Fingolimod shows superior efficacy to interferon beta-1a in pediatric multiple sclerosis: the PARADIGMS trial

1. Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower annualized rate of relapse and lower incidence of new lesions identified on T2-weighted magnetic resonance imaging (MRI) compared to interferon beta-1a.

2. Fingolimod was associated with an increase in serious adverse events compared to interferon beta-1a, most commonly seizures and infection.

Evidence Rating Level: 1 (Excellent)     

Study Rundown: Although the onset of MS is typically in young adults, up to five percent appear in childhood or adolescence. Those affected usually demonstrate a relapse-remitting pattern, often with more frequent and severe relapses than the adult population. Yet, no disease-modifying therapies are currently approved for patients under 18 years of age. Fingolimod is an oral agent that has shown efficacy as a disease-modifying agent in the adult population. The authors of this study compared the efficacy and safety of fingolimod to interferon beta-1a in the pediatric MS population for up to 24 months. The primary outcome, annualized relapse rate, was significantly lower in the fingolimod group compared to interferon beta-1a during the trial period. Among secondary outcomes, fingolimod was associated with a significantly lower annualized rate of new or newly enlarged T2 MRI lesions and lower total number of gadolinium-enhancing T1 lesions. However, fingolimod was associated with a higher incidence of serious adverse events than interferon beta-1a, notably seizures and infections. Though long-term data is still needed, the results of this study suggest fingolimod has potential to become the new standard of care in pediatric MS.

This was the first randomized, double-blind, parallel-group trial designed specifically for the pediatric MS population. The study included a large sample size in relation to the pediatric MS population. Additional strengths include the active comparison to interferon beta-1a, currently the standard of care for pediatric MS. The 24-month duration is the major limitation of the trial, as durability and potential adverse events related to fingolimod require longer-duration studies for a complete assessment.

Click to read the study in NEJM

Relevant Reading: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis

In-Depth [randomized controlled trial]: This was a randomized controlled trial that enrolled 215 patients from 10 to 17 years of age with a diagnosis of multiple sclerosis to either oral fingolimod (n=107) or intramuscular interferon beta-1a (n=108) for up to 24 months. The primary outcome was the annualized relapse rate, confirmed by an independent physician based on clinically validated Expanded Disability Status Scale (EDSS) or functional system (FS) scores. The key secondary outcome was the annualized rate of new or newly enlarged T2-weighted MRI lesions relative to baseline. Other secondary outcomes included time to the first confirmed relapse, percentage of patients free of relapse at the end of the trial period, number of gadolinium-enhancing lesions, and safety profile of the two medications.

Completion of the trial occurred in 188 (87.4%) of the enrolled patients, 100 (93.5%) in the fingolimod group and 88 (81.5%) in the interferon beta-1a group. At up to 24 months, the adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (rate ratio, 0.18; 95% confidence interval [CI], 0.11 to 0.30; P<0.001). The annualized rate of new or newly enlarged lesions on T2 MRI at up to 24 months was 4.39 with fingolimod and 9.27 with interferon beta-1a (rate ratio, 0.47; 95% CI, 0.36 to 0.62; P<0.001). In patients treated with fingolimod versus interferon beta-1a the median time to first relapse was 720 days versus 488 days, the percentage of patients free of relapse at month 24 was 85.7% versus 38.8%, and the mean number of gadolinium-enhancing lesions was 0.44 versus 1.28, respectively. The overall incidence of adverse events was 88.8% in the fingolimod group (most common being headache, leukopenia, and upper respiratory tract infection) and 95.3% in the interferon beta-1a group (most common being an influenza-like illness). A serious adverse event occurred in 18 (16.8%) patients in the fingolimod group and 7 (6.5%) patients in the interferon beta-1a group, all single events with the exception of convulsions (6 patients receiving fingolimod and 1 patient receiving interferon beta-1a).

Image: PD

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