleeding after treatment), size and growth of brain injury on follow-up scans, recovery of strength and language, and overall quality of life and survival. Imaging will be reviewed centrally by a specialized team, and results will be analyzed to see how well Endovascular Therapy performs using this new patient selection method.
The DONE SYMPLE Trial is sponsored by Foundacio Ictus in Barcelona Spain and the University of Iowa is the Central Coordinating Center for the Study. It will take place at up to 20 hospitals worldwide. All patients will be followed closely with exams and imaging at specific time points up to 90 days after treatment.
If successful, this trial could change stroke care around the world by proving that Endovascular Therapy can be used safely and effectively even without advanced imaging, using tools available in most hospitals. This could help more stroke patients, especially in rural or resource-limited areas, access treatments that may improve their chances of recovery and reduce long-term disability.
Description
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.
Eligibility
Inclusion Criteria:
- 18 to 80 years of age:
- Pre-stroke score (mRS) of 0-1 in participants aged 18 to 70 years.
- Pre-stroke Modified Rankin Scale (mRS) score of 0 in participants older than 70 years.
- Presenting with signs and symptoms consistent with an acute ischemic stroke within
24-72 hours from last known well. *
- Baseline NIHSS ≥8.
- NCCT imaging indicating the existence of an anterior circulation LVO by an automated software, or CTA (when available).
- Core volume ≤ 70 cc determined by a deep learning algorithm in automated software and/or ASPECTS scoring ≥ 6. **
- Arterial puncture within 72 hours (after the first symptoms or LKW).
- Arterial puncture within 90 minutes from initial CT.
- Ability to randomize within 72 hours after stroke onset (last seen well).
- Ability to obtain signed informed consent or subject's Legally Authorized
representative (LAR) has signed Consent form ***
- Patients in the 6-24-hour after Last Known Well (LKW) may be enrolled only in
centers where thrombectomy is not offered as standard of care due to the
absence of advanced imaging capabilities.
- In cases of discrepancy between the automated tool LVO detection and
volume, and ASPECT Score or CTA judgment or Computed Tomography
Angiography CTA findings, ASPECTS and CTA will take precedence.
- If approved by local ethics committee and country regulations, the investigator is allowed to enroll a patient utilizing emergency informed consent procedures if neither the patient nor the representative or person of trust is available to sign the informed consent form. However, as soon as possible, the patient is informed, and his/her consent is requested for the possible continuation of this research.
- In cases of discrepancy between the automated tool LVO detection and
volume, and ASPECT Score or CTA judgment or Computed Tomography
Angiography CTA findings, ASPECTS and CTA will take precedence.
- Patients in the 6-24-hour after Last Known Well (LKW) may be enrolled only in
centers where thrombectomy is not offered as standard of care due to the
absence of advanced imaging capabilities.
Exclusion Criteria:
- Females who are pregnant, or those of child-bearing potential with positive urine or serum beta Human Chorionic Gonadotropin (HCG) test.
- Known severe allergy (more than a rash) to contrast media uncontrolled by medications.
- Refractory hypertension (defined as persistent systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg) despite medication.
- CT evidence of the following conditions:
- Midline shift or herniation.
- Evidence of intracranial hemorrhage.
- Mass effect with effacement of the ventricles.
- Bilateral strokes.
- Clot retrieval previously attempted <6 hours.
- Treated with thrombolytics >4.5 hours after last seen well.
- Intracranial tumors.
- Life expectancy less than 90 days prior to stroke onset.
- Participation in another randomized clinical trial that could confound the evaluation of the study.
- Presumed septic embolus, or suspicion of bacterial endocarditis.
- Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, e.g. dementia with prescribed anti-cholinesterase inhibitor (e.g. Aricept).
- Any other condition (in the opinion of the site investigator) that precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was performed.