An exploratory, randomized, double-blinded, placebo-controlled, two-center clinical trial to determine the maximum tolerated dosage of intravenous tirofiban in patients with aneurysmal subarachnoid hemorrhage (aSAH) post-endovascular coiling. The study will also assess pharmacology and safety, with exploratory endpoints including delayed cerebral ischemia (DCI), vasospasm, and functional outcomes.
Age 18-85
Baseline Modified Rankin Scale (mRS) 0-3 (pre-SAH)
SAH attributed to ruptured cerebral aneurysm
Admission Computed Tomography (CT) scan shows Modified Fisher grade 1-4 due to aSAH primarily in the supratentorial space
None
Parallel
Tirofiban
DrugIV infusion at 0.10 microgram/kilogram/minute (mcg/kg/min) for 1 day, 3 days, 5 days, or 7 days according to the dose escalation procedure.
Placebo
DrugIV infusion at the same infusion duration as the study drug; same adjustments
Tirofiban dosage-limiting toxicity (DLT)
Presence of any of the following: any intracranial hemorrhage, major extracranial hemorrhage (defined as clinically overt bleeding leading to death; OR clinically overt bleeding causing a reduction in hemoglobin of ≥2g/dl; OR clinically overt bleeding necessitating transfusion of ≥2 units of packed red cells or whole blood; OR clinically overt bleeding in a critical area or organ other than the intracranial compartment (including intraspinal, intraocular, pericardial, intra-articular, retroperitoneal, intramuscular \[with compartment syndrome\])), thrombocytopenia, or serious adverse event (SAE) due to tirofiban.
Pharmacokinetic parameters - total clearance (Cltot)
Pharmacokinetic parameters - Volume of distribution (Vd)
Pharmacokinetic parameters - Maximum (peak) plasma concentration (Cmax)
Highest concentration of tirofiban in the blood after a dose is administered
Pharmacokinetic parameters - Minimum (trough) plasma concentration (Cmin)
Lowest observed concentration of tirofiban in the blood after a dose is administered
Delayed cerebral ischemia (DCI) or death without DCI
This is the primary exploratory efficacy outcome, which is a composite binary outcome. DCI is defined as any of the following: a. Focal neurological impairment, b. decrease of at least 2 points on the Glasgow coma scale and/or c. cerebral infarction present on final CT or MRI, which was not present on a CT or MRI between 24-48 hours post-endovascular therapy and not attributable to other causes.
Cerebral vasospasm
Cerebral vasospasm requires confirmation of vasospasm on either CTA or DSA confirming mild vasospasm (decrease in vessel diameter by ≤25% of normal artery diameter), moderate vasospasm (decrease in vessel diameter by \>25 to ≤50% of normal diameter but cerebral vasospasm), or severe vasospasm (decrease in vessel diameter by \>50% of normal vessel diameter)
Mortality
Death of any cause
Total number of days in the ICU for the index admission
Total number of days from ICU admission to ICU discharge during the index hospitalization
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Dr David Hasan, M.D.
Lead sponsor
Duke University
Sponsor institution
National Institutes of Health (NIH)
Collaborator
National Institute of Neurological Disorders and Stroke (NINDS)
Collaborator
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