Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial

Endothelial Dysfunction Clinical Trial

— SUSHI  

Official title:

Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03318783
• Other study ID #: 17614
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 2, 2018
• Est. completion date: January 9, 2020

Study information

• Verified date: December 2020
• Source: Oregon Health and Science University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: January 9, 2020
• Est. primary completion date: April 3, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Ischemia
• Cerebral Infarction
• Delayed Cerebral Ischemia
• Endothelial Dysfunction
• Hemorrhage
• Ischemia
• Subarachnoid Hemorrhage
• Subarachnoid Hemorrhage, Aneurysmal
• Vasospasm, Cerebral
• Vasospasm, Intracranial

Intervention

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

Locations

Country	Name	City	State
United States	Oregon Health & Science University	Portland	Oregon

Sponsors (3)

Lead Sponsor	Collaborator
Oregon Health and Science University	Foundation for Anesthesia Education and Research, GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hospital Length of Stay in Days	The hospital length of stay will be recorded in days, at the time of hospital discharge.	90 days
Other	Discharge Disposition	The disposition from the hospital in one of the following categories: home, home with services, rehab, long term acute care facility, skilled nursing facility, hospice, death	90 days
Other	Number of Participants With New Stroke on Hospital Discharge Imaging	The last head CT or other brain imaging to detect the presence of a new area of cerebral infarction will be reviewed at the time of hospital discharge. A cerebral infarction will be defined as a one identified on hospital discharge that was not present on imaging between 24-48 hours after aneurysm occlusion, and not attributable to other causes such as surgical clipping or endovascular treatment. Hypodensities resulting from extraventricular drains or residual intraparencyhmal hematomas will not be considered new strokes.	90 days
Other	Modified Rankin Scale (mRS) at Hospital Discharge and 90 Day Follow up	The mRS score will be determined by patient or surrogate interview, at both hospital discharge and 90 day follow up. Scores will be assigned based on the following: 0 - no symptoms, 1 - no significant disability, able to carry out all usual activities despite some symptoms, 2 - slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities, 3 - moderate disability, requires some help, but able to walk unassisted, 4 - moderately severe disability, unable to attend to own bodily needs without assistance, and unable to walk unassisted, 5 - severe disability, requires constant nursing care and attention, bedridden, incontinent, 6 - deceased.	90 days
Other	Extended Glasgow Outcome Scale (GOSE) Score at 90 Day Follow up	At 90 day follow up, the GOSE will be determined by patient or surrogate telephone interview, based on a structured interview of 19 questions. The GOSE is a scale of 1-8 where 1 - deceased, 2 - vegetative state, 3 - low severe disability, 4 - upper severe disability, 5 - low moderate disability, 6 -upper moderate disability, 7 - low good recovery, 8 - upper good recovery.	90 days
Primary	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	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
Secondary	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
Secondary	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
Secondary	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-a) (pg/mL), Interleukin 1ß (IL-1ß) (pg/mL), Interferon gamma (IFN-?) (pg/mL), Interleukin 6 (IL-6) (pg/mL), Interleukin 8 (IL-8) (pg/mL), Monocyte chemoattractant protein 1 (MCP-1) (pg/mL)	10 days