Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: further insights from PARADIG MS

Abstract

Background: In PARADIGMS, a double-blind phase III trial in 215 paediatric patients with multiple sclerosis (MS) (10 to <18 years), fingolimod administered for up to 2 years significantly reduced the annualised relapse rate (ARR) and rate of new/newly enlarged T2 (n/neT2) lesions compared with interferon (IFN) β-1a.

Objectives: To investigate (1) differences between treatment groups across subpopulations (treatment-naïve, younger/prepubertal patients); (2) disability progression.

Methods: ARRs at 10, 11 and 12 years were estimated based on predefined modelling extrapolations. Changes in Expanded Disability Status Scale (EDSS), and in 3 month (3M) and 6 month (6M) confirmed disability progression (CDP) were evaluated post hoc.

Results: In the treatment-naïve subpopulation, fingolimod reduced ARR and n/neT2 lesions by 85.8% and 53.4%, respectively versus INF β-1a (both p<0.001), compared with 81.9% and 52.6% in the overall population. Model-based ARR reductions in younger patients (≤12 years) were 91.9%-94.6%. Twice as many IFN β-1a-treated than fingolimod-treated patients had worse EDSS scores at study end (20.6% vs 10.5%, p=0.043). Risk reductions in 3M-CDP and 6M-CDP were 77.2% (p=0.007) and 80.2% (p=0.040), respectively.

Conclusions: Fingolimod in paediatric MS was associated with consistent control of disease activity versus IFN β-1a (including treatment-naïve and younger patients) and resulted in less disability progression for up to 2 years.

Trial registration number: NCT01892722.

Keywords: PARADIGMS; disability progression; fingolimod; gilenya; paediatric multiple sclerosis.

Conflict of interest statement

Competing interests: KD received personal compensation for speaker activities from Novartis. PH received compensation for serving on a scientific advisory board from Novartis, and for speaking from Bayer Health care. BB has served as a remunerated central MRI reviewer for the present trial (Novartis). EW volunteers on an advisory board for a Novartis trial. She is a site PI for clinical trials with Roche and Novartis. JG in the last 3 years has received honoraria for lectures and consultancy fees from Bayer, Teva and Novartis. LK has received personal compensation for activities as a speaker, consultant and/or participant on an advisory board from Biogen Idec, Novartis, Teva Neurosciences and Multicell. In addition, LK has received royalty or licence fees from ER Squibb & Sons, Avenir, Johnson & Johnson and Osmotica, and has received research support from Novartis, Biogen Idec, Celgene Corporation and Genentech. TC has received personal compensation for advisory boards/consulting for F. Hoffman-La Roche, Biogen and Novartis; TC has also received financial support for research activities from Biogen, Merck Serono, Verily and Novartis. TS, GLP and MM are employees of Novartis.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Supportive and sensitivity analyses of primary and key secondary end points: percentage reductions in ARR (A) and in new or newly enlarged T2 lesions (B) with fingolimod vs INF β-1a at study end (up to month 24). Fingolimod vs IFN β-1a comparison: *p=0.03, **paThe relapses considered for the analyses are confirmed relapses unless stated ‘all relapses’. bEstimated at a given age at baseline by fitting a negative binomial regression model adjusted for treatment, age at baseline, region, pubertal status (stratified variable), number of relapses within the previous 2 years before randomisation as well as age and treatment interaction. cObtained from fitting a Bayesian-negative binomial regression model with mixture priors adjusted for treatment, age, number of relapses within the previous 2 years before randomisation as well as age and treatment interaction; post-prob=100% (pubertal patients) and 93.8% (prepubertal patients). ARR, annualised relapse rate; FAS, full analysis set; IFN, interferon; NAbs+, neutralising antibodies-positive; post-prob, posterior probability of rate ratio <1; PPS, per-protocol set.

Figure 2

Changes in EDSS from baseline (A) mean EDSS changes; (B) categorical EDSS changes†. *P5.0: change of ≤−0.5 point defined as improvement, zero change as stable, change of ≥0.5 point as deterioration. EDSS, Expanded Disability Status Scale; EOS, end of study, defined as the last assessment taken on or before the final study phase visit date; IFN, interferon; n, number of patients.

Figure 3

Kaplan-Meier plot for (A) time to 3M-CDP; (B) time to 3M-CDP sustained until last observationa; (C) time to 6M-CDP. aPost hoc analysis of full analysis set. bEstimated using a Cox regression model adjusted for treatment, pubertal status and baseline EDSS. 3M-CDP, 3 month confirmed disability progression; 6M-CDP, 6 month confirmed disability progression; EDSS, Expanded Disability Status Scale; IFN, interferon.