Fingolimod May Benefit Intracranial Hemorrhage

July 21, 2014

The multiple sclerosis drug fingolimod (Gilenya, Novartis), may be useful in treating patients with intracranial haemorrhage (ICH), the results of a preliminary study suggest.

In this pilot study in patients with ICH, administration of oral fingolimod within 72 hours of symptom onset was safe and was associated with reduced perihematomal edema and neurologic deficits.

The study was conducted by a Chinese group led by Ying Fu, MD, Tianjin Medical University General Hospital, China. They explain that inflammatory reactions are known to contribute to perihematomal edema and secondary brain injury after ICH, and fingolimod, believed to have both anti-inflammatory and neuroprotective effects, has shown some promising results in animal models of ICH.

The researchers conclude that: "The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials."

The study results were published online July 7 in JAMA Neurology.

Findings "Provocative"

In an accompanying editorial, Kevin N. Sheth, MD, Yale University School of Medicine, New Haven, Connecticut, and Jonathan Rosand, MD, Massachusetts General Hospital, Boston, Massachusetts, describe the study as "provocative," but point out that it is too small to draw any definitive conclusions.

However, they note that fingolimod use was associated with "multiple independent measures of short-term improvement (neuroimaging and clinical)," which, they say, "suggests that there may indeed be an effect of the treatment."

In an interview with Medscape Medical News, Dr. Rosand cautioned about overinterpreting the clinical results because the control group performed very badly.

"The difference in neurologic outcomes between the 2 groups was much greater than would be expected — it was out of proportion to the edema and inflammatory observations. This is because the control group fared so poorly, which is obviously a concern," he commented. "But the edema and lymphocyte reductions are encouraging and this study represents a new strategy of using immunomodulatory drugs in ICH. That in itself is very exciting," he added.

For the study, 11 patients with ICH with hematomal volume of 5 to 30 mL were treated with fingolimod, 0.5 mg orally, for 3 consecutive days, with the first dose administered within 72 hours of symptom onset. They were compared with 12 control patients with ICH who were matched for clinical and neuroimaging features and who were treated with standard care without fingolimod.

Results showed that circulating CD4+, CD8+, and CD19+ B cell counts were lower in treated patients and the amount of perihematomal edema at 7 days was reduced.

Patients treated with fingolimod exhibited a reduction of neurologic impairment as measured by several clinical scores, including the Glasgow coma scale (GCS), National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and modified Barthel Index (mBI).

Table. Outcomes After ICH By Treatment Allocation

Outcome Fingolimod Control P Value
GCS score, day 7 6 11 .01
GCS score, day 14 7 11 .04
NIHSS score, day 7 12.5 8.1 .03
NIHSS score, day 14 10.8 5.8 <.001
mRS score, day 7 4.5 3.7 .001
mRS score, day 14 4.1 3.6 .05
mBI score, day 7 20.0 35.9 .06
mBI score, day 14 27.5 42.3 .06

 

At 3 months, a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions as defined by mBI score range, 95 to 100 (63% vs 0%) or mRS score range, 0 to 1 (63% vs 0%). Fewer fingolimod recipients also reported ICH-related lung infections.

Occurrence of adverse events did not differ between the groups.

In their editorial, Dr. Sheth and Dr. Rosand note that, to date, most interventions for ICH have targeted hematoma expansion, but this occurs early after onset and only in a subset of patients. In contrast, secondary injury and the development of perihematomal edema continue for several days, so therapies aimed at preventing this would have a larger window of opportunity.

They explain that increasing evidence suggests an important role for the migration of peripheral immune cells into the brain after ICH and fingolimod is thought to act by blocking such movement.

They point out that the study included only patients with basal ganglia ICH, in whom the clinical effect of edema is least likely to be confounded by intraventricular hemorrhage or brain stem injury. And the findings in this group mirrors preclinical experiments.

But they say there are also important limitations, such as the small sample size, nonrandomized design, and differences in time points at which edema was measured between the 2 groups. They further note that all the patients had ICH volumes less than 30 mL, so it is "curious" that the control group performed so poorly.

They state that methods for detecting edema after ICH need to be refined, but they conclude that "the current study only bolsters the case for this line of inquiry."

This study was supported by grants from the National Basic Research Program of China, the National Science Foundation of China, the National Key Clinical Specialty Construction Program of China, the US National Institutes of Health, and the American Heart Association. The study authors have disclosed no relevant financial relationships. Dr. Sheth consults for Remedy Pharmaceuticals. Dr. Rosand consults for Boehringer Ingelheim.

JAMA Neurol. Published online July 7, 2014. Abstract Editorial

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