Eicosapentaenoic Acid Cerebral Vasospasm Therapy Study (EVAS)

Eicosapentaenoic Acid Cerebral Vasospasm Therapy Study (EVAS): Effect of Eicosapentaenoic Acid on Cerebral Vasospasm Following Subarachnoid Hemorrhage

Cerebral vasospasm following subarachnoid hemorrhage (SAH) is the most common cause of morbidity and mortality. Recent studies indicate that Rho-kinase play an important role in the occurrence of such cerebral vasospasm. Eicosapentaenoic acid (EPA) inhibits sphingosylphosphorylcholine (SPC)-induced Rho-kinase activation in vitro. So this study examines whether EPA prevents cerebral vasospasm occurrence after SAH in patients.

Study Overview

• Status: Completed
• Conditions: Subarachnoid Hemorrhage; Cerebral Vasospasm
• Intervention / Treatment: Drug: Eicosapentaenoic acid ethyl ester

Detailed Description

Cerebral vasospasm occasionally seen after subarachnoid hemorrhage (SAH) due to a ruptured intracranial aneurysm is the most common cause of morbidity and mortality in these cases. Recent studies indicate that Rho-kinase plays an important role in such cerebral vasospasm and that numerous agents, such as thromboxane A2 (TXA2), sphingosylphosphorylcholine (SPC) and arachidonic acid (AA), can activate Rho-kinase directly or through receptors in the cell membrane; among these agents, SPC has been described as a novel messenger for Rho-kinase-mediated Ca2+ sensitization of vascular smooth muscle contraction. Eicosapentaenoic acid (EPA) has recently been reported to inhibit SPC-induced Rho-kinase activation in vitro, and thereby vascular smooth muscle contraction, through the inhibition of Src family protein tyrosine kinases translocation. Moreover, the concentration of AA increases in the cerebrospinal fluid of patients with SAH, suggesting that this substance has a potential role in the occurrence of cerebral vasospasm following SAH, while EPA is known to change the constitution ratios of AA and EPA in cell membrane phospholipid, resulting in the inhibition of TXA2 synthesis. These observations lead us to hypothesize that EPA may inhibit cerebral vasospasm following SAH through the inhibition of Rho-kinase activation.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan, 803-8543
      • Ootemachi Hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8570
      • Nakamura Memorial Hospital
  • Iwate
    • Morioka, Iwate, Japan, 020-8505
      • Iwate Medical University
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
      • Tohoku University
  • Yamaguchi
    • Ube, Yamaguchi, Japan, 755-8505
      • Yamaguchi University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subarachnoid hemorrhage (SAH)
• The ruptured cerebral aneurysms conformed by cerebral angiography
• The patients with treated by craniotomy and clip application within 72h after the onset of SAH

Exclusion Criteria:

• Traumatic or mycotic aneurysms
• A history or complication of serious stroke
• Moya Moya disease
• A history of SAH
• Complication of serious heart or hepatic disease or infection or renal failure
• Malignant tumor
• Patients judged to be inappropriate by physician in charge

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; Patients in the group A are orally administered eicosapentaenoic acid ethyl ester.	Drug: Eicosapentaenoic acid ethyl ester; Orally administered 900 mg eicosapentaenoic acid ethyl ester three times a day (2700 mg ⁄ day) from the surgery next day to 30 days after the onset of SAH.; Other Names: EPADEL S900 TM (EPA ethyl ester, purity >98%)
No Intervention: B; Patients in the group B (control) are not administered eicosapentaenoic acid ethyl ester.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cerebral vasospasms: Symptomatic vasospasm defined as documented arterial vasospasm consistent with new neurological deterioration. New low-density areas on CT scans associated with vasospasm.	Between 4 and 30 days after the onset of SAH

Secondary Outcome Measures

Outcome Measure	Time Frame
Patient's Glasgow Outcome Scale (GOS).	At 1 month after onset of SAH.

Collaborators and Investigators

• Sponsor: Yamaguchi University Hospital
• Collaborators: Iwate Medical University; Tohoku University; Nakamura Memorial Hospital; Ootemachi Hospital
• Investigators: Principal Investigator: Michiyasu Suzuki, MD, PhD, Yamaguchi University Hospital

Publications and helpful links

General Publications

• Yoneda H, Shirao S, Nakagawara J, Ogasawara K, Tominaga T, Suzuki M. A prospective, multicenter, randomized study of the efficacy of eicosapentaenoic acid for cerebral vasospasm: the EVAS study. World Neurosurg. 2014 Feb;81(2):309-15. doi: 10.1016/j.wneu.2012.09.020. Epub 2012 Sep 29.

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: February 4, 2009
• First Submitted That Met QC Criteria: February 6, 2009
• First Posted (Estimate): February 9, 2009

Study Record Updates

• Last Update Posted (Estimate): September 3, 2009
• Last Update Submitted That Met QC Criteria: September 1, 2009
• Last Verified: September 1, 2009

More Information

Terms related to this study

• Keywords: subarachnoid hemorrhage; cerebral vasospasm; eicosapentaenoic acid
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Platelet Aggregation Inhibitors; Lipid Regulating Agents; Eicosapentaenoic acid ethyl ester
• Other Study ID Numbers: Y-2004