Fingolimod as a Treatment of Cerebral Edema After Intracerebral Hemorrhage

Early Phase 1

Completed

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

Interventions: Drug: Fingolimod
Drug: Placebo
Drug: Open-label Fingolimod

Registration Number: NCT04088630

Lead Sponsor: Wake Forest University Health Sciences

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. For those patients who meet all inclusion criteria without exclusion criteria subjects will receive oral or nasogastric tube (NGT) or Dobhoff feeding tube administration of fingolimod versus placebo. 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 neuroimaging at these follow up time-points and will be assessed with the pre-selected outcome assessments established by the NINDS Common Data Elements for Stroke.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

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). When the LAR is not available for consent, Docusign for econsent may be obtained.

Stated willingness to comply with all study procedures and availability for the duration of the study.

Men and non-pregnant women ages 18-80 years old Has a confirmed diagnosis of spontaneous supratentorial ICH. The presence of cerebellar ICH is exclusionary. Presence of hydrocephalus due to mass effect and cerebral edema is not exclusionary. If the patient has hydrocephalus requiring 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 a GCS score ≥ 5 on presentation. Has a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 on presentation.

Maintenance of SBP < 200 mmHg at the time of enrollment and randomization. Historical Modified Rankin Scale score of 0-2.

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 imaging.

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. 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 Class 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 infection that is deemed by the Principal Investigator to be clinically significant.

Chronic viral or fungal infection. Active use of antineoplastic, immunosuppressive, or immunomodulating therapies. Leukopenia with a WBC < 2.0 x 109/L. Not expected to survive to the 365 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fingolimod	Fingolimod	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.
Placebo Control	Placebo	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
Open-label Fingolimod	Open-label Fingolimod	In addition to standard of care treatment,10 subjects who are unable to be administered oral medication will be assigned to the open-label group who will receive a single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset to assess feasibility of administration through NGT or Dobhoff tube.

Primary Outcome Measures

Name	Time	Method
Rate of Neurologic Decline	up to 30 days post-ictus	considered a change ≥ 4 points of the NIHSS between enrollment and 30 days post-ictus. A higher score indicates higher severity and poorer prognosis. Scale is 0-42.
Number of Participants With Clinically Significant Cardiac Events	up to 30 days post-ictus	Number of participants with clinically significant cardiac events. Clinically significant cardiac events include myocardial infarction, unstable angina, stroke, transient ischemic attack, any heart failure, bradycardia and heart block. Cardiac events were monitored with telemetry up to and after 72 hours while hospitalized. A check in was performed at 30 days with an in-person clinical or hospital visit to ascertain any cardiac events via patient discussion and medical record review.
Rate of Nosocomial Infections (UTI, Sepsis, and Pneumonia)	up to 90 days post-ictus	Rate of nosocomial infections (UTI, sepsis, and pneumonia) by group

Secondary Outcome Measures

Name	Time	Method
Mortality	90 days	Mortality at 90 days
All Cause Mortality	up to 365 days	All cause mortality within 365 days
Rate of Successful Administration of Fingolimod Through an NGT or Dobhoff Tube	Enrollment	Rate of successful administration of fingolimod through an NGT or Dobhoff tube in Open-label group only
Percent Change in Lymphocyte Subpopulations of CD4+ T Cells	Enrollment to 30 days	Percent Change in Lymphocyte Subpopulations of CD4+ T Cells
Percent Change in Lymphocyte Subpopulations of CD8+ T Cells	Enrollment and 30 days	Percent change in lymphocyte subpopulations of CD8+ T Cells
Percent Change in Lymphocyte Subpopulations of CD19+ B Cells	Enrollment and 30 days	Percent change in lymphocyte subpopulations of CD19+ B cells
Change in Hematoma Volume Obtained by MRI	Enrollment and 365 days	Average decrease per day by group in volumetric measurement calculations of hematoma obtained by MRI between enrollment and 365 days. All MRI imaging data obtained on hematoma volume between enrollment and 365 days were used to calculate estimates via a linear mixed effects model controlling for repeated measures within subject.
Change in Hematoma Volume Obtained by CT	Enrollment and 365 days	Average decrease per day by group in volumetric measurement calculations of hematoma obtained by CT between enrollment and 365 days. All CT imaging data obtained on hematoma volume between enrollment and 365 days were used to calculate estimates via a linear mixed effects model controlling for repeated measures within subject.
Change in Peri-hematomal Edema Volume Obtained by CT	Enrollment to 365 days	Average decrease per day by group in volumetric measurement calculations of peri-hematomal edema volume between enrollment and 365 days. All CT imaging data obtained on peri-hematomal edema volume between enrollment and 365 days were used to calculate estimates via a linear mixed effects model controlling for repeated measures within subject.
Change in Peri-hematomal Edema Volume Obtained by MRI	Enrollment to 365 days	Average decrease per day by group in volumetric measurement calculations of peri-hematomal edema obtained from radiographic imaging (MRI) between enrollment and 365 days. All MRI imaging data obtained on peri-hematomal edema volume between enrollment and 365 days were used to calculate estimates via a linear mixed effects model controlling for repeated measures within subject.
National Institutes of Health Stroke Scale Total Score (NIHSS)	365 days	The scoring range is 0 to 42 points, with higher numbers indicating greater severity. (NIHSS)
Interviewer-administered Modified Rankin Scale (mRS)	365 days post-ictus	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) with 6 indicating death. Lower scores denote better outcome.
Patient-Reported Outcomes Measurement Information (PROMIS) 10 Questionnaire	365 days	Patient-Reported Outcomes Measurement Information System (PROMIS) 10 questionnaire will measure patient self-reporting of physical and neurobehavioral functions. Mean T-score for general population is 50 with standard deviation of 10. Higher T-scores indicate better physical and mental health. Typically, T-score ranges from 20 to 80.
Montreal Cognitive Assessment (MoCA)	365 days	Montreal Cognitive Assessment (MoCA) will measure recovery (neurocognitive). Scores range from 0 to 30 with higher scores denoting better outcomes.
Western Aphasia Battery-Revised (WAB-R)	365 days	Western Aphasia Battery-Revised (WAB-R) will measure recovery (neurocognitive and speech). Language and Aphasia subscale scores both range from 0 to 100. Higher scores denote better outcome.