Safety and Efficacy Study of Etanercept for Aneurysmal Subarachnoid Hemorrhage

NCT01865630 | Withdrawn Phase 1 DMC

• 1 other identifier: 13-3007-ETP
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Subarachnoid Hemorrhage, Aneurysmal

Keywords

Prophylactic treatment with Etanercept in aSAH.; Safety of Etanercept in the prevention of DCI in aSAH.

Outcome Measures

Primary Outcomes (1)

• Safety, blood brain barrier (BBB) permeability and potential efficacy of the TNFa antagonist, etanercept, in humans with subarachnoid hemorrhage (SAH).

  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, 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 cerebrospinal fluid (CSF) samples, and brain imaging typically magnetic resonance imaging/angiography (MRI/MRA) within 48 hours of coiling, and CTA at day 7-11 post-bleed. Etanercept levels 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 study duration for each patient is 12 weeks, including hospital stay and clinical follow-up at 4 and 12 weeks post-SAH.

  Up to Week 12 post-SAH

Secondary Outcomes (1)

• Pharmacokinetics (plasma and CSF concentrations) of etanercept by measuring daily plasma and CSF concentrations by enzyme-linked immunosorbent assay (ELISA).

  Up to Week 12 post-subarachnoid hemorrhage

Other Outcomes (1)

• Serum biomarkers, radiologic and clinical outcomes. This is a composite outcome measure.

  Up to Week 12 post-subarachnoid hemorrhage.

Study Arms (1)

Etanercept

EXPERIMENTAL

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

Interventions

Etanercept DRUG

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.

Also known as: Enbrel (Amgen Inc., CA)

Etanercept

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Unity Health Toronto: lead

Study Sites (1)

St. Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Related Publications (5)

• Beeftink MM, Ruigrok YM, Rinkel GJ, van den Bergh WM. Relation of serum TNF-alpha and TNF-alpha genotype with delayed cerebral ischemia and outcome in subarachnoid hemorrhage. Neurocrit Care. 2011 Dec;15(3):405-9. doi: 10.1007/s12028-011-9556-1.

  PMID: 21562930 BACKGROUND

• Gruber A, Rossler K, Graninger W, Donner A, Illievich MU, Czech T. Ventricular cerebrospinal fluid and serum concentrations of sTNFR-I, IL-1ra, and IL-6 after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2000 Oct;12(4):297-306. doi: 10.1097/00008506-200010000-00001.

  PMID: 11147377 BACKGROUND

• Kerensky TA, Gottlieb AB, Yaniv S, Au SC. Etanercept: efficacy and safety for approved indications. Expert Opin Drug Saf. 2012 Jan;11(1):121-39. doi: 10.1517/14740338.2012.633509. Epub 2011 Nov 11.

  PMID: 22074366 BACKGROUND

• Vecchione C, Frati A, Di Pardo A, Cifelli G, Carnevale D, Gentile MT, Carangi R, Landolfi A, Carullo P, Bettarini U, Antenucci G, Mascio G, Busceti CL, Notte A, Maffei A, Cantore GP, Lembo G. Tumor necrosis factor-alpha mediates hemolysis-induced vasoconstriction and the cerebral vasospasm evoked by subarachnoid hemorrhage. Hypertension. 2009 Jul;54(1):150-6. doi: 10.1161/HYPERTENSIONAHA.108.128124. Epub 2009 May 26.

  PMID: 19470883 BACKGROUND

• Zhou QH, Sumbria R, Hui EK, Lu JZ, Boado RJ, Pardridge WM. Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor. J Pharmacol Exp Ther. 2011 Nov;339(2):618-23. doi: 10.1124/jpet.111.185876. Epub 2011 Aug 10.

  PMID: 21831964 BACKGROUND

MeSH Terms

Conditions

Subarachnoid Hemorrhage

Interventions

Etanercept

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins

Study Officials

• Andrew Baker, MD

  Unity Health Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 27, 2013
• First Posted: May 31, 2013
• Study Start: January 1, 2021
• Primary Completion: January 1, 2022
• Study Completion: January 1, 2022
• Last Updated: November 2, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)