Phase I Safety, Blood Brain Barrier Permeability and Potential Efficacy of Etanercept for Aneurysmal Subarachnoid Hemorrhage
18 Years
75 Years
Both
Subarachnoid Hemorrhage, Aneurysmal
Trial Information
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.
Inclusion Criteria:
- Male or female 18 to 75 years old.
- World Federation of Neurological Surgeons (WFNS) grade 2 to 4.
- Subarachnoid hemorrhage (SAH) on admission computed tomographic (CT) scan (diffuse
clot present in both hemispheres or local thick SAH).
- Ruptured saccular aneurysm, confirmed by angiography (catheter or CT angiography
[CTA]) and treated by neurosurgical clipping or endovascular coiling.
- External ventricular drain placed as part of routine care.
- Able to be dosed within 36 hours of injury
- Historical modified Rankin score of 0 or 1.
- Hemodynamically stable after resuscitation (systolic blood pressure [SBP] > 100 mm
Hg).
- Aminotransferase levels no greater than twice the upper limit of normal, hemoglobin >
85 g/dL, platelets > 125,000 cells/mm3, serum creatinine < 177 μmol/L.
- Informed consent.
Exclusion Criteria:
- SAH due to causes other than saccular aneurysm (such as trauma or rupture of fusiform
or infective aneurysm).
- Intraventricular or intracerebral hemorrhage, in the absence of SAH, or with only
local, thin SAH.
- Angiographic vasospasm prior to clipping or endovascular procedure.
- Major complication during clipping or endovascular coiling, such as massive
intraoperative hemorrhage, arterial occlusion or inability to clip or coil the
ruptured aneurysm.
- Cardio-pulmonary resuscitation required following SAH.
- Women with a positive urine pregnancy test at screening.
- Body mass index > 35
- Severe or unstable concomitant condition or disease (e.g., known significant
neurologic deficit, cancer, hematologic, or coronary disease), or chronic condition
(e.g., psychiatric disorder), which, in the opinion of the investigator, would affect
the assessment of the safety and tolerability of etanercept.
- Patients who have received an investigational product or participated in another
clinical trial within 28 days prior to randomization or those who have already
participated in the current study.
- History of hepatitis B or C, history of heart failure (etanercept may exacerbate
heart failure), active infection or serious infection in the last 6 months, history
of tuberculosis and history of malignancy, multiple sclerosis or history of
seizures.
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
Outcome Measure:
To determine the safety, blood brain barrier (BBB) permeability and potential efficacy of the TNFa antagonist, etanercept, in humans with subarachnoid hemorrhage (SAH).
Outcome Description:
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.
Outcome Time Frame:
Up to Week 12 post-subarachnoid hemorrhage
Safety Issue:
Yes
Principal Investigator
Robert Loch Macdonald, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
St. Michael's Hospital, Toronto
Authority:
Canada: Health Canada
Study ID:
13-3007-ETP
NCT ID:
NCT01865630
Start Date:
July 2013
Completion Date:
July 2015
Related Keywords:
- Subarachnoid Hemorrhage, Aneurysmal
- Prophylactic treatment with Etanercept in aSAH.
- Safety of Etanercept in the prevention of DCI in aSAH.
- Hemorrhage
- Subarachnoid Hemorrhage
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