NCT02501434暂停2 期
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
Robert F. James9 个研究点 分布在 1 个国家目标入组 88 人开始时间: 2016年4月最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 暂停
- 发起方
- 入组人数
- 88
- 试验地点
- 9
- 主要终点
- Montreal Cognitive Assessment (MoCA)
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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 has additional 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.
- •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).
- •New intraparenchymal 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 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.
- •Prior neurological disease/deficit or psychiatric disease that may continue to alter the results of neuropsychological evaluation, such as dementia, Multiple sclerosis, seizure disorder, severe traumatic brain injury, previous ruptured cerebral aneurysm or active major depression. Childhood seizures that have resolved and no longer require treatment are not part of this exclusion criteria.
- •Active Immunosuppression therapy including chronic corticosteroid usage.
- •History of gastrointestinal hemorrhage or major systemic hemorrhage within 30 days (including large flank or large retroperitoneal hematoma due to current admission coiling procedure requiring treatment), hemoglobin less than 6 g/dL, INR ≥1.5 after reversal of anticoagulants.
- •Major surgery (including open femoral, aortic, or carotid surgery) within previous 30 days.
- •Currently pregnant.
- •Enrollment in another research study that prescribes a therapeutic treatment that differs from the local standard of care, or that would conflict with this study in some other significant fashion. Registries or coil comparison studies are appropriate.
研究组 & 干预措施
LDIVH (Unfractionated Heparin)
Experimental
Continuous Low-Dose IV Unfractionated Heparin Infusion
干预措施: Continuous Low-Dose IV Unfractionated Heparin Infusion (Drug)
结局指标
主要结局
Montreal Cognitive Assessment (MoCA)
时间窗: 90-day follow-up visit
Primary Clinical Outcome Measure- mean score compared between groups
Rate of "Major Bleeding" or "Clinically Relevant Non-Major Bleeding"
时间窗: 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-
次要结局
- Rate of Type II Heparin Induced Thrombocytopenia (HIT)(Enrollment through 90-day follow-up visit)
- Incidence of multiple fevers (> 2 episodes)(Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks)
- Glasgow Coma Score(Enrollment, post-enrollment days #6, 10, discharge, and 90-day follow-up visit)
- National Institutes of Health Stroke Scale (NIHSS)(Enrollment, post-enrollment days #6, 10, upon discharge from hospital stay an expected average of about 3 weeks after admission, 90-day follow-up visit)
- Center for Epidemiologic Studies Depression Scale (CES-D)(90-day follow-up visit and 1-year follow-up visit)
- Rate of Serious Adverse Events (SAEs)(From 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)
- Rate of "Major Bleeding"(Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks)
- 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)
- Mean daily fever burden(Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks)
- Montreal Cognitive Assessment (MoCA)(Enrollment, post-enrollment days #6, 10, 1 year follow-up)
- Trail Making Test Parts A&B(90-day follow-up visit)
- Ordinal Regression Analysis of the modified Rankin Scale score (mRS)(90-day follow-up visit and 1 year follow-up visit)
- Relative frequency of "good outcome" as defined by dichotomized mRS score 0-2(90-day follow-up visit and 1 year follow-up visit)
- Incidence of CT or MRI imaging demonstrating cerebral vasospasm related cerebral infarction(Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks)
- Return to work status(90-day follow-up and 1 year follow-up visit)
- Checklist Individual Strength- Subscale Fatigue (CIS-F)(90-day follow-up visit and 1 year follow-up visit)
- Cerebral Vasospasm(Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks)
- Incidence of clinical cerebral vasospasm requiring rescue therapy(Participants will be followed for the duration of the hospital stay, an expected average of 3 weeks)
- Barthel Index(90-day follow-up visit and 1 year follow-up visit)
- Lawton instrumental activities of daily living (IADL)(90-day follow-up visit and 1 year follow-up visit)
- Quality of Life in Brain Injury - Overall Scale (QOLIBRI-OS)(90-day follow-up visit and 1 year follow-up visit)
- Plasma biomarker level (hsCRP)(Enrollment, post-enrollment days #2,4,6,10)
- Cerebrospinal Fluid (CSF) biomarker level (hsCRP)(Enrollment, post-enrollment days #2,4,6,10)
研究者
Robert F. James
Professor of Neurosurgery
Indiana University
研究点 (9)
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