Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Study days 7 and 10 serum EET/DHET ratios Study days 7 and 10 cerebrospinal fluid (CSF) EET/DHET ratios Study days 7 and 10 serum EPOME/DPOME ratio 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

Official Title
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Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial

Conditions
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Subarachnoid Hemorrhage, Aneurysmal, Delayed Cerebral Ischemia, Vasospasm, Cerebral, Endothelial Dysfunction

Intervention / Treatment
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* Drug: GSK2256294
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 Head CT evidence of subarachnoid hemorrhage Digital subtraction cerebral angiography or CT angiogram documenting the presence of a cerebral aneurysm. Exclusion Criteria: Symptom onset compatible with SAH of > 3 days prior to admission to OHSU Absence of an indwelling external ventricular drain Administration of any of the following inducers/inhibitors of CYP3A4: ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, chloramphenicol, ketoconazole, itraconazole, nefazodone, cobicistat or enzalutamide. Suspected or confirmed pregnancy Preexisting severe neurologic deficit or condition Chronic renal failure requiring dialysis Severe terminal disease with life expectancy <6 months Unable to read or understand written or spoken English or Spanish Refusal of informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized to one of the two treatment arms based on an unrestricted or fair-coin randomization procedure.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GSK2256294<br>10mg capsules of GSK2256294 will be administered in a single dose once daily enterally for a duration of 10 days. | Drug: GSK2256294<br>* GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days.<br>|
| Placebo Comparator: Placebo<br>10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days. | Drug: Placebo<br>* Placebo will be administered in a single dose once daily enteral for a duration of 10 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Adverse Events | Summary tables and listings will be provided for all reported adverse events, defined as adverse events that start on or after the first administration of study drug. The reported adverse event term will be assigned a standardized preferred term. Adverse events will be summarized based on the number and percentage of patients experiencing the event. In the event a patient experiences repeat episodes of the same adverse event, then the event with the highest severity grade and strongest causal relationship to study treatment will be used for purposes of incidence tabulations. All deaths will be reported in a patient listing, which will include the primary cause of death and the number of days between the date of the last dose of study drug and death. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Day 7 and Study Day 10 Serum and CSF EET/ Dihyroxyeicosatrienoic (DHET) Ratio, by Mass Spectroscopic Analysis (ng/mL) | Day 7 and day 10 serum EET/DHET ratios will be measured by liquid chromatography and mass spectroscopy of collected blood samples. Day 7 and day 10 CSF EET/DHET ratios will be measured by liquid chromatography and mass spectroscopy of collected CSF samples. | 10 days | 
| Study Day 7 and Study Day 10 Serum Epoxyoctadecenoic Acid (EPOME) to Dihydroxyoctadec-12-enoic Acid (DPOME) Ratio, by Mass Spectroscopic Analysis (ng/mL) | Study day 7 and study day 10 serum epoxyoctadecenoic acid (EPOME) to dihydroxyoctadec-12-enoic acid (DPOME) ratio, will be measure by mass spectroscopic analysis of collected blood samples. | 10 days | 
| Serum Biomarkers of Endothelial Injury From Blood Samples Obtained on Study Day 7 and Study Day 10 | The following serum biomarkers will be obtained from collected blood samples by Luminex assay: e-selectin, p-selectin, Vascular cell adhesion marker (VCAM-1), Platelet endothelial cell adhesion marker (PECAM-1, CD31), intercellular adhesion molecule (ICAM-1). | 10 days | 
| CSF Biomarkers of Neuroinflammation, From Blood Samples Obtained on Study Day 7 and Study Day 10 | The following CSF biomarker will be obtained from collected CSF samples by Luminex assay: Tumor necrosis factor alpha (TNF-α) (pg/mL), Interleukin 1β (IL-1β) (pg/mL), Interferon gamma (IFN-γ) (pg/mL), Interleukin 6 (IL-6) (pg/mL), Interleukin 8 (IL-8) (pg/mL), Monocyte chemoattractant protein 1 (MCP-1) (pg/mL) | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eicosanoids, Epoxyeicosatrienoic Acids