Fingolimod as a Treatment of Cerebral Edema After Intracerebral Hemorrhage

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to test the safety and effectiveness of a single dose of fingolimod in patients with primary spontaneous intracerebral hemorrhage (ICH).

Detailed Description
-----------------
This is a double-blinded, placebo-controlled pilot trial of fingolimod in patients with primary spontaneous intracerebral hemorrhage. Eligible participants will be allocated to study groups using fixed allocation randomization and a computer-based random number-generating allocation. Participants will be monitored at time of enrollment and days 1, 3 5, 7, and 14 (discharge dependent) by 2 blinded assessors (neuroscience subspecialists) and will receive standard of care for the duration of the study. After discharge from the hospital, participants will enter a follow up phase of 12 months, with clinic visits at 30±14 days, 90±14 days, 180±14 days, and 365±14 days. They will receive a standard of care MRI scan at the 30 day visit and standard of care CT of the brain at the 90 and 365 day visit and will be assessed with the pre-selected outcome assessments established by the NINDS Common Data Elements for Stroke at these time points.

Official Title
-----------------
Fingolimod as a Treatment of Cerebral Edema After Intracerebral Hemorrhage

Conditions
-----------------
Intracerebral Hemorrhage, Cerebral Edema, Stroke Hemorrhagic, Intracerebral Hemorrhage, Hypertensive, Intracerebral Hemorrhage Intraparenchymal

Intervention / Treatment
-----------------
* Drug: Fingolimod 0.5 mg
* Drug: Placebo
* Other: Standard of care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has given written informed consent to participate in the study in accordance with required regulations; if a participant is not capable of providing informed consent, written consent must be obtained from the participant's legally authorized representative (LAR). Stated willingness to comply with all study procedures and availability for the duration of the study. Has a confirmed diagnosis of spontaneous ICH ≥ 15 mL measured utilizing ABC/2 method using radiographic imaging (computed tomography (CT), CT angiogram (CTA), etc). The presence of cerebellar ICH is exclusionary. Presence of hydrocephalus due to mass effect an cerebral edema is not exclusionary. If the patient has hydrocephalus requiring cerebrospinal fluid (CSF) drainage, an external ventricular drain will be placed as standard of care and will not be exclusionary. Symptoms less than 24 hours prior to enrollment if all eligibility criteria are met. An unknown time of onset is exclusionary. Use the time the patient was last known to be well for patients that awaken from sleep with symptoms. Has Glasgow Coma Scale (GCS) score ≥ on presentation. Has a National Institutes of Health Stroke Scale (NIHSS) score ≥ on presentation. Maintenance of systolic blood pressure (SBP) < 200 mmHg at the time of enrollment and randomization. Historical Modified Rankin Scale (mRS) score of 0 or 1. Exclusion Criteria: Men or women < 18 years old Incarcerated patients ICH known as a result of trauma Primary intraventricular hemorrhage without significant intraparenchymal component. Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, Moyamoya disease, hemorrhagic conversion of an ischemic infarct, recurrence of recent (< 1 year) hemorrhage, neoplasms diagnosed with radiographic imagining. Patients with unstable mass or evolving intracranial compartment syndrome. Brainstem hemorrhage or irreversible impaired brain stem function (bilateral fixed, dilated pupils and extensor motor posturing), GCS ≤ 4. Platelet count < 100,000; INR > 1.4. Any irreversible coagulopathy or known clotting disorder. Various degrees of dysphagia (determined by either formal speech and swallow or bedside swallow evaluation) or nausea/vomiting that could render oral administration of fingolimod difficult. Known history of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome. Admission within the past 6 months for the following: myocardial infarction, unstable angina, stroke, decompensated heart failure requiring hospitalization, or Class III/IV heart failure. Baseline QTc interval ≥500 ms. Current treatment with Cass Ia or Class III anti-arrhythmic drugs. Implanted cardiac devices that are not compatible with the desired MRI sequences needed for the study (non-contrast T1, T2, SWI/GRE, and FLAIR sequences). Abnormal liver function or liver failure Active acute or chronic viral infections Active use of antineoplastic, immunosuppressive, or immunomodulating therapies. Not expected to survive to the 180 day visit due to co-morbidities or is DNR/DNI status prior to randomization. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements. Concomitant enrollment in another interventional study. Inability or unwillingness of participant or legal guardian/representative to give written informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blinded, placebo-controlled pilot trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fingolimod Group<br>In addition to Standard of care treatment, those participants randomized to the fingolimod group will receive a single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset. | Drug: Fingolimod 0.5 mg<br>* A single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset<br>* Other names: Gilenya;Other: Standard of care<br>* Standard of care protocol for the treatment of spontaneous ICH<br>|
| Placebo Comparator: Control Group<br>In addition to Standard of care treatment, those participants randomized to the control group will receive a single dose placebo pill within 24 hours of symptom onset | Drug: Placebo<br>* A single oral placebo pill within 24 hours of symptom onset<br>Other: Standard of care<br>* Standard of care protocol for the treatment of spontaneous ICH<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinically significant cardiac events |  | up to 30 days post-ictus | 
| Rate of nosocomial infections (UTI, sepsis, and pneumonia) | nosocomial infections (UTI, sepsis, and pneumonia) | up to 90 days post-ictus | 
| Rate of neurologic decline | considered a change ≥ 4 points of the NIHSS | up to 30 days post-ictus | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lymphocyte subpopulations | The lymphocyte subsets of CD4+ T, CD8+ T, and CD19+ B cells will be compared between the two treatment groups and the trends will be followed over time in all participants. | 30 days | 
| Hematoma volume - CT | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT). | Enrollment | 
| Peri-hematomal edema volume - CT | Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (CT). | Enrollment | 
| Hematoma volume - MRI | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (MRI). | Enrollment | 
| Peri-hematomal edema volume - MRI | Volumetric measurement calculations of the peri-hematoma area will be obtained from radiographic imaging (MRI). | Enrollment | 
| Hematoma volume- CT | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT). | 24 hours post-ictus | 
| Peri-hematomal edema volume- CT | Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (CT). | 24 hours post-ictus | 
| Hematoma volume - MRI | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (MRI). | 72 hours post-ictus | 
| Peri-hematomal edema volume - MRI | Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (MRI). | 72 hours post-ictus | 
| Hematoma volume - CT | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT). | Between days 5 to 7 post-ictus | 
| Peri-hematomal edema volume - CT | Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (CT). | Between days 5 to 7 post-ictus | 
| Hematoma volume - CT | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT). | Between days 10 to 14 post-ictus | 
| Peri-hematomal edema volume - CT | Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (CT). | Between days 10 to 14 post-ictus | 
| Hematomal volume- MRI | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (MRI). | Follow-Up visit 1 - Between days 16 to 44 | 
| Peri-hematomal edema volume- MRI | Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (MRI). | Follow-Up visit 1 - Between days 16 to 44 | 
| Hematoma volume- CT | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT). | Follow-Up visit 2- Between days 76 to 104 | 
| Peri-hematomal edema volume- CT | Volumetric measurement calculations of peri- hematoma will be obtained from radiographic imaging (CT). | Follow-Up visit 2- Between days 76 to 104 | 
| Hematoma volume- CT | Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT). | Follow-Up visit 4 Between days 351 and 379 | 
| Peri-hematomal edema volume- CT | Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (CT). | Follow-Up visit 4 Between days 351 and 379 | 
| National Institutes of Health Stroke Scale | As per ischemia stroke criteria, a change ≥ 4 in the NIHSS will be considered a neurologic change and will be followed over time. 0 being normal functioning and 4 being completely impaired. Lower scores denote better outcome. | 365 days | 
| Interviewer-administered Modified Rankin Scale (mRS) | The modified Rankin Scale (mRS) will measure functional recovery and ability to perform activities of daily living. The mRS is a 6 point disability scale with scores ranging from 0 (no symptoms) to 5 (severe disability). Lower scores denote better outcome. | 365 days post-ictus | 
| Patient-Reported Outcomes Measurement Information (PROMIS) 10 questionnaire | Patient-Reported Outcomes Measurement Information System (PROMIS) 10 questionnaire will measure patient self reporting of physical and neurobehavioral functions.Qualitative methods will be used to analyze this data. | up to 365 days | 
| Montreal Cognitive Assessment (MoCA) | Montreal Cognitive Assessment (MoCA) will measure recovery (neurocognitive). Scores range from 0 to 30 with higher scores denoting better outcomes. | up to 365 days | 
| Western Aphasia Battery-Revised (WAB-R) | Western Aphasia Battery-Revised (WAB-R) will measure recovery (neurocognitive and speech). Scores range from 0 to 76+. Higher scores denote better outcome. | up to 365 days | 
| Mortality |  | 30 days | 
| Mortality |  | 90 days | 
| All cause mortality |  | up to 365 days | 
| Number of home days | This will be an assessment of the participant's discharge disposition, followed by length of stay at a facility (inpatient rehabilitation, skilled nursing facility, assisted living facility), compared to number of days at home. | up to 365 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Fingolimod, Neurologic Deficits, Brain Injury, Stroke, Intracerebral hemorrhage, Neuroimmunomodulation