FREEDOMS II TRIAL.

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Presentation transcript:

FREEDOMS II TRIAL

Study Design 24-month, RCT of fingolimod 0.5 mg and 1.25 mg vs placebo 3 years into the study, 1.25 mg discontinued and patients placed on 0.5 mg in blinded manner Relapsing-remitting MS patients >1 relapses within previous year or >2 relapses in previous 2 years; no relapses or steroids within 30 days of randomization EDSS score: 0 to 5.5 Any IFN B or GA stopped >3 months prior to randomization; any natalizumab stopped >6 months prior Abbreviations: EDSS, Expanded Disability Status Scale; GA, glatiramer acetate; IFN B, interferon beta; RCT, randomized controlled trial Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Study Endpoints Primary endpoint: Annualized relapse rate Key secondary endpoints: Percent brain volume change from baseline Time to disability progression confirmed at 3 months Other Safety and tolerability Time to first relapse and proportion of relapse-free patients Effect on MRI measures of inflammatory disease activity Time to disability progression confirmed at 6 months Change on MSFC score Abbreviation: MSFC, Multiple Sclerosis Functional Composite Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Efficacy: Relapse Endpoint 0.5 mg (n=358) 1.25 mg (n=370) Placebo Primary Endpoint: Annualized relapse rate Rate ratio vs placebo 0.21 0.52* 0.20 0.50* 0.40 Time to first relapse HR vs placebo 0.50 * Patients relapse-free (%) 71.5%* 73.2%* 52.7% * P<.0001 vs placebo Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Efficacy: MRI Measures Endpoint 0.5 mg (n=358) 1.25 mg (n=370) Placebo (n=355) Key Secondary Endpoint: Brain volume change Mean Difference from placebo -0.858% -0.41% a -0.595% -0.63% b -1.279% New Gd+ T1 lesions at 24 months Mean number Patients free of lesions (%) Mean change in volume (%) 0.4 b 87% b 12.64% c 0.2b 96% b -4.69% d 1.2 65% 26.42% New/enlarging T2 lesions at 24 months 2.3 b 50% b 13.74% b 1.6 b 63% b -7.69 b 8.9 26% 25.06% Free of new inflammatory activity All P values vs placebo: a P=.0002 ; b P<.0001; c P=0.372; d P=0.205. Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Efficacy: Disability Progression Endpoint 0.5 mg (n=358) 1.25 mg (n=370) Placebo (n=355) Key Secondary Endpoint: Patients without disability progression at 3 months (%) Mean HR 74.7% (P=.320)* 0.83 (P=.227)* 78.3% (P=.056)* 0.72 (P=.041)* 71.0% Patients without disability progression at 6 months (%) 86.2% (P=.101)* 86.9% (P=.113)* 82.2% * P vs placebo Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Adverse Events More Frequent with Fingolimod (0.5 mg) Placebo Lymphopenia 27 (8%) 0 (0%) Increased ALT 29 (8%) 6 (2%) Herpes zoster infection 9 (3%) 3 (1%) Hypertension 32 (9%) 11 (3%) First-dose bradycardia 5 (1%) 1 (<0.5%) First-degree atrioventricular block 17 (5%) 7 (2%) Abbreviations: ALT, alanine transaminase Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Serious Adverse Events Fingolimod (0.5 mg) Placebo All serious events 53 (15%) 45 (13%) Basal cell carcinoma 10 (3%) 2 (1%) Macular edema 3 (1%) Infections 11 (3%) 4 (1%) Neoplasms 13 (4%) 8 (2%) Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Conclusions Compared to placebo, fingolimod 0.5 mg resulted in Reduction in annualized relapse rate and time to first relapse; increase in % patients relapse-free Reduction in % brain volume loss, number/ volume of new Gd+T1 lesions, and number/ volume of new/enlarging T2 lesions; increase in patients free of new inflammatory activity Increase in quality of life No difference in disability progression Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.

Conclusions Certain adverse events occurred with greater frequency with fingolimod than placebo, but there were no new safety signals observed No clinically relevant effects of fingolimod were noted in terms of cardiac or pulmonary toxicity However, clinicians should be aware of contraindications in patients with specific cardiac risks Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.