Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial

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Sponsorlar

Oregon Health and Science University

KLINIK ÇALIŞMA: NCT03318783

BioSeek: NCT03318783

Anahtar kelimeler

Öz

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.

Açıklama

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

Tarih

Son Doğrulandı:	03/31/2019
İlk Gönderilen:	10/09/2017
Tahmini Kayıt Gönderildi:	10/17/2017
İlk Gönderilen:	10/23/2017
Son Güncelleme Gönderildi:	04/07/2019
Son Güncelleme Gönderildi:	04/09/2019
Fiili Çalışma Başlangıç Tarihi:	05/01/2018
Tahmini Birincil Tamamlanma Tarihi:	05/31/2021
Tahmini Çalışma Tamamlanma Tarihi:	11/30/2021

Durum veya hastalık

Subarachnoid Hemorrhage, Aneurysmal

Delayed Cerebral Ischemia

Vasospasm, Cerebral

Endothelial Dysfunction

Müdahale / tedavi

Drug: GSK2256294

Drug: Placebo

Evre

Evre 1/Evre 2

Kol Grupları

Kol	Müdahale / tedavi
Active Comparator: GSK2256294 10mg capsules of GSK2256294 will be administered in a single dose once daily enterally for a duration of 10 days.	Drug: GSK2256294 GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days.
Placebo Comparator: Placebo 10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days.	Drug: Placebo Placebo will be administered in a single dose once daily enteral for a duration of 10 days.

Uygunluk kriterleri

Çalışmaya Uygun Yaşlar	18 Years İçin 18 Years
Çalışmaya Uygun Cinsiyetler	All
Sağlıklı Gönüllüleri Kabul Ediyor	Evet
Kriterler	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

Sonuç

Birincil Sonuç Ölçütleri

1. Number of participants with treatment-related adverse events [90 days]

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. Tabular summaries will be provided for all adverse events, the relationship to study drug treatment the maximum severity grade, action taken, and whether the event qualified serious adverse event or not. 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.

İkincil Sonuç Ölçütleri

1. Study day 7 and study day 10 serum and CSF EET/ dihyroxyeicosatrienoic (DHET) ratio, by mass spectroscopic analysis (ng/mL) [10 days]

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.

2. Study day 7 and study day 10 serum epoxyoctadecenoic acid (EPOME) to dihydroxyoctadec-12-enoic acid (DPOME) ratio, by mass spectroscopic analysis (ng/mL) [10 days]

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.

3. Serum biomarkers of endothelial injury from blood samples obtained on study day 7 and study day 10 [10 days]

The following serum biomarkers will be obtained from collected blood samples by Luminex assay: e-selectin (pg/mL), p-selectin (pg/mL), Vascular cell adhesion marker (VCAM-1) (pg/mL), Platelet endothelial cell adhesion marker (PECAM-1, CD31) (pg/mL), intercellular adhesion molecule (ICAM-1) (pg/mL)

4. CSF biomarkers of neuroinflammation, from blood samples obtained on study day 7 and study day 10 [10 days]

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)

Diğer Sonuç Ölçütleri

1. Hospital length of stay in days [90 days]

The hospital length of stay will be recorded in days, at the time of hospital discharge.

2. Discharge disposition [90 days]

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

3. Incidence of new stroke on hospital discharge imaging [90 days]

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.

4. Modified Rankin scale (mRS) at hospital discharge and 90 day follow up [90 days]

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.

5. Extended Glasgow Outcome Scale (GOSE) Score at 90 day follow up [90 days]

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 will be recorded on an 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.

Subarachnoid Hemorrhage and Soluble Epoxide Hydrolase Inhibition Trial

Anahtar kelimeler

hydrolase

kanama

enflamasyon

i̇skemi

beyin enfarktüsü

beyin iskemisi

subaraknoid kanama

i̇nme

anevrizma

Öz