Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS

Abstract

Objective: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod.

Methods: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24.

Results: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7-2.6]) and 12-week WO groups (1.7 [1.3-2.2]) and higher in the 16-week WO group (8.2 [7.3-9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2-0.6]; 12 weeks, 2.1 [1.6-2.6]; 16 weeks, 3.6 [3.0-4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67-22.53]) than in the 12-week (21.3 [1.41-41.19]) or 16-week (18.5 [8.40-28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred.

Conclusions: Initiating fingolimod therapy 8-12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO.

Classification of evidence: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods.

Figure 1. CONSORT flow diagram

WO = washout.

Figure 2. Active T2 lesions

(A) Number of active T2 lesions (sum of all active T2 lesions on MRI scans during specified time interval in each group) since last infusion of natalizumab for the washout (WO) period and 8 weeks of fingolimod therapy (adjusted for observation time). (B) Kaplan-Meier estimate of time to a new or newly enlarged T2 lesion (adjusted for observation time; modified full analysis set population). The number of new or newly enlarged T2 lesions (C) since the last natalizumab infusion for the WO period only and (D) for the first 8 weeks of fingolimod therapy only (adjusted for the observation time; full analysis set population). *Two-sided statistical significance at 0.05 level, calculated using a negative binomial regression model adjusted for WO group and baseline T2 lesion volume, with the logarithm of the observation period as the offset variable. **Difference was statistically significant for the 8-week vs the 12-week (p < 0.0001) and 16-week (p = 0.0013) WO groups for the first key secondary endpoint and for the second key secondary endpoint, for the 8-week vs the 16-week WO group (p = 0.0351). A 2-sided statistical significance at 0.05 level was indicated, calculated using the negative binomial regression model adjusted for WO group, baseline T2 lesion volume, and observation period. CI = confidence interval.