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Aneurysmal Subarachnoid Hemorrhage Trial RandOmizing Heparin

Information source: University of Louisville
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Aneurysmal Subarachnoid Hemorrhage; Neurobehavioral Manifestations; Vasospasm, Intracranial; Intracranial Aneurysm; Heparin-induced Thrombocytopenia Type II

Intervention: Continuous Low-Dose Intravenous Unfractionated Heparin Infusion (14 days) (Drug)

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: Robert F James, MD, FACS, FAANS

Official(s) and/or principal investigator(s):
Robert F James, MD, Principal Investigator, Affiliation: University of Louisville
J Marc Simard, MD, PhD, Principal Investigator, Affiliation: University of Maryland
J Mocco, MD, MSc, Principal Investigator, Affiliation: Icahn School of Medicine at Mount Sinai
Kevin N Sheth, MD, Principal Investigator, Affiliation: Yale University

Overall contact:
Ann Jerde, RN, Phone: 502-852-5152, Email: ann.jerde@louisville.edu

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Montreal Cognitive Assessment (MoCA)

Rate of Serious Adverse Events (SAEs)

Secondary outcome:

Rate of "Major Bleeding"

Rate of "Major Bleeding" or "Clinically Relevant Non-Major Bleeding"

Rate of Type II Heparin Induced Thrombocytopenia (HIT)

Rate of Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE)

Mortality Rate

Incidence of Any Fever (> 38.3 degrees C; > or = 101.0 degrees F)

Incidence of multiple fevers (> 2 episodes)

Mean daily fever burden

Glasgow Coma Score

National Institutes of Health Stroke Scale (NIHSS)

Montreal Cognitive Assessment (MoCA)

Center for Epidemiologic Studies Depression Scale (CES-D)

Trail Making Test Parts A&B

Cerebral Vasospasm

Incidence of clinical cerebral vasospasm requiring rescue therapy

Incidence of CT or MRI imaging demonstrating cerebral vasospasm related cerebral infarction

Group shift analysis of the modified Rankin Scale score (mRS)

Relative frequency of "good outcome" as defined by dichotomized mRS score 0-2

Barthel Index

Return to work status

Lawton instrumental activities of daily living (IADL)

Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS)

Plasma biomarker levels (hsCRP, procalcitonin, IL-6, TNF-alpha, P-Selectin, sICAM-1, HMGB-1, MRP-8/14)

Cerebrospinal Fluid (CSF) biomarker levels (hsCRP, procalcitonin, IL-6, TNF-alpha, P-Selectin, sICAM-1, HMGB-1, MRP8/14)

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.

Eligibility

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Age ≥ 18 and ≤ 70 years 2. WFNS SAH grade ≤ 2, 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. 3. Admission head CT showing modified Fisher grade 3 aSAH bleed pattern in the supratentorial space and that is confirmed by a physician investigator at the clinical site who has completed study specific training on interpretation of the modified Fisher score. Minimal intraventricular hemorrhage is acceptable. • Delayed confirmation of modified Fisher grade 3 scoring will be performed by the Core Imaging Lab. Any site that has had one or more scoring error that results in an inappropriate enrollment may be required to submit admission CT images to the Imaging Core Lab as part of the screening process prior to patient enrollment. In this situation, approval of admission CT suitability (modified Fisher score 3) by the Imaging Core Lab would be required prior to patient enrollment. 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.] 4. 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 significant 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. 5. Onset of symptoms of aSAH (ictus) occurred < 24 hours prior to presentation at the treating facility. 6. 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]. 7. 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) 8. 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. 9. After recovering from anesthesia following the aneurysm coiling procedure, the patient must remain a WFNS SAH grade ≤ 2 without evidence of a 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. 10. Patient is willing and able to return for study follow-up visits. 11. Patient is available by phone. 12. Patient or their Legally Authorized Representative (LAR) has provided written informed consent. Exclusion Criteria: 1. Angio-negative SAH. 2. Time of aneurysmal rupture onset cannot be reliably assessed or estimated to a high degree of certainty (within 6 hours precision). 3. Well described sentinel hemorrhage several days prior to admission due to the increased risk of early vasospasm. 4. SAH not caused by aneurysm rupture or aneurysm is identified to be traumatic, mycotic, blister or fusiform type by catheter DSA. 5. Surgical clipping of the ruptured aneurysm or any non-ruptured aneurysm on the same admission prior to enrollment. Any intracranial stent placement or intra-aneurysmal device (i. e., stent-assisted coiling with Neuroform, Enterprise, LVIS, LVIS Jr, Barrel Stent, Pulse Rider, Web, or a similar device) where the stent device is implanted to treat the ruptured aneurysm and 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 coil embolization would result in these 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 these additional aneurysms. 7. A 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). [This exclusion reduces the risk that enrolled patients will develop Type II Heparin Induced Thrombocytopenia] 9. Platelet count less than 100,000 at the time of enrollment. If clumping is suspected, the platelet count should be repeated and if the repeat is greater than 100,000 the clumped result can be ignored. 10. Confirmed active disseminated intravascular coagulation (DIC). 11. Diagnosis of sepsis (SIRS criteria plus the presence of known or suspected infection) or other current documented active bacterial or viral infection prior to enrollment. 12. New parenchymal hemorrhage or new infarction larger than 15cc in volume, or significantly 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. 13. Patient has a documented history of heparin induced thrombocytopenia (HIT). 14. Patient has a documented history of coagulopathy and/or bleeding diathesis including but not limited to hemophilia, Von Willebrand's, and Lupus anticoagulant. 15. Serious complication during endovascular aneurysm treatment procedure that could impact the results of this study. (Example of an exclusion: iatrogenic carotid dissection that requires full anti-coagulation following the treatment procedure.) • Intraprocedural aneurysm rupture is not an exclusion as long as the rupture was controlled, the aneurysm is adequately secured, and there is no neurological or imaging worsening after the procedure (remains WFNS SAH Scale score ≤ 2, NIHSS has not increased by ≥ 4 points, post-procedure CT remains modified Fisher grade 3). 16. Patients who have current endotracheal intubation and are unable to undergo extubation prior to enrollment. 17. aSAH induced cardiac stunning diagnosed prior to enrollment where the patient has an ejection fraction < 40% or requires intravenous inotropics or vasoconstrictors for blood pressure maintenance (not including HHH therapy). 18. Antiplatelet or oral anticoagulant therapy prior or during the coil embolization procedure. A single 325 mg Aspirin (or lower dose) given in the coil embolization peri-procedural period is acceptable if this is the local standard of care, but should be documented. 19. Plan for antiplatelet or oral anticoagulant 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. A single 325 mg Aspirin (or lower dose) given in the coil embolization peri-procedural period is acceptable if this is the local standard of care, but should be documented. 20. Recent (within 6 months) coronary, carotid, or other stent requiring antiplatelet therapy. Stents placed more than 6 months prior cannot still be on anti-platelet or anticoagulation therapy. 21. Flow diversion as the embolization technique for securing the ruptured aneurysm. 22. Concurrent intracranial pathology identified prior to enrollment, including but not limited to, Moyamoya disease, high suspicion or documented CNS vasculitis, fibromuscular dysplasia, arteriovenous malformation, arteriovenous fistula, significant cervical or intracranial atherosclerotic stenotic disease (>70%), or malignant brain tumor. 23. Uncontrollable hypertension (>180 systolic and/or >115 diastolic) that is not correctable prior to enrollment. 24. Known seizure or epilepsy disorder (diagnosed prior to this aSAH diagnosis) where anti-epileptic medications were 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. 25. Patient with a documented and known allergic hypersensitivity reaction to heparin or any other absolute contraindication to heparin therapy. If the patient states she/he is allergic to heparin and is certain of the previous symptoms and these symptoms are very clearly not an allergic hypersensitivity reaction, then the patient would not need to be excluded as long as they are still willing to provide consent. 26. Serious co-morbidities that could confound study results including but not limited to: uncorrectable coagulation abnormality, multi-system organ failure, systemic inflammatory response syndrome (SIRS), cancer likely to cause death in 2 years, Parkinsons's disease, Alzheimer's disease, multiple sclerosis, or history of any dementia or other progressive neurological disease. 27. Thrombolytic therapy within 24 hours prior to enrollment (tPA, urokinase, etc). 28. Immunosuppression therapy including chronic corticosteroid usage 29. Measured body weight < 50 kg 30. Historical mRS ≥ 2. 31. Any untreated chronic subdural hematoma or subdural hygroma > 5mm in thickness or a history of surgical treatment of any epidural or subdural hematoma. 32. Previous craniotomy within the past 6 months. 33. Any history of primary intracerebral parenchymal hemorrhage (ICH) prior to admission unrelated to current aneurysm rupture. 34. Remote history of previous ruptured cerebral aneurysm. 35. Active peptic ulcer disease, major systemic hemorrhage within 30 days, hematocrit < 28, INR > 1. 5, severe liver impairment (AST, ALT, AP, GGT > 2 x normal, cirrhosis), creatinine > 2. 0 mg/dL, BUN greater than 60. 36. Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days. 37. Dementia or psychiatric problem that prevents the patient from following an outpatient program reliably. 38. Co-morbid conditions that are likely to limit survival to less than 1 year. 39. Known pregnancy is considered an exclusion because of the increased risk of bleeding complications in high-risk pregnancies though heparin does not cross the placental barrier. 40. Enrollment in another research study that would conflict with this study.

- Patient participation in registries and prospective clinical databases that do

not prescribe any specific treatment and do not require any invasive testing other than blood draws are allowable.

- Studies comparing different types of coils are permissive as long as there are

no other treatment differences, outcome testing is not invasive while the patient is actively enrolled in ASTROH, and the types of coils are currently FDA approved and could be utilized outside of the context of the coiling study.

Locations and Contacts

Ann Jerde, RN, Phone: 502-852-5152, Email: ann.jerde@louisville.edu

Additional Information

Related publications:

Simard JM, Schreibman D, Aldrich EF, Stallmeyer B, Le B, James RF, Beaty N. Unfractionated heparin: multitargeted therapy for delayed neurological deficits induced by subarachnoid hemorrhage. Neurocrit Care. 2010 Dec;13(3):439-49. doi: 10.1007/s12028-010-9435-1. Review.

Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010 Aug;41(8):e519-36. doi: 10.1161/STROKEAHA.110.581975. Epub 2010 Jul 1. Review.

Schweizer TA, Al-Khindi T, Macdonald RL. Mini-Mental State Examination versus Montreal Cognitive Assessment: rapid assessment tools for cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. J Neurol Sci. 2012 May 15;316(1-2):137-40. doi: 10.1016/j.jns.2012.01.003. Epub 2012 Jan 26.

Wong GK, Lam SW, Ngai K, Wong A, Mok V, Poon WS. Quality of Life after Brain Injury (QOLIBRI) Overall Scale for patients after aneurysmal subarachnoid hemorrhage. J Clin Neurosci. 2014 Jun;21(6):954-6. doi: 10.1016/j.jocn.2013.09.010. Epub 2013 Nov 9.

Hong CM, Tosun C, Kurland DB, Gerzanich V, Schreibman D, Simard JM. Biomarkers as outcome predictors in subarachnoid hemorrhage--a systematic review. Biomarkers. 2014 Mar;19(2):95-108. doi: 10.3109/1354750X.2014.881418. Epub 2014 Feb 5. Review.

Romero FR, Bertolini Ede F, Figueiredo EG, Teixeira MJ. Serum C-reactive protein levels predict neurological outcome after aneurysmal subarachnoid hemorrhage. Arq Neuropsiquiatr. 2012 Mar;70(3):202-5.

Fountas KN, Tasiou A, Kapsalaki EZ, Paterakis KN, Grigorian AA, Lee GP, Robinson JS Jr. Serum and cerebrospinal fluid C-reactive protein levels as predictors of vasospasm in aneurysmal subarachnoid hemorrhage. Clinical article. Neurosurg Focus. 2009 May;26(5):E22. doi: 10.3171/2009.2.FOCUS08311.

Tosun C, Kurland DB, Mehta R, Castellani RJ, deJong JL, Kwon MS, Woo SK, Gerzanich V, Simard JM. Inhibition of the Sur1-Trpm4 channel reduces neuroinflammation and cognitive impairment in subarachnoid hemorrhage. Stroke. 2013 Dec;44(12):3522-8. doi: 10.1161/STROKEAHA.113.002904. Epub 2013 Oct 10.

Simard JM, Aldrich EF, Schreibman D, James RF, Polifka A, Beaty N. Low-dose intravenous heparin infusion in patients with aneurysmal subarachnoid hemorrhage: a preliminary assessment. J Neurosurg. 2013 Dec;119(6):1611-9. doi: 10.3171/2013.8.JNS1337. Epub 2013 Sep 13.

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.

Starting date: November 2015
Last updated: July 15, 2015

Page last updated: August 23, 2015

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