Clinical trial NCT03318783: Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial
Official title: Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Subarachnoid Hemorrhage, Aneurysmal
Delayed Cerebral Ischemia
Vasospasm, Cerebral
Endothelial Dysfunction
Keywords: Eicosanoids
Epoxyeicosatrienoic Acids
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
Collaborators: name: Foundation for Anesthesia Education and Research
name: GlaxoSmithKline
First posted: 2017-10-24
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomized to one of the two treatment arms based on an unrestricted or "fair-coin" randomization procedure.
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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

Primary outcomes:
measure: Participants With Adverse Events
timeFrame: 90 days
Secondary outcomes:
measure: Study Day 7 and Study Day 10 Serum and CSF EET/ Dihyroxyeicosatrienoic (DHET) Ratio, by Mass Spectroscopic Analysis (ng/mL)
timeFrame: 10 days
measure: Study Day 7 and Study Day 10 Serum Epoxyoctadecenoic Acid (EPOME) to Dihydroxyoctadec-12-enoic Acid (DPOME) Ratio, by Mass Spectroscopic Analysis (ng/mL)
timeFrame: 10 days
measure: Serum Biomarkers of Endothelial Injury From Blood Samples Obtained on Study Day 7 and Study Day 10
timeFrame: 10 days
measure: CSF Biomarkers of Neuroinflammation, From Blood Samples Obtained on Study Day 7 and Study Day 10
timeFrame: 10 days
Other outcomes:
measure: Hospital Length of Stay in Days
timeFrame: 90 days
measure: Discharge Disposition
timeFrame: 90 days
measure: Number of Participants With New Stroke on Hospital Discharge Imaging
timeFrame: 90 days
measure: Modified Rankin Scale (mRS) at Hospital Discharge and 90 Day Follow up
timeFrame: 90 days
measure: Extended Glasgow Outcome Scale (GOSE) Score at 90 Day Follow up
timeFrame: 90 days
Locations:
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
Study officials:
affiliation: Oregon Health and Science University
name: Ross Martini, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Martini RP, Siler D, Cetas J, Alkayed NJ, Allen E, Treggiari MM. A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care. 2022 Jun;36(3):905-915. doi: 10.1007/s12028-021-01398-8. Epub 2021 Dec 6.