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Induced Suppression of Platelets Activity in Aneurysmal SAH Management (iSPASM)

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ClinicalTrials.gov Identifier: NCT03691727
Recruitment Status : Recruiting
First Posted : October 2, 2018
Last Update Posted : January 31, 2019
Sponsor:
Information provided by (Responsible Party):
David Hasan, University of Iowa

Brief Summary:
This is a phase 1/2a, single-center, randomized, open-label, control vs.Aggrastat study. The generalizedinvestigational plan is to explore the safety profile of 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.

Condition or disease Intervention/treatment Phase
Subarachnoid Hemorrhage, Aneurysmal Drug: tirofiban hydrochloride (AGGRASTAT®) Diagnostic Test: MRI Diagnostic Test: Neurological Exam Behavioral: Questionnaires Diagnostic Test: Vital Signs Other: Standard of Care Treatment Phase 1 Phase 2

Detailed Description:

This is a phase 1/2a, single-center, randomized, open-label, control vs. Aggrastat study. The generalized investigational plan is to explore the safety profile of 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.

As a part of the study, qualifying subjects will undergo 2 MRIs administered within 24 hours post Coil Embolization procedure and prior to discharge to monitor for the ischemic changes, neurological exam and vital signs administered at screening and/or randomization visit(s), daily during drug administration, and at follow-up visits. Additional interventions include administration of questionnaires including mRS score documentation, IADL, QOLIBRI-OS.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 282 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 1:1. All subjects will be randomized to control (standard of care) or experimental arms.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2a Exploratory Clinical Trial: Induced Suppression of Platelets Activity in Aneurysmal SAH Management (iSPASM)
Actual Study Start Date : January 24, 2019
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

Arm Intervention/treatment
Experimental: tirofiban hydrochloride (AGGRASTAT®)

tirofiban hydrochloride (AGGRASTAT®) administered continuously over the course of 7 days.

MRI Neurological Exam Vital Signs Questionnaires

Drug: 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.

Diagnostic Test: MRI
Participants will undergo 2 MRIs administered within 24 hours post Coil Embolization procedure and prior to discharge to monitor for the ischemic changes.

Diagnostic Test: Neurological Exam
Neurological exams will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits.

Behavioral: Questionnaires
Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS) and the Lawton Instrumental Activities of Daily Living (IADL) will be administered at the participants 6 month and 1 year follow up visits.

Diagnostic Test: 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.

Active Comparator: Standard of Care Control Arm
Standard of Care Treatment MRI Neurological Exam Vital Signs Questionnaires
Diagnostic Test: MRI
Participants will undergo 2 MRIs administered within 24 hours post Coil Embolization procedure and prior to discharge to monitor for the ischemic changes.

Diagnostic Test: Neurological Exam
Neurological exams will be done at screening, randomization, days 2-7, discharge, 6 week, 6 month, and one year follow up visits.

Behavioral: Questionnaires
Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS) and the Lawton Instrumental Activities of Daily Living (IADL) will be administered at the participants 6 month and 1 year follow up visits.

Diagnostic Test: 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.

Other: Standard of Care Treatment
Participants will receive stand of care treatment and will not receive study drug.




Primary Outcome Measures :
  1. Symptomatic Hemorrhage [ Time Frame: Day 1 compared to Day 7 ]
    The risk of symptomatic hemorrhage 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.

  2. Asymptomatic Hemorrhage [ Time Frame: Day 1 compared to Day 7 ]
    The risk of asymptomatic hemorrhage secondary to ventriculostomy/VPS placement during the course of Aggrastat use is within 30% difference when compared to control using Day 1 and Day 7 non-contrast head CT to determine.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Inclusion Criteria:

  • Age >= 18 and <= 80 years
  • Historical modified Rankin Scale Score 0-1
  • WFNS SAH Scale grade <= 4, due to a spontaneous subarachnoid hemorrhage attributable to a ruptured cerebral aneurysm.
  • Initial WFNS grade may be determined at admission or enrollment, preferably after the patient's mental status has been optimized by resuscitation and interval treatment of hydrocephalus (i.e., placement of intraventricular catheter) or reversal/wearing-off of sedating medications used commonly during patient transfers and transport or procedure related anesthesia.
  • Admission head CT showing modified Fisher grade 1-3 aSAH Snapshot images of up to four relevant axial cuts from the admission head CT will need to be uploaded via the imaging database to confirm the modified Fisher grade 1-3 eligibility of the potential subject prior to enrollment. Minimal intraventricular hemorrhage is acceptable.
  • 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)
  • Angiographic location of the aneurysm will be confirmed by catheter digital subtraction angiography (DSA) usually obtained during the coil embolization procedure. Onset of symptoms of aSAH (ictus) occurred < 24 hours prior to presentation at the treating facility.
  • Initiation of aneurysm securement procedure occurred < 48 hours from the ictus AND less than 12 hours from admission to the treating facility.
  • In patients where the exact time of the ictus is uncertain, an estimated time of ictus may be assigned and that time will be used for the inclusion criteria above assuming the estimation is deemed to be reasonably reliable [i.e., actual time is highly likely to be within 6 hours of estimated time].
  • 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 and CT perfusion on admission and follow after recovering from anesthesia following the aneurysm coiling procedure, the patient must remain a WFNS SAH grade <= 4 without evidence of a significant new focal neurological deficit including monoparesis / monoplegia, hemiparesis / hemiplegia, or receptive, expressive or global aphasia. New minor cranial nerve defect without any other new findings is permissible. If an NIHSS score was obtained prior to the aneurysm coiling procedure, a post-coiling (pre-enrollment) NIHSS score must not have increased by >= 4 points and GCS score must not be decreased by <= 2 points. The clinician at the local site should use their best clinical judgment 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.
  • Ability to obtain MRI for ischemic changes evaluation

Exclusion Criteria:

  • Angio-negative SAH.
  • A likely hemorrhage event within several days prior to admission related hemorrhage 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 DSA.
  • 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, WEB, LUNA, Medina or a similar device) where the stent device is implanted to treat the ruptured aneurysm and / or antiplatelet therapy is needed.
  • Patient has remaining aneurysm(s) that are untreated and could reasonably be considered a possible alternate cause of the aSAH based on the observed bleeding pattern. Adequate treatment of these aneurysms by coiling embolization would result in the aneurysms no longer causing an exclusion. MRI may be used in some situations to determine that the associated aneurysms did not rupture based on lack of blood seen adjacent to the additional aneurysms.
  • 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.
  • Diagnosis of sepsis (SIRS criteria plus the presence of known or suspected infection) or current documented active bacterial or viral infection prior to enrollment (Example: significant URI, community-acquired pneumonia). A minor noncomplicated community-acquired urinary tract infection would not be an exclusion but should be treated promptly.
  • New parenchymal hemorrhage or new infarction larger the 15cc in volume, or significant increased mass effect 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%, or requiring IV medications for blood pressure maintenance.
  • 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.
  • Uncontrollable hypertension (>180 systolic and/or >110 diastolic) that is not correctable prior to enrollment.
  • 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 exclusion criteria
  • Serious co-morbidities that could confound study results including but not limited to: Multiple Sclerosis, dementia, severe major depression, cancer likely to cause death in 2 years, multi-system organ failure, or any other conditions that could cause any degree of cognitive impairment.
  • Immunosuppression therapy including chronic corticosteroid usage.
  • Remote history of previous ruptured cerebral aneurysm.
  • History of gastrointestinal hemorrhage or major systemic hemorrhage within 30 days, hemoglobin less than 8 g/dL, INR=1.5, severe liver impairment (AST< ALT< AP<GGT > 2 x normal or cirrhosis), creatinine > 2.0 mg/dL, or estimated GFR <60 ml/min.
  • Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days.
  • Currently pregnant.
  • Contraindication for MRI
  • Aspirin and Clopidogrel resistant.
  • Pregnancy and breast feeding mothers

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03691727


Contacts
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Contact: David Hasan, MD (319) 384-8669 david-hasan@uiowa.edu
Contact: Debra OConnell Moore, MBA 319-356-1693 debra-oconnell-moore@uiowa.edu

Locations
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United States, Iowa
University of Iowa Recruiting
Iowa City, Iowa, United States, 52242
Contact: Lauren Allan, MD    319-356-7892    lauren-allan@uiowa.edu   
Contact: Debra OConnell Moore, MBA    319-356-1693    debra-oconnell-moore@uiowa.edu   
Principal Investigator: David Hasan, MD         
Sponsors and Collaborators
David Hasan

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Responsible Party: David Hasan, Principal Investigator, University of Iowa
ClinicalTrials.gov Identifier: NCT03691727     History of Changes
Other Study ID Numbers: 201805823
First Posted: October 2, 2018    Key Record Dates
Last Update Posted: January 31, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Platelet Aggregation Inhibitors
Hemorrhage
Subarachnoid Hemorrhage
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Tirofiban
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action