Safety of Rapid Local Ischemic Postconditioning After Thrombectomy in Acute Stroke: A Dose-Finding Trial (RAPID SAVE)

Rapid local ischemic postconditioning may protect the brain after acute ischemic stroke, but its safety and optimal dosing in successfully reperfused patients after mechanical thrombectomy remain undefined.

This investigator-initiated, prospective, adaptive, multicenter phase I single-arm dose-finding trial employed a Bayesian Optimal Interval (Bayesian Optimal Interval Phase I/II) design. Patients with anterior circulation large-vessel occlusion and modified Thrombolysis in Cerebral Infarction 2b/3 reperfusion were enrolled without randomization. Within 5 minutes of recanalization, rapid local ischemic postconditioning was delivered via a balloon-guiding catheter positioned at the ipsilateral C1-intracranial internal carotid artery, alternating inflation/deflation to interrupt antegrade flow. Six dose levels were prespecified by inflation/deflation durations and cycles: 15/15s ×5; 1/1, 2/2, 3/3, 4/4, and 5/5 minutes ×4. The dose-limiting toxicity (including malignant infarction, procedure-related complications requiring treatment, or other procedure-attributable serious adverse events) threshold was 15%. The efficacy target (absence of infarct growth >10 mL at 72 hours) was 60%. Doses were eliminated if the posterior probability that toxicity exceeded 15% was ≥0.95 or efficacy <60% was ≥0.90. The dose with the highest utility meeting these criteria was selected.

Five cohorts (n=25, 5 each) were enrolled. Four cohorts received 2/2 minutes×4 (n=20): 14 met the efficacy end point (posterior probability true efficacy <60%, ≈0.15), and 1 had a dose-limiting toxicity due to large infarction growth (probability true toxicity >15%, ≈0.16). One cohort received 3/3 minutes×4 (n=5): 3 met the efficacy end point (probability true efficacy <60%, ≈0.31) and 2 had dose-limiting toxicities due to large infarction growth (probability true toxicity >15%, ≈0.95). This triggered the predefined safety rule, preventing further testing at 3/3-minute and higher doses. Bayesian Optimal Interval Phase I/II selected 2/2 minutes×4 as the optimal regimen with a favorable efficacy-toxicity profile.

Rapid local ischemic postconditioning initiated immediately after thrombectomy was feasible. The 2/2 minutes×4 regimen met prespecified safety and efficacy thresholds and warrants evaluation in a larger, definitive trial.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT06526429.