A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.
BACKGROUND
Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis.


METHODS
In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point).


RESULTS
A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension.


CONCLUSIONS
As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)
Kappos
Ludwig
L
Department of Neurology, University Hospital, University of Basel, Switzerland. lkappos@uhbs.ch
Radue
Ernst-Wilhelm
EW
O'Connor
Paul
P
Polman
Chris
C
Hohlfeld
Reinhard
R
Calabresi
Peter
P
Selmaj
Krzysztof
K
Agoropoulou
Catherine
C
Leyk
Malgorzata
M
Zhang-Auberson
Lixin
L
Burtin
Pascale
P
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001921:Brain / Q000473:pathology; D004185:Disability Evaluation; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D000068876:Fingolimod Hydrochloride; D006566:Herpesviridae Infections / Q000209:etiology / Q000401:mortality; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008111:Liver Function Tests; D008269:Macular Edema / Q000139:chemically induced; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D011409:Propylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013110:Sphingosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine