Elsevier

The Lancet Neurology

Volume 10, Issue 6, June 2011, Pages 520-529
The Lancet Neurology

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Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study

https://doi.org/10.1016/S1474-4422(11)70099-0Get rights and content

Summary

Background

In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod.

Methods

Patients randomly assigned to receive 0·5 mg or 1·25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0·5 mg or 1·25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834.

Findings

1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0·5 mg fingolimod [n=356], 0·12 [95% CI 0·08–0·17] in months 0–12 vs 0·11 [0·08–0·16] in months 13–24; 1·25 mg fingolimod [n=330], 0·15 [0·10–0·21] vs 0·11 [0·08–0·16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0·5 mg fingolimod [n=167], 0·31 [95% CI 0·22–0·43] in months 0–12 vs 0·22 [0·15–0·31], in months 13–24 p=0·049; interferon beta-1a to 1·25 mg fingolimod [n=174], 0·29 [0·20–0·40] vs 0·18 [0·12–0·27], p=0·024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p<0·0001 for T2 lesions at both doses; p=0·002 for T1 at 0·5 mg; p=0·011 for T1 at 1·25 mg), and the pattern of adverse events shifted towards that typical for fingolimod. Over 24 months, in continuous fingolimod groups compared with the group that switched from interferon beta-1a to fingolimod, we recorded lower ARRs (0·18 [95% CI 0·14–0·22] for 0·5 mg; 0·20 [0·16–0·25] for 1·25 mg; 0·33 [0·27–0·39] for the switch group; p<0·0001 for both comparisons), fewer new or newly enlarged T2 lesions (p=0·035 for 0·5 mg, p=0·068 for 1·25 mg), and fewer patients with Gd-enhancing T1 lesions (p=0·001 for 0·5 mg fingolimod vs switch group; p=0·002 for 1·25 mg fingolimod vs switch group). There was no benefit on disability progression.

Interpretation

Switching from interferon beta-1a to fingolimod led to enhanced efficacy with no unexpected safety concerns. Compared with patients switched from interferon beta-1a to fingolimod, continuous treatment with fingolimod for 2 years provides a sustained treatment effect with improved clinical and MRI outcomes.

Funding

Novartis Pharma AG.

Introduction

Fingolimod is the first in a new class of drugs—the sphingosine 1-phosphate receptor modulators—and is approved for the treatment of relapsing multiple sclerosis at a recommended dose of 0·5 mg once daily. The efficacy of fingolimod in relapsing-remitting multiple sclerosis (RRMS) has been shown in a clinical programme that includes two large multicentre phase 3 studies: a 1-year active-controlled study, TRANSFORMS (trial assessing injectable interferon versus FTY720 oral in RRMS),1 in which fingolimod had better efficacy than a first-line treatment (intramuscular interferon beta-1a) on relapse and MRI outcomes, and a 2-year placebo-controlled study, FREEDOMS (FTY720 research evaluating effects of daily oral therapy in multiple sclerosis),2 that showed efficacy on relapses, disability progression, and MRI measures. We present results from the second year of TRANSFORMS, a 1-year extension in which patients originally randomly assigned to receive fingolimod continued with treatment at the same dose as in the core study, and patients originally assigned to receive interferon beta-1a in the core study were randomly reassigned to receive fingolimod 0·5 mg or 1·25 mg. We did within-group comparisons to assess the efficacy and safety of fingolimod during months 13–24 compared with months 0–12 in patients who had switched from interferon beta-1a at month 12. We compared groups of patients receiving fingolimod for up to 2 years with patients who switched treatment to assess the effect of delayed onset of fingolimod.

Section snippets

Participants

Patients eligible for inclusion in the core study: were aged 18–55 years; had a diagnosis of multiple sclerosis in accordance with the 2005 revised McDonald criteria,3 with a relapsing-remitting disease course; had one or more documented relapses in the year before randomisation or two or more documented relapses in the 2 years before randomisation; had an expanded disability status scale (EDSS) score of 0–5·5;4 and were neurologically stable, with no evidence of relapse or corticosteroid

Results

1123 (87%) of 1292 patients completed the core study on a study drug.1 1027 (92%) of the 1123 patients entered our extension and received study drugs, and 882 (86%) of these patients completed 24 months of treatment (figure 1). Baseline demographics and disease characteristics for the eITT population were similar across all treatment groups (table 1), and were consistent with those of the core ITT population.1 Completion rates were slightly higher for patients who received continuous treatment

Discussion

Our findings show that, in patients with RRMS, there were improvements in clinical and MRI measures of efficacy after switching from interferon beta-1a to fingolimod without the emergence of unexpected adverse events. Patients who received continuous fingolimod had reduced relapse rates and MRI lesion activity over 2 years relative to patients who received interferon beta-1a during the first year and fingolimod during the second year. We did not identify a loss of efficacy during months 13–24

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