Subarachnoid Hemorrhage, Aneurysmal
Conditions
Brief summary
This is a phase 1/2a, randomized, double blind, single-center study comparing standard care alone to standard care with Aggrastat in patients diagnosed with aneurysmal subarachnoid hemorrhage.
Detailed description
This is a phase 1/2a, randomized, double blind, single-center study comparing standard care alone to standard care with Aggrastat in patients diagnosed with aneurysmal subarachnoid hemorrhage. The investigational plan is to explore the safety profile of Aggrastat administered continuously over 7 days, beginning at least 12 hours after a clinically indicated Endovascular Coil Embolization procedure. As a part of the study, qualifying subjects will undergo two MRI scans, one at baseline and again prior to discharge. A neurological exam and vital signs will be administered at baseline, daily during drug administration, and at follow-up visits. Additional assessments include administration of the following questionnaires: mRS score, IADL, and QOLIBRI-OS.
Interventions
DRUGtirofiban hydrochloride (AGGRASTAT®)
Participants will have intravenous Aggrastat administered continuously over the course of 7 days in the setting of subarachnoid hemorrhage at least 12 hours post clinically indicated Endovascular Coil Embolization procedure.
DIAGNOSTIC_TESTMRI
Participants will undergo 2 MRIs administered within 24 hours post Coil Embolization procedure and prior to discharge to monitor for ischemic changes.
DIAGNOSTIC_TESTNeurological Exam
Neurological exams will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits.
BEHAVIORALQuestionnaires
Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS) and the Lawton Instrumental Activities of Daily Living (IADL) will be administered at 6 month and 1 year follow up visits.
DIAGNOSTIC_TESTVital Signs
Vital signs which include temperature, respiration rate, blood pressure and O2 stats will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits.
OTHERStandard of Care Treatment
Participants will receive standard of care treatment and will not receive study drug.
Sponsors
David Hasan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
All subjects will be randomized 2:1, Aggrastat vs. placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 and ≤ 85 years * Hunt and Hess scale ≤ 4 at time of admission or following EVD placement. * CT showing modified Fisher grade 1-4 aSAH on admission. * The Modified Fisher CT rating scale: Grade 1 (minimal or diffuse thing SAH without IVH); Grade 2 (minimal or thin SAH with IVH), Grade 3 (thick cisternal clot without IVH), Grade 4 (thick cisternal clot with IVH) * Placement of EVD on admission. * Diagnosis of aSAH occurred \< 24 hours prior to presentation at the treating facility. * Initiation of aneurysm securement procedure occurred ≤ 24 hours from admission to the treating facility. * All aneurysm(s) suspected to be responsible for the hemorrhage or potentially responsible for the hemorrhage must be secured in the following manner prior to enrollment: Endovascular Coil Embolization with a post-embolization Raymond-Roy Score of 1 (Complete) or 2 (Residual Neck) * Ability to screen the patient and obtain head CT, CT perfusion, and CCTA on admission, a head CT following EVD placement, during EVD weaning period and following VP shunt placement. * No evidence of a significant new focal neurological deficit after the angiogram, including monoparesis / monoplegia, hemiparesis / hemiplegia, or receptive, expressive, or global aphasia. Minor cranial nerve defect without any other new findings is permissible. The treating physician should use their best clinical judgement as to whether a significant neurological decline has occurred due to the procedure. * Patient or their Legally Authorized Representative (LAR) has provided written informed consent.
Exclusion criteria
* Angio-negative SAH, defined as a subarachnoid hemorrhage with an angiogram that does not show a related intracranial hemorrhage. * A likely hemorrhage event preceding the ictus due to the increased risk of early vasospasm. Prior sentinel headache with negative CT or prior sentinel headache where the patient did not seek medical attention does not exclude the patient. * Surgical clipping of the ruptured aneurysm or any non-ruptured aneurysm on the same admission prior to enrollment. * SAH not caused by aneurysm rupture or aneurysm is identified to be traumatic, mycotic, blister or fusiform type by catheter angiography. * Any intracranial stent placement or non-coil intra-aneurysmal device (i.e., stent- assisted coiling with Neuroform, Enterprise, LVIS, LVIS Jr, Barrel Stent, Pulse Rider, LUNA, Medina or a similar device) where the stent device is implanted to treat the ruptured aneurysm. * A medical diagnosis that requires continuous use of clopidogrel, ticagrelor, or tirofiban during study drug infusion. * Antiplatelet therapy using clopidogrel, ticagrelor or tirofiban during the endovascular procedure that continues \> 24 post embolization. * Multiple aneurysms that may have been untreated and a potential etiology for rupture. * Femoral arteriotomy stick above the inferior epigastric artery OR angiographic, CT, or clinical evidence of an arteriotomy related retroperitoneal hematoma or large flank hematoma. A stable groin hematoma is not an exclusion. * Thrombocytopenia (platelet count less than 100,000 - assuming clumping has been ruled out as a cause), confirmed active disseminated intravascular coagulation (DIC) at the time of enrollment OR a documented history of coagulopathy or bleeding diathesis. * New parenchymal hemorrhage or new infarction larger the 15cc in volume (clinically significant), or worsening midline shift as seen on the post-coiling, pre-enrollment head CT when compared to baseline admission head CT. New hyperdensity on CT scan related to contrast staining is not an exclusion. * Patient developed SAH-induced cardiac stunning prior to enrollment, with an ejection fraction \< 40%. * Thrombolytic therapy within 24 hours prior to enrollment (rtPA, urokinase, etc.) * Concurrent significant intracranial pathology identified prior to enrollment, including but not limited to, Moyamoya disease, high suspicion or documented CNS vasculitis, severe fibromuscular dysplasia, arteriovenous malformation, arteriovenous fistula, significant cervical or intracranial atherosclerotic stenotic disease ≥ 70%, or malignant brain tumor. * Known seizure or epilepsy disorder (diagnosed prior to this aSAH diagnosis) where anti-epileptic medication was previously taken by the patient or have been recommended to be taken by the patient. Childhood seizures that have resolved and no longer require treatment are not part of this
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Intracranial Hemorrhage (Symptomatic and Asymptomatic) | Day 1 to Day 7 | The hypothesis is that the prevalence of intracranial hemorrhage (symptomatic and asymptomatic) secondary to ventriculostomy/VPS placement during the course of Aggrastat use is within 10% difference when compared to control using Day 1 and Day 7 non-contrast head CT to determine. |
| Number of Participants With Delayed Cerebral Ischemia /Clinical Vasospasm | Day 1 to Day 7 | The measurement of then incidence of delayed cerebral ischemia /clinical vasospasm in Tirofiban/Aggrastat group vs. placebo |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tirofiban Hydrochloride (AGGRASTAT®) tirofiban hydrochloride (AGGRASTAT®) administered continuously over the course of 7 days.
MRI Neurological Exam Vital Signs Questionnaires
tirofiban hydrochloride (AGGRASTAT®): Participants will have intravenous Aggrastat administered continuously over the course of 7 days in the setting of subarachnoid hemorrhage at least 12 hours post clinically indicated Endovascular Coil Embolization procedure.
MRI: Participants will undergo 2 MRIs administered within 24 hours post Coil Embolization procedure and prior to discharge to monitor for ischemic changes.
Neurological Exam: Neurological exams will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits.
Questionnaires: Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS) and the Lawton Instrumental Activities of Daily Living (IADL) will be administered at 6 month and 1 year follow up visits.
Vital Signs: Vital signs which include temperature, respiration rate, blood pressure and O2 stats will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits. | 18 |
| Standard of Care Control Arm Standard of Care Treatment MRI Neurological Exam Vital Signs Questionnaires
MRI: Participants will undergo 2 MRIs administered within 24 hours post Coil Embolization procedure and prior to discharge to monitor for ischemic changes.
Neurological Exam: Neurological exams will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits.
Questionnaires: Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS) and the Lawton Instrumental Activities of Daily Living (IADL) will be administered at 6 month and 1 year follow up visits.
Vital Signs: Vital signs which include temperature, respiration rate, blood pressure and O2 stats will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits.
Standard of Care Treatment: Participants will receive standard of care treatment and will not receive study drug. | 12 |
| Total | 30 |
Baseline characteristics
| Characteristic | Tirofiban Hydrochloride (AGGRASTAT®) | Standard of Care Control Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 11 Participants | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 13 Participants | 9 Participants | 22 Participants |
| Region of Enrollment United States | 18 Participants | 12 Participants | 30 Participants |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 24 Participants |
| Sex: Female, Male Male | 6 Participants | 0 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 18 | 0 / 12 |
| other Total, other adverse events | 18 / 18 | 12 / 12 |
| serious Total, serious adverse events | 18 / 18 | 12 / 12 |
Outcome results
Primary
Number of Participants With Delayed Cerebral Ischemia /Clinical Vasospasm
The measurement of then incidence of delayed cerebral ischemia /clinical vasospasm in Tirofiban/Aggrastat group vs. placebo
Time frame: Day 1 to Day 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tirofiban Hydrochloride (AGGRASTAT®) | Number of Participants With Delayed Cerebral Ischemia /Clinical Vasospasm | 1 Participants |
| Standard of Care Control Arm | Number of Participants With Delayed Cerebral Ischemia /Clinical Vasospasm | 4 Participants |
Primary
Number of Participants With Intracranial Hemorrhage (Symptomatic and Asymptomatic)
The hypothesis is that the prevalence of intracranial hemorrhage (symptomatic and asymptomatic) secondary to ventriculostomy/VPS placement during the course of Aggrastat use is within 10% difference when compared to control using Day 1 and Day 7 non-contrast head CT to determine.
Time frame: Day 1 to Day 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tirofiban Hydrochloride (AGGRASTAT®) | Number of Participants With Intracranial Hemorrhage (Symptomatic and Asymptomatic) | 2 Participants |
| Standard of Care Control Arm | Number of Participants With Intracranial Hemorrhage (Symptomatic and Asymptomatic) | 1 Participants |