Phase I Safety, Blood Brain Barrier Permeability and Potential Efficacy of Etanercept for Aneurysmal Subarachnoid Hemorrhage
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
To determine the safety, blood brain barrier (BBB) permeability and potential efficacy of the TNFa antagonist, etanercept, in humans with subarachnoid hemorrhage (SAH).
This is a preliminary phase 1 safety and feasibility study in which patients with aneurysmal subarachnoid hemorrhage (SAH) 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.
Up to Week 12 post-subarachnoid hemorrhage
Robert Loch Macdonald, MD
St. Michael's Hospital, Toronto
Canada: Health Canada