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| Name | Class |
|---|---|
| Foundation for Anesthesia Education and Research | OTHER |
| GlaxoSmithKline | INDUSTRY |
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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.
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:
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GSK2256294 | Active Comparator | 10mg capsules of GSK2256294 will be administered in a single dose once daily enterally for a duration of 10 days. |
|
| Placebo | Placebo Comparator | 10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GSK2256294 | Drug | GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Hospital Length of Stay in Days | The hospital length of stay will be recorded in days, at the time of hospital discharge. | 90 days |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ross Martini, MD | Oregon Health and Science University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Oregon Health & Science University | Portland | Oregon | 97239 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34873674 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | GSK2256294 | 10mg capsules of GSK2256294 will be administered in a single dose once daily enterally for a duration of 10 days. GSK2256294: GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days. |
| FG001 | Placebo | 10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days. Placebo: Placebo will be administered in a single dose once daily enteral for a duration of 10 days. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
1 subject in the placebo group died on study day 9 after having received 9 of 10 doses of study drug. Data is included for this subject throughout the analysis
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| ID | Title | Description |
|---|---|---|
| BG000 | GSK2256294 | 10mg capsules of GSK2256294 will be administered in a single dose once daily enterally for a duration of 10 days. GSK2256294: GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Count of Participants | Participants | 90 days |
|
Adverse event data was collected up to 90 days after hospital discharge at the time of followup phone visit
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | GSK2256294 | 10mg capsules of GSK2256294 will be administered in a single dose once daily enterally for a duration of 10 days. GSK2256294: GSK2256294 will be administered in a single dose once daily enteral for a duration of 10 days. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Delayed Cerebral Ischemia | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ross Martini | Oregon Health and Science University | 4013386803 | martinir@ohsu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 29, 2018 | Oct 1, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D020301 | Vasospasm, Intracranial |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| C584201 | N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide |
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Subjects will be randomized to one of the two treatment arms based on an unrestricted or "fair-coin" randomization procedure.
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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.
| Placebo | Drug | Placebo will be administered in a single dose once daily enteral for a duration of 10 days. |
|
| 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 |
| 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 |
| 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-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) | 10 days |
| 90 days |
| 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 |
| 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 |
| 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 |
10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days. Placebo: Placebo will be administered in a single dose once daily enteral for a duration of 10 days. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m^2 |
|
| Smoking | Count of Participants | Participants |
|
| History of Hypertension | Count of Participants | Participants |
|
| History of Seizure | Count of Participants | Participants |
|
| History of Prior Brain Aneurysm | Count of Participants | Participants |
|
| Pre-Admission Antihypertensives | Count of Participants | Participants |
|
| Pre-Admission Anticoagulants | Count of Participants | Participants |
|
| Pre-Admission Antiplatelet Agents | Count of Participants | Participants |
|
| Pre-Admission Statins | Count of Participants | Participants |
|
| Pre-Admission Antidiabetic Agents | Count of Participants | Participants |
|
| Hunt and Hess Scale | The Hunt and Hess scale is a grading system used to classify the severity of a subarachnoid hemorrhage based on the patient's clinical condition. Description:
| Mean | Standard Deviation | units on a scale |
|
| Modified Fisher Grade | The modified Fisher scale is a method for grading subarachnoid hemorrhage (SAH) severity seen on non-contrast CT. The risk of vasospasm increases with each grade of the modified Fisher scale. grade 0: no visible SAH or intraventricular hemorrhage (IVH) grade 1: thin SAH, no IVH, grade 2: thin focal or diffuse SAH with IVH grade 3: thick focal or diffuse SAH without IVH grade 4: thick focal or diffuse SAH, IVH present | Mean | Standard Deviation | units on a scale |
|
| Glasgow Coma Scale at Randomization | The Glasgow coma scale is used to assess responsiveness. The initial score correlates with the severity of brain injury and prognosis. The Glasgow Coma Scale provides a score in the range 3-15 and the sum of eye opening, motor and verbal responses. A higher score indicates less severe brain injury. | Mean | Standard Deviation | units on a scale |
|
| Location of Aneurysm | Count of Participants | Participants |
|
| Treatment of Aneursym | Count of Participants | Participants |
|
| Baseline Aspartate Aminotransferase | Mean | Standard Deviation | units/liter |
|
| Baseline Aanine Transaminase | Mean | Standard Deviation | units/liter |
|
| Baseline QTc Interval | Mean | Standard Deviation | milliseconds |
|
| Admitted Intubated | Count of Participants | Participants |
|
| OG001 | Placebo | 10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days. Placebo: Placebo will be administered in a single dose once daily enteral for a duration of 10 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. | Missing data occurred due to no sample collection from the CSF in patients who had external ventricular drains removed as part of their standard ICU care, prior to the study visit for sample collection. Missing serum samples are the result of one patient in the placebo group who died prior to sample collection visit, and multiple unsuccessful attempts at blood collection from another patient. | Posted | Mean | Standard Deviation | ration | 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. | Missing data occurred due to no sample collection from the CSF in patients who had external ventricular drains removed as part of their standard ICU care, prior to the study visit for sample collection. Missing serum samples are the result of one patient in the placebo group who died prior to sample collection visit, and multiple unsuccessful attempts at blood collection from another patient. | Posted | Mean | Standard Deviation | ration | 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). | Missing data occurred due to no sample collection from the CSF in patients who had external ventricular drains removed as part of their standard ICU care, prior to the study visit for sample collection. Missing serum samples are the result of one patient in the placebo group who died prior to sample collection visit, and multiple unsuccessful attempts at blood collection from another patient. | Posted | Mean | Standard Deviation | ng/mL | 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-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) | Missing data occurred due to no sample collection from the CSF in patients who had external ventricular drains removed as part of their standard ICU care, prior to the study visit for sample collection. Missing serum samples are the result of one patient in the placebo group who died prior to sample collection visit, and multiple unsuccessful attempts at blood collection from another patient. | Posted | Mean | Standard Deviation | pg / mL | 10 days |
|
|
|
| Other Pre-specified | Hospital Length of Stay in Days | The hospital length of stay will be recorded in days, at the time of hospital discharge. | Posted | Mean | Standard Deviation | days | 90 days |
|
|
|
| Other Pre-specified | 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 | Posted | Count of Participants | Participants | 90 days |
|
|
|
| Other Pre-specified | 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. | Posted | Count of Participants | Participants | 90 days |
|
|
|
| Other Pre-specified | 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. | One subject in GSK2256294 group lost to followup | Posted | Mean | Standard Deviation | units on a scale | 90 days |
|
|
|
| Other Pre-specified | 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. | Missing data due to one subject in the GSK2256294 lost to followup | Posted | Mean | Standard Deviation | score on a scale | 90 days |
|
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|
| 0 |
| 10 |
| 4 |
| 10 |
| 0 |
| 10 |
| EG001 | Placebo | 10mg matched placebo capsules will be administered in a single dose once daily enterally for a duration of 10 days. Placebo: Placebo will be administered in a single dose once daily enteral for a duration of 10 days. | 1 | 9 | 5 | 9 | 0 | 10 |
| Rebleed of Unsecured Aneurysm | Nervous system disorders | Non-systematic Assessment |
|
| Aspiration Pneumonia | Infections and infestations | Non-systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Deep Vein Thrombosis | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Central Line Associated Bloodstream Infection | Infections and infestations | Non-systematic Assessment |
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| Acute Respiratory Distress Syndrome | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Pseudomonas Ventriculitis, Bacteremia, Urinary Tract Infection | Infections and infestations | Non-systematic Assessment |
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| Urinary Tract Infection | Infections and infestations | Non-systematic Assessment |
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| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Study day 10 CSF 14,15-EET/DHET ratio |
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| Study day 7 serum 14,15-EET/DHET ratio |
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| Study day 10 serum 14,15-EET/DHET ratio |
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| Day 10 serum 12,13 EpOME/DiHOME ratio |
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| Serum Day 10 ICAM |
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| Serum Day 7 VCAM |
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| Serum Day 10 VCAM |
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| Serum Day 7 PECAM-1 |
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| Serum Day 10 PECAM-1 |
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| Serum Day 7 E-Selectin |
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| Serum Day 10 E-Selectin |
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| Serum Day 7 P-Selectin |
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| Serum Day 10 P-Selectin |
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| CSF Day 10 IFN-gamma |
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| CSF Day 7 IL-1b |
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| CSF Day 10 IL-1b |
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| CSF Day 7 IL-6 |
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| CSF Day 10 IL-6 |
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| CSF Day 7 IL-8 |
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| CSF Day 10 IL-8 |
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| CSF Day 7 TNF-alpha |
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| CSF Day 10 TNF-alpha |
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| 90 day follow-up mRS |
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