Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study.

Abstract

IMPORTANCE:

Pronounced inflammatory reactions occurring shortly after intracerebral hemorrhage (ICH) contribute to the formation and progression of perihematomal edema (PHE) and secondary brain injury. We hypothesized that modulation of brain inflammation reduces edema, thus improving clinical outcomes in patients with ICH.

OBJECTIVE:

To investigate whether oral administration of fingolimod, a Food and Drug Administration-approved sphingosine 1-phosphate receptor modulator for multiple sclerosis, is safe and effective in alleviating PHE and neurologic deficits in patients with ICH.

DESIGN, SETTING, AND PARTICIPANTS:

In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30 mL. Clinical and neuroimaging feature-matched patients were treated with standard care with or without oral fingolimod. The study was conducted in Tianjin Medical University General Hospital, Tianjin, China.

INTERVENTIONS:

All patients received standard management alone (control participants) or combined with fingolimod (FTY720, Gilenya), 0.5 mg, orally for 3 consecutive days. Treatment was initiated within 1 hour after the baseline computed tomographic scan and no later than 72 hours after the onset of symptoms.

MAIN OUTCOMES AND MEASURES:

Neurologic status and hematomal and PHE volumes (Ev) and relative PHE, defined as Ev divided by hematomal volume, were monitored by clinical assessment and magnetic resonance imaging, respectively, for 3 months.

RESULTS:

Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day 7 (100% vs 50%, P = .01), and had a National Institutes of Health Stroke Scale score reduction of 7.5 vs 0.5 (P < .001). Neurologic functions improved in these patients in the first week coincident with a reduction of circulating lymphocyte counts. At 3 months, a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions (modified Barthel Index score range, 95-100; 63% vs 0%; P = .001; modified Rankin Scale score range, 0-1; 63% vs 0%; P = .001), and fewer reported ICH-related lung infections. Perihematomal edema volume and rPHE were significantly smaller in fingolimod-treated patients than in control individuals (Ev at day 7, 47 mL vs 108 mL, P = .04; Ev at day 14, 55 mL vs 124 mL, P = .07; rPHE at day 7, 2.5 vs 6.4, P < .001; rPHE at day 14, 2.6 vs 7.7, P = .003, respectively). We recorded no differences between groups in the occurrence of adverse events.

CONCLUSIONS AND RELEVANCE:

In patients with small- to moderate-sized deep primary supratentorial ICH, administration of oral fingolimod within 72 hours of disease onset was safe, reduced PHE, attenuated neurologic deficits, and promoted recovery. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier:NCT02002390.

• Authors: Ying Fu, Junwei Hao, Ningnannan Zhang, Li Ren, Na Sun, Yu-Jing Li, Yaping Yan, DeRen Huang, Chunshui Yu, Fu-Dong Shi
• Journal: JAMA neurology (JAMA Neurol) Vol. 71 Issue 9 Pg. 1092-101 (Sep 2014) ISSN: 2168-6157 [Electronic] United States
• PMID: 25003359 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Propylene Glycols
• Fingolimod Hydrochloride
• Sphingosine

Topics

• Aged
• Cerebral Hemorrhage (blood, drug therapy, pathology, physiopathology)
• Female
• Fingolimod Hydrochloride
• Glasgow Coma Scale
• Humans
• Immunosuppressive Agents (administration & dosage, adverse effects, pharmacology)
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Propylene Glycols (administration & dosage, adverse effects, pharmacology)
• Recovery of Function (drug effects)
• Severity of Illness Index
• Single-Blind Method
• Sphingosine (administration & dosage, adverse effects, analogs & derivatives, pharmacology)
• Treatment Outcome