Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-05-02

Study Completion Date

2020-01-09

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.

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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:

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

Conditions

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Subjects will be randomized to one of the two treatment arms based on an unrestricted or "fair-coin" randomization procedure.

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Investigational pharmacy staff will maintain the randomization list and study/drug placebo assignment. Participants, care providers, the investigators and outcomes assessors will be blinded to the grouping.

Study Groups

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GSK2256294

10mg capsules of GSK2256294 will be administered in a single dose once daily enterally for a duration of 10 days.

Group Type ACTIVE_COMPARATOR

GSK2256294

Intervention Type DRUG

GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days.

Placebo

10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Placebo will be administered in a single dose once daily enteral for a duration of 10 days.

Interventions

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GSK2256294

GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days.

Intervention Type DRUG

Placebo

Placebo will be administered in a single dose once daily enteral for a duration of 10 days.

Intervention Type DRUG

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No