Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial

Abstract

Objective: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population.

Results: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported.

Conclusion: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching.

Classification of evidence: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Figure 1. Patient disposition

Reasons for discontinuation from FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were reported previously. Only those patients who completed FREEDOMS were eligible to enter the extension phase; 38 patients in the fingolimod 0.5 mg group, 43 in the fingolimod 1.25 mg group, and 32 in the placebo group decided not to participate in the extension. GCP = good clinical practice. ITT = intent to treat.

Figure 2. Between-group comparisons (month 0 to end of study, FREEDOMS ITT population)

(A) Annualized relapse rate (ARR) estimated from a negative binomial model adjusted for treatment, pooled country, number of relapses in the 2 years before enrollment, and FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) baseline Expanded Disability Status Scale score; p values are for the ARR ratio between active treatment ARR and placebo ARR. (B) Time to first confirmed relapse with Kaplan-Meier estimate of patients free from relapse at end of study (EoS). ^aCensor flags indicate the time in study for patients with no confirmed relapse during the time interval, patients for whom follow-up ended before a confirmed relapse occurred, and patients who dropped out prior to a relapse. (C) Time to 3-month confirmed disability progression based on EDSS score with Kaplan-Meier estimate of patients free from progression at EoS. (D) Cumulative number of new or newly enlarged T2 lesions compared using a negative binomial model adjusted for treatment, FREEDOMS baseline volume of T2 lesions, and pooled country. (E) Cumulative number of gadolinium (Gd)-enhancing T1 lesions from month 0 to EoS, including patients with all assessments during that time interval; p values are for comparisons with the placebo–fingolimod group. AbRR = absolute risk reduction; CI = confidence interval; NNT = number needed to treat.

Figure 3. Percentage brain volume change

(A) Between-group comparisons of changes in brain volume from month 0 to end of study in the FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) intent-to-treat (ITT) population. Percentage brain volume change was compared using a rank analysis of covariance adjusted by treatment, normalized brain volume at FREEDOMS baseline, and country. (B) Within-group comparisons (months 24–48 vs months 0–24) in the extension ITT population and 48-month completer subgroup. Comparisons were made with the Wilcoxon signed-rank test. All patients receiving fingolimod 1.25 mg/day were switched to fingolimod 0.5 mg/day after the 1.25 mg/day dose was discontinued from all multiple sclerosis clinical studies. In this analysis, the evaluable individuals in the extension ITT population coincided with those evaluable in the 48-month completer subgroup; therefore the findings shown represent those for both groups. n = number of patients with brain volume change data for both time periods. CI = confidence interval.