Safety and Efficacy Study of Etanercept for Aneurysmal Subarachnoid Hemorrhage
Subarachnoid hemorrhage (SAH) is a special type of stroke that typically results from a ruptured intracranial aneurysm, a weakening in the wall of a blood vessel. This type of life-threatening bleeding occurs in over 3000 Canadians per year, usually in working age adults. Although this type of stroke accounts for only 5-10% of strokes, it contributes a disproportionately larger percent of overall stroke morbidity and mortality due in part to the young age of those affected. If one is fortunate enough to survive the initial bleeding episode and the subsequent surgical treatment of the aneurysm, a patient may still develop secondary strokes 3 to 14 days after the initial bleed. These delayed strokes are the most significant cause of morbidity and mortality after SAH and may be potentially preventable. Currently, there is only one medication (an anti-hypertensive) that has convincingly shown to improve outcomes after SAH. The molecular pathway causing these delayed strokes is still not clear, and this is an active area of research.
Animal studies have revealed that these delayed strokes may be caused by a pro-inflammation molecule called tumor necrosis factor alpha (TNFa). Delayed strokes were prevented experimentally by a TNFa blocker called etanercept. This clinical study, utilizing prophylactic treatment with etanercept in patients with SAH, will ensure the safety of this drug and determine its effectiveness in preventing delayed strokes.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||Phase I Safety, Blood Brain Barrier Permeability and Potential Efficacy of Etanercept for Aneurysmal Subarachnoid Hemorrhage|
- Safety, blood brain barrier (BBB) permeability and potential efficacy of the TNFa antagonist, etanercept, in humans with subarachnoid hemorrhage (SAH). [ Time Frame: Up to Week 12 post-subarachnoid hemorrhage ] [ Designated as safety issue: Yes ]
This is a preliminary phase 1 safety, feasibility study in which patients with aneurysmal subarachnoid hemorrhage (aSAH) will be treated with etanercept, 25 mg subcutaneously starting within 36 hours of SAH, and then receive doses 3.5 days and 7 days later for a total of 3 doses. Patients must have the aneurysm secured by neurosurgical clipping or endovascular coiling and have an external ventricular drain placed as part of routine care. Other aspects of routine care include clinical monitoring (vital signs, neurological exam), daily bloodwork, daily CSF samples, and brain imaging (typically MRI/MRA within 48 hours of coiling procedure and CTA at day 7-11 post-bleed. Etanercept levels, as determined by ELISA, will be measured in the blood and CSF samples, as well as IL-1 levels.
Adverse events will be recorded in case-report forms. Total duration of study for each patient is 12 weeks, including hospital stay and clinical follow-up at 4 and 12 weeks post-subarachnoid hemorrhage.
- Pharmacokinetics (plasma and CSF concentrations) of etanercept by measuring daily plasma and CSF concentrations by enzyme-linked immunosorbent assay (ELISA). [ Time Frame: Up to Week 12 post-subarachnoid hemorrhage ] [ Designated as safety issue: Yes ]Pharmacokinetic sampling to monitor plasma and cerebrospinal fluid levels of etanercept will be performed daily after first administration of etanercept until post-SAH day 14 or hospital discharge, whichever comes first.
- Serum biomarkers, radiologic and clinical outcomes. This is a composite outcome measure. [ Time Frame: Up to Week 12 post-subarachnoid hemorrhage. ] [ Designated as safety issue: Yes ]
- To measure biomarkers that may reflect the effects of etanercept, including plasma C reactive protein, plasma and CSF interleukin-1β (IL-1β) and white blood cell counts.
- To determine radiologic outcomes as determined by angiographic vasospasm on computed tomographic angiograms (CTA), comparing baseline and 7 to 11 days after SAH, and cerebral infarctions on magnetic resonance imaging (MRI).This is standard of care performed within 48 hours of endovascular coiling and at 4-6 weeks).
- To determine clinical outcome, assessed at 30 and 90 days after SAH using modified Rankin scale (mRS), extended Glasgow outcome scale (GOSe), telephone interview of cognitive status (TICS), dysexecutive questionnaire, and the Montreal cognitive assessment (MoCA).
|Study Start Date:||September 2014|
|Estimated Study Completion Date:||June 2016|
|Estimated Primary Completion Date:||June 2016 (Final data collection date for primary outcome measure)|
Patients with aneurysmal subarachnoid hemorrhage will be treated with etanercept, 25 mg subcutaneously starting within 36 hours of SAH, and then receive doses 3.5 days and 7 days later for a total of 3 doses.
Lyophilized powder for reconstitution/ 25 mg/vial. 25 mg subcutaneously starting within 36 hours of SAH, and then receive doses 3.5 days and 7 days later for a total of 3 doses.
Other Name: Enbrel (Amgen Inc., CA)
SAH from a ruptured cerebral aneurysm has an incidence of 10 per 100,000 Canadians (over 3000 people annually). If a person survives SAH from a ruptured intracranial aneurysm, the most common complication is delayed cerebral ischemia (DCI). This is the delayed neurologic deterioration associated with angiographic vasospasm. Vasospasm refers to the arterial constriction that typically begins 3 days after SAH, is maximal 7 to 8 days later and generally resolves by 14 days. About two-thirds of patients with SAH develop vasospasm, one-third develop DCI and one-sixth of SAH patients die or sustain permanent disability from DCI, despite aggressive medical/surgical intervention.
Nimodipine, a calcium-channel antagonist, is currently the only drug to convincingly improve outcomes after SAH. Randomized multi-centre clinical trials utilizing clazosentan, an endothelin receptor antagonist, demonstrated no change in clinical outcome despite significant decrease in large vessel vasospasm. These results have shifted the research in the pathophysiology of DCI to alternative mechanisms other than large vessel vasospasm.
It is known that the presence of blood in the subarachnoid space triggers massive local and systemic inflammation, including increase in the production of a pro-inflammatory cytokine called tumor necrosis factor alpha (TNFa). We have shown in mice that global, and smooth muscle-specific knockout of TNFa prevents increased myogenic tone and reduces brain injury after SAH. Furthermore, systemic or intrathecal treatment with etanercept may prevent the increase in myogenic tone observed after SAH and may reduce brain injury. Administration of etanercept to patients with SAH is a critical step in determining the safety and potential efficacy of TNFa antagonists in SAH.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01865630
|Contact: Marlene S. Santos, MD||416-864-6060 ext email@example.com|
|Contact: Jane Topolovec-Vranic, PhD||416-864-6060 ext 3421||Topolovec-VranicJ@smh.ca|
|St. Michael's Hospital||Not yet recruiting|
|Toronto, Ontario, Canada, M5B 1W8|
|Contact: Marlene S. Santos, MD 416-864-6060 ext 2322 firstname.lastname@example.org|
|Principal Investigator: Andrew Baker, MD|
|Sub-Investigator: Steffan-Sebastian Bolz, MD|
|Sub-Investigator: Jinglu Ai, MD|
|Sub-Investigator: Michael Tso, MD|
|Principal Investigator:||Andrew Baker, MD||St. Michael's Hospital, Toronto|