Induced Suppression of Platelet Activity in Aneurysmal Subarachnoid Hemorrhage Management-2 (iSPASM-2)

This is an exploratory, two-center, randomized, double-blinded study. The primary objective is to determine the maximum tolerated dosage (MTD) of tirofiban in the context of patients with aSAH status post-endovascular coiling. The dosage regimen of tirofiban will be 0.10µg/kg/min (actual weight) within 48 hours of aneurysm securing and within 72 hours of ictus. The study will involve a dose escalation stage and a cohort expansion stage. During the dosage-escalation stage, the intervention doses include continuous intravenous (IV) tirofiban or IV placebo for 1 day, 3 days, 5 days, or 7 days. Dose-escalation will follow the time-to-event Bayesian Optimal Intervention (TITE-BOIN) design. Unlike the majority of existing phase I designs, which require suspending the accrual after treating each cohort of patients, the TITE-BOIN design allows for real-time dose assignment decisions for new patients while the toxicity data are still pending for some patients under treatment. This shortens the trial duration and reduces the logistical difficulties caused by frequent suspensions of accrual. For parallel comparison under real-world conditions, patients will be randomly assigned to tirofiban and placebo in a 2:1 ratio in the dose escalation stage. The data from the placebo patients will not be analyzed to inform dose escalation but included in the final analysis upon study completion. Upon the completion of the dose escalation stage, the MTD will be selected using isotonic regression. MTD will be selected as the dosage for which the isotonic estimate of the toxicity rate is closest to the target dosage-limiting toxicity rate (30%). If there is a tie, we will select the higher dosage level when the isotonic estimate is lower than the target toxicity rate, and we will select the lower dosage level when the isotonic estimate is greater than or equal to the target toxicity rate. During the cohort expansion stage, patients will be randomized to tirofiban at MTD and placebo at the corresponding dosage level to achieve balanced sample sizes (30 tirofiban at MTD and 30 placebo for any infusion duration, combined from both phases) across the two groups. The analysis of the exploratory endpoints will be performed on the tirofiban patients at MTD and placebo patients with any infusion duration. An interim pharmacokinetic (PK) analysis will be performed after 10 evaluable patients are treated with tirofiban to determine possible dose modification. At the completion of the study, PK and pharmacodynamic (PD) analysis will be conducted using all evaluable patients treated with tirofiban to determine whether augmented renal clearance in aSAH interacts with the pharmacokinetics and pharmacodynamics of tirofiban.