Aneurysmal Subarachnoid Hemorrhage Trial RandOmizing Heparin

NCT02501434 | Suspended Phase 2 DMC FDA Drug

• 1 other identifier: 10550
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 9

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. - STUDY IS TEMPORARILY SUSPENDED WITH PLAN TO RESUME SOON. NO SAFETY CONCERNS

Conditions

Aneurysmal Subarachnoid Hemorrhage; Neurobehavioral Manifestations; Vasospasm, Intracranial; Intracranial Aneurysm; Heparin-induced Thrombocytopenia Type II

Keywords

aneurysmal subarachnoid hemorrhage; unfractionated heparin; neurobehavioral manifestations; delayed ischemic neurological deficits; cerebral aneurysm; coil embolization; Montreal Cognitive Assessment

Outcome Measures

Primary Outcomes (2)

• Montreal Cognitive Assessment (MoCA)

  Primary Clinical Outcome Measure- mean score compared between groups

  90-day follow-up visit

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

  As defined by the International Society of Thrombosis and Heamostasis (ISTH) Primary Safety Outcome Measure-

  Patients will be followed for the duration of the hospital stay; an expected average of 3 weeks

Secondary Outcomes (25)

• Rate of "Major Bleeding"

  Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks

• Rate of Type II Heparin Induced Thrombocytopenia (HIT)

  Enrollment through 90-day follow-up visit

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

  Enrollment through 90-day follow-up visit

• All Cause - Mortality Rate

  Enrollment through 90-day follow-up visit

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

  Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks

Other Outcomes (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,

  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

Study Arms (2)

Control

NO INTERVENTION

Standard of Care

LDIVH (Unfractionated Heparin)

EXPERIMENTAL

Continuous Low-Dose IV Unfractionated Heparin Infusion

Drug: Continuous Low-Dose IV Unfractionated Heparin Infusion

Interventions

Continuous Low-Dose IV Unfractionated Heparin Infusion DRUG

Continuous intravenous infusion of a low-dose unfractionated heparin drip

Also known as: Heparin, Unfractionated Heparin, Heparin drip, IV Heparin

LDIVH (Unfractionated Heparin)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 and ≤ 70 years
• Historical modified Rankin Scale Score 0-1
• Aneurysmal subarachnoid hemorrhage caused by a ruptured saccular aneurysm confirmed by catheter angiography that is repaired by endovascular coil embolization. Initiation of the coil embolization procedure should occur within 48 hours from the time of the aneurysm rupture (ictus). In patients where the exact time of the ictus is uncertain, a reasonable estimate of the time of ictus may be assigned. This reasonable time estimate should be considered likely accurate to within hours of the true unknown time.
• Quality of aneurysm embolization is interpreted to be Raymond-Roy Score of 1 (Complete) or 2 (Residual Neck) indicating that the aneurysm is adequately secured. A tiny amount of contrast in the body of the aneurysm is acceptable as long as the physician considers the aneurysm secured and to NOT represent a Raymond-Roy Score of 3 (Residual Aneurysm).
• WFNS grade 1 or 2 as assessed after repair of the aneurysm during screening but prior to randomization. A patient who presents with a WFNS greater than 2 who then improves with resuscitation, ventriculostomy, or time is acceptable.
• The pre-repair, admission head CT demonstrates an aSAH bleed pattern of "thick and diffuse" or "thick and focal" hemorrhage within the subarachnoid basal cisterns measuring ≥ 4 mm in the short axis and ≥ 20 mm in the long axis which is consistent with a modified Fisher grade 3 or 4. Intraventricular hemorrhage is acceptable. Enrollable patients must NOT have a parenchymal hemorrhage greater than 10 cc. Please refer to diagram below for examples. The hemorrhage location should be substantially within the supratentorial space and not isolated to the infratentorial space.
• The location of the aneurysm should be the anterior circulation, posterior communicating, OR a basilar terminus (apex). Angiographic location of the aneurysm should 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 should not be included because they typically cause primarily infratentorial bleed patterns.
• Ability to screen the patient and obtain a head CT 2-12 hours after the completion of the coiling procedure and the ability to initiate the study drug 12 ± 8 hours after the completion of aneurysm coiling procedure.
• 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.
• Patient is willing and able to return for study follow-up visits.
• Patient or their Legally Authorized Representative (LAR) has provided written informed consent.

You may not qualify if:

• Angio-negative SAH.
• History or imaging suggesting that the current hemorrhage presentation is a recent re-rupture of the aneurysm. 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 (or plan for clipping) of the ruptured aneurysm or any non- ruptured aneurysm on the same admission.
• Aneurysm is identified to be traumatic, mycotic, blister or fusiform type by catheter DSA.
• Any intracranial stent placement or non-coil intra-aneurysmal device where dual- antiplatelet therapy is needed during admission.
• Patient received heparin in any form within the last 100 days prior to current presentation / admission.
• Thrombocytopenia (platelet count less than 100,000 - assuming clumping has been ruled out as a cause).
• Patient has a documented history of heparin induced thrombocytopenia (HIT).
• Patient developed SAH-induced cardiac stunning prior to enrollment, with an ejection fraction \<30%, or requiring IV medications for blood pressure maintenance.
• 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, or malignant brain tumor.
• Thrombolytic therapy within 24 hours prior to enrollment (rtPA, urokinase, etc.)
• 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. A single 325 mg Aspirin (or lower dose) given during the coil embolization peri-procedural period is acceptable if this is the local standard of care but should be documented.
• Concomitant serious or uncontrolled disease such as severe infection, active (non- remission) cancer, severe organ dysfunction (severe heart failure, severe chronic kidney impairment requiring dialysis or severe chronic liver disease) or any coagulopathy (including DIC or bleeding diathesis).
• Uncontrollable hypertension (\>180 systolic and/or \>110 diastolic) that is not correctable prior to enrollment.
• Active Immunosuppression therapy including chronic corticosteroid usage.

Sponsors & Collaborators

• Robert F. James: lead
• Indiana University School of Medicine: collaborator

Study Sites (9)

Yale University

New Haven, Connecticut, United States

Location

University of Florida

Gainesville, Florida, United States

Location

Tallahassee Neurological Clinic

Tallahassee, Florida, United States

Location

Rush University

Chicago, Illinois, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

University of Michigan

Ann Arbor, Michigan, United States

Location

Mount Sinai Ichan School of Medicine

New York, New York, United States

Location

University of Texas Southwestern

Dallas, Texas, United States

Location

Related Publications (10)

• 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.

  PMID: 20809188 BACKGROUND

• 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.

  PMID: 20595669 BACKGROUND

• 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.

  PMID: 22280947 BACKGROUND

• 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.

  PMID: 24373816 BACKGROUND

• 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.

  PMID: 24499240 BACKGROUND

• 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. doi: 10.1590/s0004-282x2012000300009.

  PMID: 22392113 BACKGROUND

• 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.

  PMID: 19409001 BACKGROUND

• 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.

  PMID: 24114458 BACKGROUND

• 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.

  PMID: 24032706 BACKGROUND

• 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.

  BACKGROUND

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Neurobehavioral Manifestations; Vasospasm, Intracranial; Intracranial Aneurysm

Interventions

Heparin

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neurologic Manifestations; Signs and Symptoms; Intracranial Arterial Diseases; Aneurysm

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Robert F James, MD

  Indiana University

  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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurosurgery

Study Record Dates

• First Submitted: July 13, 2015
• First Posted: July 17, 2015
• Study Start: April 1, 2016
• Primary Completion: January 1, 2023
• Study Completion: January 1, 2024
• Last Updated: March 4, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)