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Aneurysmal Subarachnoid Hemorrhage Trial RandOmizing Heparin (ASTROH)

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ClinicalTrials.gov Identifier: NCT02501434
Recruitment Status : Recruiting
First Posted : July 17, 2015
Last Update Posted : October 25, 2017
Sponsor:
Information provided by (Responsible Party):
Robert F James, MD, FACS, FAANS, University of Louisville

Brief Summary:
A Blind-adjudication Multi-center Phase II Randomized Clinical Trial of Continuous Low-dose Intravenous Heparin Therapy in Coiled Low-grade Aneurysmal Subarachnoid Hemorrhage Patients with Significant Hemorrhage Burden.

Condition or disease Intervention/treatment Phase
Aneurysmal Subarachnoid Hemorrhage Neurobehavioral Manifestations Vasospasm, Intracranial Intracranial Aneurysm Heparin-induced Thrombocytopenia Type II Drug: Continuous Low-Dose IV Unfractionated Heparin Infusion Phase 2

Detailed Description:

The primary objective of this study is to investigate the safety and clinical effect of a continuous low-dose intravenous unfractionated heparin (LDIVH) infusion for the prevention of aneurysmal subarachnoid hemorrhage (aSAH) induced neurocognitive dysfunction and other delayed neurological deficits.

Additionally, increased blood and CSF levels of certain inflammatory biomarkers (IL-6, hsCRP, etc) have been correlated to aSAH patients with poor clinical outcomes. Unfractionated heparin (UFH) has known anti-inflammatory actions. As a result, a secondary objective of this study will be to evaluate whether LDIVH can reduce blood and CSF inflammatory biomarkers levels compared to controls and whether there is any association between inflammatory biomarker levels and cognitive outcomes in aSAH.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Blind-adjudication Multi-center Phase II Randomized Clinical Trial of Continuous Low-dose Intravenous Heparin Therapy in Coiled Low-grade Aneurysmal Subarachnoid Hemorrhage Patients With Significant Hemorrhage Burden
Actual Study Start Date : April 2016
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: Control
Standard of Care
Experimental: LDIVH (Unfractionated Heparin)
Continuous Low-Dose IV Unfractionated Heparin Infusion
Drug: Continuous Low-Dose IV Unfractionated Heparin Infusion
Continuous intravenous infusion of a low-dose unfractionated heparin drip
Other Names:
  • Heparin
  • Unfractionated Heparin
  • Heparin drip
  • IV Heparin




Primary Outcome Measures :
  1. Montreal Cognitive Assessment (MoCA) [ Time Frame: 90-day follow-up visit ]
    Primary Clinical Outcome Measure- mean score compared between groups

  2. Rate of "Major Bleeding" or "Clinically Relevant Non-Major Bleeding" [ Time Frame: Patients will be followed for the duration of the hospital stay; an expected average of 3 weeks ]
    As defined by the International Society of Thrombosis and Heamostasis (ISTH) Primary Safety Outcome Measure-


Secondary Outcome Measures :
  1. Rate of "Major Bleeding" [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks ]
    As defined by the International Society of Thrombosis and Haemostasis (ISTH)

  2. Rate of Type II Heparin Induced Thrombocytopenia (HIT) [ Time Frame: Enrollment through 90-day follow-up visit ]
  3. Rate of Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) [ Time Frame: Enrollment through 90-day follow-up visit ]
  4. All Cause - Mortality Rate [ Time Frame: Enrollment through 90-day follow-up visit ]
  5. Incidence of Any Fever (> 38.3 degrees C; > or = 101.0 degrees F) [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks ]
  6. Incidence of multiple fevers (> 2 episodes) [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks ]
  7. Mean daily fever burden [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks ]
    Daily fever burden = Sum of hourly fever burden over 24 hours; Hourly fever burden = Any hourly temperature recording > 37 degrees C - (minus) 37 degrees C; if temperature is less than or equal to 37 degrees C then the hourly fever burden would be zero.

  8. Glasgow Coma Score [ Time Frame: Enrollment, post-enrollment days #2, 4, 6, 10, discharge, and 90-day follow-up visit ]
  9. National Institutes of Health Stroke Scale (NIHSS) [ Time Frame: Enrollment, post-enrollment days #2, 4, 6, 10, upon discharge from hospital stay an expected average of about 3 weeks after admission, 90-day follow-up visit ]
  10. Montreal Cognitive Assessment (MoCA) [ Time Frame: Enrollment, post-enrollment days #6, 10, 1 year follow-up ]
    Mean between groups and rate of MoCA score of 20 or less between groups

  11. Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: 90-day follow-up visit ]
  12. Trail Making Test Parts A&B [ Time Frame: 90-day follow-up visit ]
  13. Cerebral Vasospasm [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks ]
    Incidence of moderate and severe radiographic cerebral vasospasm (catheter angiogram, CTA, MRA) or incidence OR moderate and severe vasospasm by transcranial doppler (TCD) criteria

  14. Incidence of clinical cerebral vasospasm requiring rescue therapy [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks ]
    Rescue therapy = vasopressors or endovascular therapy for the purposes of reversing clinical vasospasm; it does not include Triple H (Hyperdynamic Therapy)

  15. Incidence of CT or MRI imaging demonstrating cerebral vasospasm related cerebral infarction [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks ]
  16. Ordinal Regression Analysis of the modified Rankin Scale score (mRS) [ Time Frame: 90-day follow-up visit and 1 year follow-up visit ]
  17. Relative frequency of "good outcome" as defined by dichotomized mRS score 0-2 [ Time Frame: 90-day follow-up visit and 1 year follow-up visit ]
  18. Barthel Index [ Time Frame: 90-day follow-up visit ]
  19. Return to work status [ Time Frame: 90-day follow-up and 1 year follow-up visit ]
  20. Lawton instrumental activities of daily living (IADL) [ Time Frame: 90-day follow-up visit ]
  21. Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS) [ Time Frame: 90-day follow-up visit and 1 year follow-up visit ]
  22. Plasma biomarker levels (hsCRP, procalcitonin, IL-6, TNF-alpha, P-Selectin, sICAM-1, HMGB-1, MRP-8/14) [ Time Frame: Enrollment, post-enrollment days #2,4,6,10 ]
  23. Cerebrospinal Fluid (CSF) biomarker levels (hsCRP, procalcitonin, IL-6, TNF-alpha, P-Selectin, sICAM-1, HMGB-1, MRP8/14) [ Time Frame: Enrollment, post-enrollment days #2,4,6,10 ]
  24. Rate of Serious Adverse Events (SAEs) [ Time Frame: From enrollment through 90-Day follow-up visit ]
    Secondary Safety Outcome Measure


Other Outcome Measures:
  1. Subgroup analysis for the following subgroups: (Clinical Site, Gender, Admission CT Hijdra Sum Score <23, WFNS grade, aneurysm location, anterior circulation aneurysm vs posterior circulation aneurysm location, infection requiring antibiotic treatment, [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks, 90-day follow-visit and 1 year follow-up visit ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 and ≤ 70 years
  2. Historical modified Rankin Scale Score 0-1
  3. WFNS SAH Scale grade ≤ 2, due to a spontaneous subarachnoid hemorrhage attributable to a ruptured cerebral aneurysm. Cranial nerve deficit (e.g. CN III paresis) is permissible even for WFNS grade 2.

    • 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.

  4. Admission head CT showing modified Fisher grade 3 aSAH primarily in the supratentorial space. 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 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) [From: Claassen J et al. Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001;32:2012-2020.]

  5. Location and pattern of the SAH must have the majority of the SAH in the supratentorial space caused by either an intradural anterior circulation aneurysm OR a basilar apex posterior circulation aneurysm with primarily supratentorial hemorrhage extension. Angiographic location of the aneurysm will be confirmed by catheter digital subtraction angiography (DSA) usually obtained during the coil embolization procedure. Patients with PICA or other posterior circulation aneurysms as the cause of the SAH will be excluded.
  6. Onset of symptoms of aSAH (ictus) occurred < 24 hours prior to presentation at the treating facility.
  7. Initiation of aneurysm securement procedure occurred < 48 hours from the ictus AND less than 36 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].

  8. 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)

  9. Ability to screen the patient and obtain a head CT 2-12 hours after the completion of the coiling procedure and then ability to initiate the study drug 12 ± 4 hours after the completion of aneurysm coiling procedure..
  10. After recovering from anesthesia following the aneurysm coiling procedure, the patient must remain a WFNS SAH grade ≤ 2 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.
  11. Patient is willing and able to return for study follow-up visits.
  12. Patient or their Legally Authorized Representative (LAR) has provided written informed consent.

Exclusion Criteria:

  1. Angio-negative SAH.
  2. 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.
  3. Surgical clipping of the ruptured aneurysm or any non-ruptured aneurysm on the same admission prior to enrollment.
  4. SAH not caused by aneurysm rupture or aneurysm is identified to be traumatic, mycotic, blister or fusiform type by catheter DSA.
  5. 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.
  6. 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.
  7. 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.
  8. Patient received heparin in any form within the last 100 days prior to admission (not including coiling procedure).
  9. 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.
  10. 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 non- complicated community-aquired urinary tract infection would not be an exclusion but should be treated promptly.
  11. 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 hyyperdensity on CT scan related to contrast staining is not an exclusion.
  12. Patient has a documented history of heparin induced thrombocytopenia (HIT)
  13. Patient developed SAH-induced cardiac stunning prior to enrollment, with an ejection fraction< 40%, or requiring IV medicaitons for blood pressure maintenance.
  14. Pre-admission daily antiplatelet therapy or any oral or subcutaneous anticoagulation therapy prior to, or during the coil embolization procedure. A single 325 mg Aspirin (or lower dose) given duiring the coil embolization peri-procedural period is acceptable if this is the local standard of care, but should be documented.
  15. Thrombolytic therapy within 24 hours prior to enrollment (rtPA, urokinase, etc.)
  16. Plan for antiplatelet or oral anticoagulation therapy from the time of the coil embolization procedure until 14 full days after enrollment. Antiplatelet therapy may be resumed after the 14-day window.
  17. 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.
  18. Uncontrollable hypertension (>180 systolic and/or >110 diastolic) that is not correctable prior to enrollment.
  19. 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
  20. 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.
  21. Immunosuppression therapy including chronic corticosteroid usage.
  22. Remote history of previous ruptured cerebral aneurysm.
  23. 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.
  24. Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days.
  25. Currently pregnant.
  26. Enrollment in another research study that would conflict with this study.

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): NCT02501434


Contacts
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Contact: Ann Jerde, RN 502-438-8787 ann.jerde@louisville.edu
Contact: Rachel A Sheppard, MBA 502-852-2162 CTU@exchange.louisville.edu

Locations
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United States, Connecticut
Yale University Recruiting
New Haven, Connecticut, United States
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States
United States, Illinois
Rush University Recruiting
Chicago, Illinois, United States
United States, Kentucky
University of Louisville Recruiting
Louisville, Kentucky, United States, 40202
Contact: Jerrad R Businger, MD    419-957-7202    j0busi01@exchange.louisville.edu   
Contact: Ann Jerde, RN    502-438-8787    ann.jerde@louisville.edu   
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States
United States, New York
Mount Sinai Ichan School of Medicine Not yet recruiting
New York, New York, United States
United States, South Carolina
Medical University of South Carolina Not yet recruiting
Charleston, South Carolina, United States
United States, Texas
University of Texas Southwestern Recruiting
Dallas, Texas, United States
Sponsors and Collaborators
Robert F James, MD, FACS, FAANS
Investigators
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Principal Investigator: Robert F James, MD University of Louisville
Principal Investigator: J Marc Simard, MD, PhD University of Maryland
Principal Investigator: J Mocco, MD, MSc Icahn School of Medicine at Mount Sinai
Principal Investigator: Kevin N Sheth, MD Yale University

Publications:
James RF, Shao EY, Page PS, Nazar RG, Martin LB, Dvorak J, Kanaan HK, Daniels MJ, Craycroft J, Rai SN, Everhart DE, Simard JM. Low-dose IV heparin preserves cognitive function in aneurysmal subarachnoid hemorrhage patients. [Unpublished Data]. Presented at AANS 82nd Annual Scientific Meeting. April 5-9, 2014. San Francisco, CA; Abstract #16572.

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Responsible Party: Robert F James, MD, FACS, FAANS, Associate Professor and Chief, Vascular Neurosurgery, University of Louisville
ClinicalTrials.gov Identifier: NCT02501434     History of Changes
Other Study ID Numbers: 15.0662
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: October 25, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to share data other than through publication or requests to Robert James by other investigators.

Keywords provided by Robert F James, MD, FACS, FAANS, University of Louisville:
aneurysmal subarachnoid hemorrhage
unfractionated heparin
neurobehavioral manifestations
delayed ischemic neurological deficits
cerebral aneurysm
coil embolization
Montreal Cognitive Assessment

Additional relevant MeSH terms:
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Aneurysm
Intracranial Aneurysm
Brain Diseases
Hemorrhage
Thrombocytopenia
Subarachnoid Hemorrhage
Neurobehavioral Manifestations
Vasospasm, Intracranial
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Blood Platelet Disorders
Hematologic Diseases
Intracranial Hemorrhages
Cerebrovascular Disorders
Central Nervous System Diseases
Nervous System Diseases
Intracranial Arterial Diseases
Neurologic Manifestations
Signs and Symptoms
Heparin
Calcium heparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action