Fingolimod as a Treatment of Cerebral Edema After Intracerebral Hemorrhage

Intracerebral Hemorrhage Clinical Trial

— FITCH  

Official title:

Fingolimod as a Treatment of Cerebral Edema After Intracerebral Hemorrhage

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04088630
• Other study ID #: IRB00060619
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: August 7, 2020
• Est. completion date: June 2024

Study information

• Verified date: February 2024
• Source: Wake Forest University Health Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 28
• Est. completion date: June 2024
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Brain Edema
• Cerebral Edema
• Cerebral Hemorrhage
• Edema
• Hemorrhage
• Hemorrhagic Stroke
• Intracerebral Hemorrhage
• Intracerebral Hemorrhage Intraparenchymal
• Intracerebral Hemorrhage, Hypertensive
• Intracranial Hemorrhage, Hypertensive
• Stroke Hemorrhagic

Intervention

Drug:
• Fingolimod 0.5 mg
A single dose of 0.5 mg oral fingolimod within 24 hours of symptom onset
• Placebo
A single oral placebo pill within 24 hours of symptom onset

Other:
• Standard of care
Standard of care protocol for the treatment of spontaneous ICH

Locations

Country	Name	City	State
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences

Country where clinical trial is conducted

United States, 

References & Publications (85)

Adeoye O, Broderick JP. Advances in the management of intracerebral hemorrhage. Nat Rev Neurol. 2010 Nov;6(11):593-601. doi: 10.1038/nrneurol.2010.146. Epub 2010 Sep 28. — View Citation

Ariesen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke. 2003 Aug;34(8):2060-5. doi: 10.1161/01.STR.0000080678.09344.8D. Epub 2003 Jul 3. — View Citation

Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011 Jun;42(6):1781-6. doi: 10.1161/STROKEAHA.110.596718. Epub 2011 Apr 28. — View Citation

Arumugam TV, Granger DN, Mattson MP. Stroke and T-cells. Neuromolecular Med. 2005;7(3):229-42. doi: 10.1385/NMM:7:3:229. — View Citation

Babu R, Bagley JH, Di C, Friedman AH, Adamson C. Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg Focus. 2012 Apr;32(4):E8. doi: 10.3171/2012.1.FOCUS11366. — View Citation

Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological). 1995;57(1):289-300

Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013 Feb;39(1):3-18. doi: 10.1111/nan.12011. — View Citation

Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993 Jul;24(7):987-93. doi: 10.1161/01.str.24.7.987. — View Citation

Budde K, Schmouder RL, Brunkhorst R, Nashan B, Lucker PW, Mayer T, Choudhury S, Skerjanec A, Kraus G, Neumayer HH. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol. 2002 Apr;13(4):1073-1083. doi: 10.1681/ASN.V1341073. — View Citation

Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Jun;13(6):545-56. doi: 10.1016/S1474-4422(14)70049-3. Epub 2014 Mar 28. Erratum In: Lancet Neurol. 2013 Jun;13(6):536. — View Citation

Chiba K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther. 2005 Dec;108(3):308-19. doi: 10.1016/j.pharmthera.2005.05.002. Epub 2005 Jun 13. — View Citation

Ching T, Huang S, Garmire LX. Power analysis and sample size estimation for RNA-Seq differential expression. RNA. 2014 Nov;20(11):1684-96. doi: 10.1261/rna.046011.114. Epub 2014 Sep 22. — View Citation

Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010 Mar-Apr;33(2):91-101. doi: 10.1097/WNF.0b013e3181cbf825. — View Citation

Cohen JA, Chun J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011 May;69(5):759-77. doi: 10.1002/ana.22426. — View Citation

Das A, Arifuzzaman S, Kim SH, Lee YS, Jung KH, Chai YG. FTY720 (fingolimod) regulates key target genes essential for inflammation in microglial cells as defined by high-resolution mRNA sequencing. Neuropharmacology. 2017 Jun;119:1-14. doi: 10.1016/j.neuropharm.2017.03.034. Epub 2017 Mar 31. — View Citation

David OJ, Kovarik JM, Schmouder RL. Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet. 2012 Jan 1;51(1):15-28. doi: 10.2165/11596550-000000000-00000. — View Citation

Delbridge MS, Shrestha BM, Raftery AT, El Nahas AM, Haylor JL. Reduction of ischemia-reperfusion injury in the rat kidney by FTY720, a synthetic derivative of sphingosine. Transplantation. 2007 Jul 27;84(2):187-95. doi: 10.1097/01.tp.0000269794.74990.da. — View Citation

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013 Jan 1;29(1):15-21. doi: 10.1093/bioinformatics/bts635. Epub 2012 Oct 25. — View Citation

Eggen BJ, Raj D, Hanisch UK, Boddeke HW. Microglial phenotype and adaptation. J Neuroimmune Pharmacol. 2013 Sep;8(4):807-23. doi: 10.1007/s11481-013-9490-4. Epub 2013 Jul 25. — View Citation

Fogelholm R, Murros K, Rissanen A, Avikainen S. Long term survival after primary intracerebral haemorrhage: a retrospective population based study. J Neurol Neurosurg Psychiatry. 2005 Nov;76(11):1534-8. doi: 10.1136/jnnp.2004.055145. — View Citation

Fu Y, Hao J, Zhang N, Ren L, Sun N, Li YJ, Yan Y, Huang D, Yu C, Shi FD. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol. 2014 Sep;71(9):1092-101. doi: 10.1001/jamaneurol.2014.1065. — View Citation

Fu Y, Zhang N, Ren L, Yan Y, Sun N, Li YJ, Han W, Xue R, Liu Q, Hao J, Yu C, Shi FD. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18315-20. doi: 10.1073/pnas.1416166111. Epub 2014 Dec 8. — View Citation

Gao L, Lu Q, Huang LJ, Ruan LH, Yang JJ, Huang WL, ZhuGe WS, Zhang YL, Fu B, Jin KL, ZhuGe QC. Transplanted neural stem cells modulate regulatory T, gammadelta T cells and corresponding cytokines after intracerebral hemorrhage in rats. Int J Mol Sci. 2014 Mar 13;15(3):4431-41. doi: 10.3390/ijms15034431. — View Citation

Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, Arumugam TV, Orthey E, Gerloff C, Tolosa E, Magnus T. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009 May;40(5):1849-57. doi: 10.1161/STROKEAHA.108.534503. Epub 2009 Mar 5. — View Citation

Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci. 2013 May 15;328(1-2):9-18. doi: 10.1016/j.jns.2013.02.011. Epub 2013 Mar 19. — View Citation

Gu L, Xiong X, Zhang H, Xu B, Steinberg GK, Zhao H. Distinctive effects of T cell subsets in neuronal injury induced by cocultured splenocytes in vitro and by in vivo stroke in mice. Stroke. 2012 Jul;43(7):1941-6. doi: 10.1161/STROKEAHA.112.656611. Epub 2012 Jun 7. — View Citation

Guo FQ, Li XJ, Chen LY, Yang H, Dai HY, Wei YS, Huang YL, Yang YS, Sun HB, Xu YC, Yang ZL. [Study of relationship between inflammatory response and apoptosis in perihematoma region in patients with intracerebral hemorrhage]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2006 May;18(5):290-3. Chinese. — View Citation

Hasegawa Y, Suzuki H, Sozen T, Rolland W, Zhang JH. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke. 2010 Feb;41(2):368-74. doi: 10.1161/STROKEAHA.109.568899. Epub 2009 Nov 25. — View Citation

Hendrix S, Nitsch R. The role of T helper cells in neuroprotection and regeneration. J Neuroimmunol. 2007 Mar;184(1-2):100-12. doi: 10.1016/j.jneuroim.2006.11.019. Epub 2007 Jan 2. — View Citation

Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol. 2015 Jan;11(1):56-64. doi: 10.1038/nrneurol.2014.207. Epub 2014 Nov 11. — View Citation

Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, Guo Y, Stephens R, Baseler MW, Lane HC, Lempicki RA. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007 Jul;35(Web Server issue):W169-75. doi: 10.1093/nar/gkm415. Epub 2007 Jun 18. — View Citation

Hurn PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, Offner H. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007 Nov;27(11):1798-805. doi: 10.1038/sj.jcbfm.9600482. Epub 2007 Mar 28. — View Citation

Jin Y, Zollinger M, Borell H, Zimmerlin A, Patten CJ. CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis. Drug Metab Dispos. 2011 Feb;39(2):191-8. doi: 10.1124/dmd.110.035378. Epub 2010 Nov 2. — View Citation

Kanazawa M, Ninomiya I, Hatakeyama M, Takahashi T, Shimohata T. Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke. Int J Mol Sci. 2017 Oct 13;18(10):2135. doi: 10.3390/ijms18102135. — View Citation

Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):387-401. doi: 10.1056/NEJMoa0909494. Epub 2010 Jan 20. — View Citation

Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012 Aug;11(8):720-31. doi: 10.1016/S1474-4422(12)70104-7. Epub 2012 Jun 13. — View Citation

Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8389-94. doi: 10.1073/pnas.1433000100. Epub 2003 Jun 26. — View Citation

Kovarik JM, Schmouder R, Barilla D, Wang Y, Kraus G. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol. 2004 May;57(5):586-91. doi: 10.1111/j.1365-2125.2003.02065.x. — View Citation

Kramer A, Green J, Pollard J Jr, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014 Feb 15;30(4):523-30. doi: 10.1093/bioinformatics/btt703. Epub 2013 Dec 13. — View Citation

Lan X, Han X, Li Q, Yang QW, Wang J. Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol. 2017 Jul;13(7):420-433. doi: 10.1038/nrneurol.2017.69. Epub 2017 May 19. — View Citation

Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39(1):151-70. doi: 10.1016/0306-4522(90)90229-w. — View Citation

Lee CW, Choi JW, Chun J. Neurological S1P signaling as an emerging mechanism of action of oral FTY720 (fingolimod) in multiple sclerosis. Arch Pharm Res. 2010 Oct;33(10):1567-74. doi: 10.1007/s12272-010-1008-5. Epub 2010 Oct 30. — View Citation

Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014 Apr 1;30(7):923-30. doi: 10.1093/bioinformatics/btt656. Epub 2013 Nov 13. — View Citation

Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009 Feb;15(2):192-9. doi: 10.1038/nm.1927. Epub 2009 Jan 25. — View Citation

Loftspring MC, McDole J, Lu A, Clark JF, Johnson AJ. Intracerebral hemorrhage leads to infiltration of several leukocyte populations with concomitant pathophysiological changes. J Cereb Blood Flow Metab. 2009 Jan;29(1):137-43. doi: 10.1038/jcbfm.2008.114. Epub 2008 Oct 1. — View Citation

Lord AS, Gilmore E, Choi HA, Mayer SA; VISTA-ICH Collaboration. Time course and predictors of neurological deterioration after intracerebral hemorrhage. Stroke. 2015 Mar;46(3):647-52. doi: 10.1161/STROKEAHA.114.007704. Epub 2015 Feb 5. — View Citation

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8. — View Citation

Lu L, Barfejani AH, Qin T, Dong Q, Ayata C, Waeber C. Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res. 2014 Mar 25;1555:89-96. doi: 10.1016/j.brainres.2014.01.048. Epub 2014 Feb 3. — View Citation

Man K, Ng KT, Lee TK, Lo CM, Sun CK, Li XL, Zhao Y, Ho JW, Fan ST. FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers. Am J Transplant. 2005 Jan;5(1):40-9. doi: 10.1111/j.1600-6143.2004.00642.x. Erratum In: Am J Transplant. 2017 Mar;17 (3):845. — View Citation

Mao LL, Yuan H, Wang WW, Wang YJ, Yang MF, Sun BL, Zhang ZY, Yang XY. Adoptive Regulatory T-cell Therapy Attenuates Perihematomal Inflammation in a Mouse Model of Experimental Intracerebral Hemorrhage. Cell Mol Neurobiol. 2017 Jul;37(5):919-929. doi: 10.1007/s10571-016-0429-1. Epub 2016 Sep 27. — View Citation

Melendez AJ. Sphingosine kinase signalling in immune cells: potential as novel therapeutic targets. Biochim Biophys Acta. 2008 Jan;1784(1):66-75. doi: 10.1016/j.bbapap.2007.07.013. Epub 2007 Aug 14. — View Citation

Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM; STICH II Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013 Aug 3;382(9890):397-408. doi: 10.1016/S0140-6736(13)60986-1. Epub 2013 May 29. Erratum In: Lancet. 2013 Aug 3;382(9890):396. Lancet. 2021 Sep 18;398(10305):1042. — View Citation

Morgenstern LB, Hemphill JC 3rd, Anderson C, Becker K, Broderick JP, Connolly ES Jr, Greenberg SM, Huang JN, MacDonald RL, Messe SR, Mitchell PH, Selim M, Tamargo RJ; American Heart Association Stroke Council and Council on Cardiovascular Nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010 Sep;41(9):2108-29. doi: 10.1161/STR.0b013e3181ec611b. Epub 2010 Jul 22. — View Citation

Mould WA, Carhuapoma JR, Muschelli J, Lane K, Morgan TC, McBee NA, Bistran-Hall AJ, Ullman NL, Vespa P, Martin NA, Awad I, Zuccarello M, Hanley DF; MISTIE Investigators. Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema. Stroke. 2013 Mar;44(3):627-34. doi: 10.1161/STROKEAHA.111.000411. Epub 2013 Feb 7. — View Citation

Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci. 2014 Nov 20;8:388. doi: 10.3389/fncel.2014.00388. eCollection 2014. — View Citation

Murthy SB, Moradiya Y, Shah J, Merkler AE, Mangat HS, Iadacola C, Hanley DF, Kamel H, Ziai WC. Nosocomial Infections and Outcomes after Intracerebral Hemorrhage: A Population-Based Study. Neurocrit Care. 2016 Oct;25(2):178-84. doi: 10.1007/s12028-016-0282-6. — View Citation

Nayak D, Huo Y, Kwang WX, Pushparaj PN, Kumar SD, Ling EA, Dheen ST. Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience. 2010 Mar 10;166(1):132-44. doi: 10.1016/j.neuroscience.2009.12.020. Epub 2009 Dec 28. — View Citation

Noda H, Takeuchi H, Mizuno T, Suzumura A. Fingolimod phosphate promotes the neuroprotective effects of microglia. J Neuroimmunol. 2013 Mar 15;256(1-2):13-8. doi: 10.1016/j.jneuroim.2012.12.005. Epub 2013 Jan 3. — View Citation

Okada T, Kajimoto T, Jahangeer S, Nakamura S. Sphingosine kinase/sphingosine 1-phosphate signalling in central nervous system. Cell Signal. 2009 Jan;21(1):7-13. doi: 10.1016/j.cellsig.2008.07.011. Epub 2008 Jul 22. — View Citation

Qin C, Fan WH, Liu Q, Shang K, Murugan M, Wu LJ, Wang W, Tian DS. Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway. Stroke. 2017 Dec;48(12):3336-3346. doi: 10.1161/STROKEAHA.117.018505. Epub 2017 Nov 7. — View Citation

Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009 May 9;373(9675):1632-44. doi: 10.1016/S0140-6736(09)60371-8. — View Citation

Qureshi AI, Suri MF, Nasar A, Kirmani JF, Ezzeddine MA, Divani AA, Giles WH. Changes in cost and outcome among US patients with stroke hospitalized in 1990 to 1991 and those hospitalized in 2000 to 2001. Stroke. 2007 Jul;38(7):2180-4. doi: 10.1161/STROKEAHA.106.467506. Epub 2007 May 24. — View Citation

Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O, Hartman R, Ostrowski R, Manaenko A, Tang J, Zhang JH. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol. 2013 Mar;241:45-55. doi: 10.1016/j.expneurol.2012.12.009. Epub 2012 Dec 21. — View Citation

Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM, Chao CC, Wilz A, Blain M, Healy L, Antel J, Quintana FJ. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):2012-2017. doi: 10.1073/pnas.1615413114. Epub 2017 Feb 6. — View Citation

Shichita T, Sakaguchi R, Suzuki M, Yoshimura A. Post-ischemic inflammation in the brain. Front Immunol. 2012 May 31;3:132. doi: 10.3389/fimmu.2012.00132. eCollection 2012. — View Citation

Sucksdorff M, Rissanen E, Tuisku J, Nuutinen S, Paavilainen T, Rokka J, Rinne J, Airas L. Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis. J Nucl Med. 2017 Oct;58(10):1646-1651. doi: 10.2967/jnumed.116.183020. Epub 2017 Mar 23. — View Citation

Sun N, Shen Y, Han W, Shi K, Wood K, Fu Y, Hao J, Liu Q, Sheth KN, Huang D, Shi FD. Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage. Stroke. 2016 Jul;47(7):1899-906. doi: 10.1161/STROKEAHA.115.012236. Epub 2016 May 12. — View Citation

Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol. 2013;2013:746068. doi: 10.1155/2013/746068. Epub 2013 Oct 10. — View Citation

Tham CS, Lin FF, Rao TS, Yu N, Webb M. Microglial activation state and lysophospholipid acid receptor expression. Int J Dev Neurosci. 2003 Dec;21(8):431-43. doi: 10.1016/j.ijdevneu.2003.09.003. — View Citation

Theodorou GL, Marousi S, Ellul J, Mougiou A, Theodori E, Mouzaki A, Karakantza M. T helper 1 (Th1)/Th2 cytokine expression shift of peripheral blood CD4+ and CD8+ T cells in patients at the post-acute phase of stroke. Clin Exp Immunol. 2008 Jun;152(3):456-63. doi: 10.1111/j.1365-2249.2008.03650.x. Epub 2008 Apr 16. — View Citation

van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010 Feb;9(2):167-76. doi: 10.1016/S1474-4422(09)70340-0. Epub 2010 Jan 5. — View Citation

Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007 May;27(5):894-908. doi: 10.1038/sj.jcbfm.9600403. Epub 2006 Oct 11. — View Citation

Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol. 2010 Dec;92(4):463-77. doi: 10.1016/j.pneurobio.2010.08.001. Epub 2010 Aug 14. — View Citation

Wasserman JK, Zhu X, Schlichter LC. Evolution of the inflammatory response in the brain following intracerebral hemorrhage and effects of delayed minocycline treatment. Brain Res. 2007 Nov 14;1180:140-54. doi: 10.1016/j.brainres.2007.08.058. Epub 2007 Sep 5. — View Citation

Wei Y, Yemisci M, Kim HH, Yung LM, Shin HK, Hwang SK, Guo S, Qin T, Alsharif N, Brinkmann V, Liao JK, Lo EH, Waeber C. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol. 2011 Jan;69(1):119-29. doi: 10.1002/ana.22186. Epub 2010 Nov 12. — View Citation

WRITING GROUP MEMBERS; Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010 Feb 23;121(7):e46-e215. doi: 10.1161/CIRCULATIONAHA.109.192667. Epub 2009 Dec 17. No abstract available. Erratum In: Circulation. 2010 Mar 30;121(12):e260. Stafford, Randall [corrected to Roger, Veronique L]. Circulation. 2011 Oct 18;124(16):e425. — View Citation

Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006 Jan;5(1):53-63. doi: 10.1016/S1474-4422(05)70283-0. — View Citation

Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol. 2016 Jul;142:23-44. doi: 10.1016/j.pneurobio.2016.05.001. Epub 2016 May 7. — View Citation

Yilmaz G, Arumugam TV, Stokes KY, Granger DN. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation. 2006 May 2;113(17):2105-12. doi: 10.1161/CIRCULATIONAHA.105.593046. Epub 2006 Apr 24. — View Citation

Zhang Z, Zhang Z, Lu H, Yang Q, Wu H, Wang J. Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage. Mol Neurobiol. 2017 Apr;54(3):1874-1886. doi: 10.1007/s12035-016-9785-6. Epub 2016 Feb 19. — View Citation

Zhao H, Garton T, Keep RF, Hua Y, Xi G. Microglia/Macrophage Polarization After Experimental Intracerebral Hemorrhage. Transl Stroke Res. 2015 Dec;6(6):407-9. doi: 10.1007/s12975-015-0428-4. Epub 2015 Oct 7. No abstract available. — View Citation

Zhou K, Zhong Q, Wang YC, Xiong XY, Meng ZY, Zhao T, Zhu WY, Liao MF, Wu LR, Yang YR, Liu J, Duan CM, Li J, Gong QW, Liu L, Yang MH, Xiong A, Wang J, Yang QW. Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3beta/PTEN axis. J Cereb Blood Flow Metab. 2017 Mar;37(3):967-979. doi: 10.1177/0271678X16648712. Epub 2016 Jul 20. — View Citation

Zhou Y, Wang Y, Wang J, Anne Stetler R, Yang QW. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol. 2014 Apr;115:25-44. doi: 10.1016/j.pneurobio.2013.11.003. Epub 2013 Nov 26. — View Citation

Zhu Z, Fu Y, Tian D, Sun N, Han W, Chang G, Dong Y, Xu X, Liu Q, Huang D, Shi FD. Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke: A Pilot Trial. Circulation. 2015 Sep 22;132(12):1104-1112. doi: 10.1161/CIRCULATIONAHA.115.016371. Epub 2015 Jul 22. — View Citation

Zollinger M, Gschwind HP, Jin Y, Sayer C, Zecri F, Hartmann S. Absorption and disposition of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in healthy volunteers: a case of xenobiotic biotransformation following endogenous metabolic pathways. Drug Metab Dispos. 2011 Feb;39(2):199-207. doi: 10.1124/dmd.110.035907. Epub 2010 Nov 2. — View Citation

* Note: There are 85 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of clinically significant cardiac events		up to 30 days post-ictus
Primary	Rate of nosocomial infections (UTI, sepsis, and pneumonia)	nosocomial infections (UTI, sepsis, and pneumonia)	up to 90 days post-ictus
Primary	Rate of neurologic decline	considered a change = 4 points of the NIHSS	up to 30 days post-ictus
Secondary	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
Secondary	Hematoma volume - CT	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT).	Enrollment
Secondary	Peri-hematomal edema volume - CT	Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (CT).	Enrollment
Secondary	Hematoma volume - MRI	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (MRI).	Enrollment
Secondary	Peri-hematomal edema volume - MRI	Volumetric measurement calculations of the peri-hematoma area will be obtained from radiographic imaging (MRI).	Enrollment
Secondary	Hematoma volume- CT	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT).	24 hours post-ictus
Secondary	Peri-hematomal edema volume- CT	Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (CT).	24 hours post-ictus
Secondary	Hematoma volume - MRI	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (MRI).	72 hours post-ictus
Secondary	Peri-hematomal edema volume - MRI	Volumetric measurement calculations of peri-hematoma will be obtained from radiographic imaging (MRI).	72 hours post-ictus
Secondary	Hematoma volume - CT	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT).	Between days 5 to 7 post-ictus
Secondary	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
Secondary	Hematoma volume - CT	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT).	Between days 10 to 14 post-ictus
Secondary	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
Secondary	Hematomal volume- MRI	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (MRI).	Follow-Up visit 1 - Between days 16 to 44
Secondary	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
Secondary	Hematoma volume- CT	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT).	Follow-Up visit 2- Between days 76 to 104
Secondary	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
Secondary	Hematoma volume- CT	Volumetric measurement calculations of hematoma will be obtained from radiographic imaging (CT).	Follow-Up visit 4 Between days 351 and 379
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Mortality		30 days
Secondary	Mortality		90 days
Secondary	All cause mortality		up to 365 days
Secondary	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

External Links

•   ENRICH: Early MiNimally-invasive Removal of IntraCerebral Hemorrhage (ICH)
•   MIND: Artemis in the Removal of Intracerebral Hemorrhage
•   Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III