Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial (SUSHI)

Oregon Health & Science University (OHSU)

Status and phase: Completed; Phase 2; Phase 1

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

Treatments: Drug: GSK2256294; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03318783

17614

Details and patient eligibility

About

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.

Full description

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

Enrollment: 20 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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20 participants in 2 patient groups, including a placebo group

GSK2256294

Active Comparator group

Description:

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

Treatment:

Drug: GSK2256294

Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo