Epub: Calabresi et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar 27. pii: S1474-4422(14)70049-3.
BACKGROUND: Fingolimod has shown reductions in clinical and MRI disease activity in RRMSers. We further assessed the efficacy and safety of fingolimod in such patients.
METHODS: We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible MSers - those aged 18-55 years with MS - to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all MSers assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134.
FINDINGS: Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 MSers: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in MSers given placebo and 0·21 (0·17-0·25) in MSers given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] MSers vs 0 MSers), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 MSers given fingolimod 0·5 mg and 45 (13%) of 355 MSers given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] MSers vs two [1%] MSers), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]).
AIMS: The phase 3 TRANSFORMS and FREEDOMS studies established the efficacy of fingolimod in RRMS and magnetic resonance imaging lesions compared with intramuscular (IM) interferon (IFN) β-1a and placebo over 12 and 24 months, respectively.
METHODS: To investigate the efficacy of fingolimod at the approved 0.5 mg dose in MSer early in the MS disease course, post hoc subgroup analyses of TRANSFORMS (n = 272) and FREEDOMS (n = 217) data were conducted in MSers who experienced their first MS symptom <3 years before randomization.
RESULTS: Fingolimod 0.5 mg reduced annualized relapse rate by 73.4% (P = 0.0002) versus IFNβ-1a IM and by 67.4% (P < 0.0001) versus placebo in MSers with <3 years since first symptom; respective reductions were 45.4% and 51.4% in subgroups of MSers with ≥3 years since first symptom. For MSers with <3 years since their first symptom, significantly fewer new/newly enlarged T2 lesions were observed with fingolimod versus IFNβ-1a IM (mean number, 1.94 vs. 2.95; P = 0.036) or placebo (4.1 vs. 10.7; P < 0.001); the mean number of gadolinium-enhancing T1 lesions was significantly reduced versus placebo (0.3 vs. 1.1; P < 0.001).