Safety and Efficacy Study of Etanercept for Aneurysmal Subarachnoid Hemorrhage

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2014 by St. Michael's Hospital, Toronto
Sponsor:
Information provided by (Responsible Party):
St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier:
NCT01865630
First received: May 27, 2013
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Subarachnoid Hemorrhage, Aneurysmal
Drug: Etanercept
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by St. Michael's Hospital, Toronto:

Primary Outcome Measures:
  • 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.



Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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).


Estimated Enrollment: 20
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)
Arms Assigned Interventions
Experimental: Etanercept
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.
Drug: Etanercept
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)

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01865630

Contacts
Contact: Marlene S. Santos, MD 416-864-6060 ext 2322 santosmar@smh.ca
Contact: Jane Topolovec-Vranic, PhD 416-864-6060 ext 3421 Topolovec-VranicJ@smh.ca

Locations
Canada, Ontario
St. Michael's Hospital Not yet recruiting
Toronto, Ontario, Canada, M5B 1W8
Contact: Marlene S. Santos, MD    416-864-6060 ext 2322    santosmar@smh.ca   
Principal Investigator: Andrew Baker, MD         
Sub-Investigator: Steffan-Sebastian Bolz, MD         
Sub-Investigator: Jinglu Ai, MD         
Sub-Investigator: Michael Tso, MD         
Sponsors and Collaborators
St. Michael's Hospital, Toronto
Investigators
Principal Investigator: Andrew Baker, MD St. Michael's Hospital, Toronto
  More Information

Publications:
Responsible Party: St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier: NCT01865630     History of Changes
Other Study ID Numbers: 13-3007-ETP
Study First Received: May 27, 2013
Last Updated: April 4, 2014
Health Authority: Canada: Health Canada

Keywords provided by St. Michael's Hospital, Toronto:
Prophylactic treatment with Etanercept in aSAH.
Safety of Etanercept in the prevention of DCI in aSAH.

Additional relevant MeSH terms:
Hemorrhage
Subarachnoid Hemorrhage
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
TNFR-Fc fusion protein
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Gastrointestinal Agents
Immunologic Factors
Immunosuppressive Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 28, 2014