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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: Tirofiban; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 82
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Beth Perry; Phone Number: 919-681-2695; Email: beth.perry@duke.edu
• Study Contact Backup: Name: Hazani Benitez-Rosas; Phone Number: 919-681-4974; Email: Hazani.benitez-rosas@duke.edu

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
      • Contact: Hazani Benitez-Rosas, AS; Phone Number: 919-681-4974; Email: hazani.benitez-rosas@duke.edu
      • Contact: Beth A Perry, RN; Phone Number: 919-681-2695; Email: beth.perry@duke.edu
      • Principal Investigator: Emad Hasan, MD
      • Principal Investigator: Brian Mac Grory, MD
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Sciences Center
      • Contact: Sprios Blackburn, MD; Phone Number: 713-486-8000; Email: Spiros.Blackburn@uth.tmc.edu
      • Principal Investigator: Spiros Blackburn, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirofiban; Continuous IV infusion of tirofiban for 1, 3, 5, or 7 days post-endovascular coiling.	Drug: 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.; Other Names: Aggrastat ®
Placebo Comparator: Placebo; Continuous IV infusion of saline placebo for 1, 3, 5, or 7 days post-endovascular coiling.	Drug: Placebo; IV infusion at the same infusion duration as the study drug; same adjustments; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Within 14 days post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters - total clearance (Cltot)		Up to 7 hours after drug discontinuation
Pharmacokinetic parameters - Volume of distribution (Vd)		Up to 7 hours after drug discontinuation
Pharmacokinetic parameters - Maximum (peak) plasma concentration (Cmax)	Highest concentration of tirofiban in the blood after a dose is administered	Up to 7 hours after drug discontinuation
Pharmacokinetic parameters - Minimum (trough) plasma concentration (Cmin)	Lowest observed concentration of tirofiban in the blood after a dose is administered	Up to 7 hours after drug discontinuation
Pharmacokinetic parameters - Average Plasma Concentration (Cavg)	Average tirofiban concentration in the blood at steady state	Up to 7 hours after drug discontinuation
Pharmacokinetic parameters - Area Under the Concentration (AUC)Time Curve	Area under the curve from time 0 extrapolated to infinite time	Up to 7 hours after drug discontinuation
Pharmacodynamic parameters - adenosine diphosphate (ADP)	The percent inhibition of ADP-induced platelet aggregation	Baseline, 2, 6, and every 24 hours and at drug cessation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Within 14 days post-randomization
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)	Within 14 days post-randomization or until discharge from the index admission, which occurred later
Mortality	Death of any cause	3 and 6 months post-randomization
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	Up to 6 months post-randomization
Total hospital stay length for the index admission	Total number of days from admission to discharge during the index admission	Up to 6 months post-randomization
Modified Rankin Scale (mRS)	It is a clinician-reported measure of global disability, widely applied for evaluating stroke patient outcomes and as an endpoint in randomized clinical trials. It is a single-item 7-point scale with a range of 0 (no symptoms at all) to 6 (death), with higher scores indicating greater disability. The elements of the mRS are as follows: (1) no symptoms at all; (2) no significant disability, but there may be slight symptoms such as weakness or numbness; (3) slight disability, but able to carry out daily activities independently; (4) moderate disability, requiring some help with daily activities; (5) moderately severe disability, requiring assistance with most daily activities; (6) severe disability, bedridden and requiring constant nursing care; and (7) death.	3 and 6 months post-randomization
Return to work	Returned to prior level of responsibilities at work	3 and 6 months post-randomization
Lawton Instrumental Activities of Daily Living (Lawton IADL)	It is an instrument to assess independent living skills among older adults, and can be used in community or hospital settings. There are 8 domains of function measured with the scale: (1) using the telephone; (2) shopping; (3) preparing food; (4) housekeeping; (5) doing laundry; (6) using transportation; (7) handling medications; (8) handling finances. Women are scored on all 8 areas of function; historically, for men, the areas of food preparation, housekeeping, and laundering are excluded. Individuals are scored according to their highest level of functioning in that category. A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women, and 0 through 5 for men.	3 and 6 months post-randomization
Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS)	It is a 6-item scale to evaluate the overall satisfaction with facets of life relevant to people with traumatic brain injury. The area covered by the questionnaire includes physical condition, cognition, emotions, function in daily life, personal and social life, and current situation and future prospects. Responses to each item were scored 1 ('Not at all') to 5 ('Very'), and the sum of all items was converted arithmetically to a percentage scale, with 0 representing the lowest possible (health-related quality of life (HRQoL) on the questionnaire and 100 the best possible HRQoL.	3 and 6 months post-randomization
Glasgow Outcome Scale-Extended (GOS-E)	It is used to assess global outcomes in persons with brain injury, by categorizing global function using an 8-point ordinal scale that focuses on disability and functioning in daily life. The scales are: 1. Dead, 2. Vegetative State, 3. Lower Severe Disability (SD), 4. Upper SD, 5. Lower Moderate Disability (MD), 6. Upper MD, 7. Lower Good Recovery (GR), 8. Upper GR	3 and 6 months post-randomization
PROMIS-29+2	The Patient-Reported Outcomes Measurement Information System® (PROMIS) is a flexible set of tools designed to measure self-reported physical, mental, and social health and wellbeing. PROMIS-29+2 is a collection of 4-item Likert-item short forms assessing the following domains: Physical function; Anxiety; Depression; Fatigue; Sleep disturbance; Ability to participate in social roles and activities; Pain interference; Cognitive Function - Abilities (2 items); Pain intensity (single item) Norm-based scores will be calculated for each domain on the PROMIS measures, so that a score of 50 represents the mean or average of the reference population. A score of 60 means that the person is one standard deviation above the reference population (standard deviation = 10). For PROMIS measures, higher scores equal more of the concept being measured (e.g., more Fatigue, more Physical Function).	3 and 6 months post-randomization
Montreal Cognitive Assessment (MoCA)	It is a 30-point test to assess people for dementia. The MoCA evaluates different types of cognitive abilities, including orientation, short-term memory / delayed recall, executive function / visuospatial ability, language ability, abstraction, animal naming, attention, and clock-drawing. Scores range from 0 to 30, with a score of 26 or higher considered normal.	3 and 6 months post-randomization

Collaborators and Investigators

• Sponsor: Dr David Hasan, M.D.
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Emad Hasan, MD, Duke University; Principal Investigator: Brian Mac Grory, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Estimated): July 23, 2026
• Primary Completion (Estimated): January 23, 2029
• Study Completion (Estimated): January 23, 2032

Study Registration Dates

• First Submitted: March 10, 2026
• First Submitted That Met QC Criteria: March 23, 2026
• First Posted (Actual): March 25, 2026

Study Record Updates

• Last Update Posted (Actual): March 25, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Subarachnoid Hemorrhage; Tirofiban; Delayed Cerebral Ischemia; Brain Aneurysm Rupture
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Hemorrhage; Intracranial Hemorrhages; Pathological Conditions, Signs and Symptoms; Subarachnoid Hemorrhage; Amino Acids, Peptides, and Proteins; Pharmaceutical Preparations; Amino Acids; Crystalloid Solutions; Isotonic Solutions; Solutions; Amino Acids, Aromatic; Amino Acids, Cyclic; Tyrosine; Tirofiban; Saline Solution
• Other Study ID Numbers: Pro00119469; UG3NS138219 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No