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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Tirofiban
  IV 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.
• Препарат Placebo
  IV infusion at the same infusion duration as the study drug; same adjustments

Первичные конечные точки

• Tirofiban dosage-limiting toxicity (DLT) [Срок оценки: Within 14 days post-randomization]

Вторичные конечные точки (7)

• Pharmacokinetic parameters - total clearance (Cltot) [Срок оценки: Up to 7 hours after drug discontinuation]
• Pharmacokinetic parameters - Volume of distribution (Vd) [Срок оценки: Up to 7 hours after drug discontinuation]
• Pharmacokinetic parameters - Maximum (peak) plasma concentration (Cmax) [Срок оценки: Up to 7 hours after drug discontinuation]
• Pharmacokinetic parameters - Minimum (trough) plasma concentration (Cmin) [Срок оценки: Up to 7 hours after drug discontinuation]
• Pharmacokinetic parameters - Average Plasma Concentration (Cavg) [Срок оценки: Up to 7 hours after drug discontinuation]
• Pharmacokinetic parameters - Area Under the Concentration (AUC)Time Curve [Срок оценки: Up to 7 hours after drug discontinuation]
• Pharmacodynamic parameters - adenosine diphosphate (ADP) [Срок оценки: Baseline, 2, 6, and every 24 hours and at drug cessation]

Критерии участия

Inclusion:

• 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
• World Federation of Neurosurgical Societies (WFNS) scale grade ≤4 at randomization
• Onset of symptoms of aSAH (ictus) occurred <72 hours prior to presentation
• If External Ventricular Drain (EVD) placed, placement is ≥12 hours prior to enrollment
• All aneurysm(s) suspected to be responsible for the hemorrhage must be secured via Endovascular Coil Embolization with a post-embolization Raymond-Roy Score of 1 (Complete) or 2 (Residual Neck) prior to enrollment
• Participant can be randomized within 48 hours of aneurysm treatment
• Participant or participant's legally-authorized representative (LAR) has provided documented informed consent

Exclusion:

• Angio-negative SAH, defined as a SAH with a digital subtraction angiogram that does not show an intracranial aneurysm
• Surgical clipping prior of the ruptured aneurysm or any non-ruptured aneurysm on the same admission to enrollment
• Remaining untreated aneurysm(s) that could reasonably be considered a possible alternate cause of the aSAH based on the observed bleeding pattern
• Uncontrollable hypertension (>180 systolic and/or >110 diastolic) that is not correctable prior to enrollment
• Active internal bleeding, or history of bleeding diathesis, major surgical procedure, or severe physical trauma within the previous month (30 days)
• A medical diagnosis that requires continuous use of aspirin, clopidogrel, ticagrelor, or tirofiban during the study drug infusion
• New parenchymal hemorrhage or new infarction larger than 15 cubic centimeters (cc) in volume by CT
• Thrombolytic therapy within 24 hours prior to enrollment (alteplase, tenecteplase, or urokinase)
• Previous intracranial hemorrhage, intracranial neoplasm, subarachnoid hemorrhage, or arterial-venous malformation
• Thrombocytopenia (platelet count <100,000/microliter (µL) assuming clumping is ruled out
• Allergy or intolerance to tirofiban
• Pregnant or lactating
• Chronic kidney disease with creatinine clearance (CrCl ≤ 30 milliliters per minute \[ml/min\]) or acute kidney injury (AKI) at study screening. AKI is defined as:

i) Increase in serum creatinine by 0.3 milligrams per deciliter (mg/dL) or more (26.5 micromoles per liter \[μmol/L\] or more) within 48 hour period; OR ii) Increase in serum creatinine to 1.5 times or more than the baseline of the prior 7 day period; OR iii) Urine volume less than 0.5 ml/kg/hour for at least 6 hours

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

США · 2 центра

• Duke University Health System — Durham
• University of Texas Health Sciences Center — Houston

Идентификаторы

NCT: NCT07493577 · Pro00119469 · UG3NS138219

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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