Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial
Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial
Soluble epoxide hydrolase (sEH) is the metabolizing enzyme of epoxyeicosatrienoic acids
 (EETs), which may play a role in reducing neuroinflammation and regulating cerebral blood
 flow after subarachnoid hemorrhage (SAH). Hypotheses: Pharmacologic inhibition of the sEH
 enzyme is safe and will result in increased EETs availability in the blood and cerebrospinal
 fluid. This study is a double-blind, placebo-controlled, phase 1b randomized trial to
 evaluate the safety and efficacy of GSK2256294, a novel soluble epoxide hydrolase inhibitor
 in patients with aneurysmal SAH.
Study Description: Soluble epoxide hydrolase (sEH) is the metabolizing enzyme of
 epoxyeicosatrienoic acids (EETs), which may play a role in reducing neuroinflammation and
 regulating cerebral blood flow after subarachnoid hemorrhage (SAH).

 Hypothesis: Pharmacologic inhibition of the sEH enzyme is safe and will result in increased
 EETs availability at the neurovascular unit, and a measured increase in the EET/DHET ratio in
 the serum and cerebrospinal fluid. This study is a double-blind, placebo-controlled, phase 1b
 randomized trial to evaluate the safety and of GSK2256294, an inhibitor of soluble epoxide
 hydrolase, in patients with aneurysmal SAH.

 Objectives:

 Primary Objective:

 Determine the safety of administration of GSK2256294 in patients with aneurysmal SAH.

 Secondary Objective:

 Determine the pharmacodynamic effect of administration of GSK2256294 in patients with
 aneurysmal SAH on reducing EETs metabolism and biomarkers of cerebrovascular inflammation and
 endothelial injury.

 Tertiary Objective:

 Provide preliminary estimates of clinical endpoints to inform the design of a larger trial

 Endpoints:

 Primary Endpoints:

 Determination of safety

 Secondary endpoints:

 1. Study days 7 and 10 serum EET/DHET ratios

 2. Study days 7 and 10 cerebrospinal fluid (CSF) EET/DHET ratios

 3. Study days 7 and 10 serum EPOME/DPOME ratio

 4. Neuroinflammatory and endothelial injury biomarker levels from the blood and CSF at day
 7 and day 10.

 Tertiary, exploratory endpoints:

 Clinical outcomes associated with SAH including neurologic status, disposition, vital status
 and incidence of delayed cerebral ischemia.

 20 subjects will be randomized. Patients age 18 or above with confirmed ruptured aneurysms
 will be approached to provide written informed consent

 Phase: Phase 1B

 Description of Sites/Facilities Enrolling Participants: The study will take place at Oregon
 Health & Science University Hospital, with enrollment of patients admitted to the OHSU NSICU,
 a part of a comprehensive stroke center certified by the American Heart Association and Joint
 Commission for Accreditation of Healthcare Organizations, with a catchment area including the
 state of Oregon, Southwest Washington and Northern California. Approximately 80-100 patients
 with aneurysmal SAH are admitted each year.

 Description of Study Intervention: Twenty patients will be equally randomized to receive once
 daily either 10 mg dose of GSK2256294 or placebo enterally for a duration of 10 days.

 Study Duration: 24 months

 Participant Duration: 90 days
Inclusion Criteria:

 1. Age > 18

 2. Head CT evidence of subarachnoid hemorrhage

 3. Digital subtraction cerebral angiography or CT angiogram documenting the presence of a
 cerebral aneurysm.

 Exclusion Criteria:

 1. Symptom onset compatible with SAH of > 3 days prior to admission to OHSU

 2. Absence of an indwelling external ventricular drain

 3. Administration of any of the following inducers/inhibitors of CYP3A4: ritonavir,
 indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, chloramphenicol,
 ketoconazole, itraconazole, nefazodone, cobicistat or enzalutamide.

 4. Suspected or confirmed pregnancy

 5. Preexisting severe neurologic deficit or condition

 6. Chronic renal failure requiring dialysis

 7. Severe terminal disease with life expectancy <6 months

 8. Unable to read or understand written or spoken English or Spanish

 9. Refusal of informed consent