freedoms ii trial. study design 24-month, rct of fingolimod 0.5 mg and 1.25 mg vs placebo – 3...
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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 priorAbbreviations: EDSS, Expanded Disability Status Scale; GA, glatiramer acetate; IFN B, interferon beta; RCT, randomized controlled trialCalabresi 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 CompositeCalabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.
Efficacy: Relapse Endpoint 0.5 mg
(n=358) 1.25 mg (n=370)
Placebo (n=355)
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
0.52*
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 Mean number Patients free of lesions (%) Mean change in volume (%)
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 50% b 63% b 26%
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 (%) Mean HR
86.2% 0.72 (P=.101)*
86.9% 0.72 (P=.113)*
82.2%
* P vs placeboCalabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.
Adverse Events More Frequent with Fingolimod
Adverse Event 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 transaminaseCalabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.
Serious Adverse Events Adverse Event Fingolimod
(0.5 mg) Placebo
All serious events 53 (15%) 45 (13%) Basal cell carcinoma 10 (3%) 2 (1%) Macular edema 3 (1%) 2 (1%) Infections 11 (3%) 4 (1%) Neoplasms 13 (4%) 8 (2%)
Calabresi PA, et al. Lancet Neurol. 2014; 13: 545-556.
ConclusionsCompared 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.