FREEDOMS II
Fingolimod
FREEDOMS II confirmed fingolimod’s relapse-reducing effect in a second placebo-controlled trial that incorporated additional FDA-requested safety assessments, including 24-hour Holter cardiac monitoring.
- Phase
- Phase III
- Population
- Relapsing-remitting multiple sclerosis (RRMS)
- Controlled period
- Jun 2006 — Jun 2011
What was compared
Fingolimod 0.5 mg
Orally once daily
n=358Placebo
Matching oral capsule once daily
n=355Additional randomized arm
Fingolimod 1.25 mg
Orally once daily; later switched to 0.5 mg by amendmentn=370Primary endpoint
Annualized relapse rate
24 months
Primary endpoint results
Annualized relapse rate
Relapses per participant-year
48% lower relapse rate; rate ratio 0.52 (95% CI 0.40–0.66; P<0.0001).
Selected secondary outcomes
Percentage brain-volume loss favored fingolimod.
The confirmatory disability endpoint was not significant.
Who was studied
Key inclusion criteria
- Age 18–55 years
- RRMS diagnosis based on McDonald criteria 2005
- Baseline EDSS 0–5.5
- At least 1 relapse in the previous year or at least 2 in the previous 2 years
Key exclusion criteria
- Relapse or corticosteroid treatment in the previous 30 days
- Active infection, macular edema, diabetes mellitus, or clinically significant systemic disease
- Immune suppression or malignancy other than treated basal-cell or squamous-cell skin cancer
- Specified cardiac, pulmonary, or hepatic disorders
- Interferon or glatiramer acetate within 3 months, or natalizumab within 6 months
Participants at baseline
| Characteristic | Fingolimod 0.5 mgN=358 | Fingolimod 1.25 mgN=370 | PlaceboN=355 |
|---|---|---|---|
| Age, years — mean ± SD | 40.6 ± 8.4 | 40.9 ± 8.9 | 40.1 ± 8.4 |
| Female sex — n (%) | 275 (77%) | 281 (76%) | 288 (81%) |
| Time since MS symptom onset, years — mean ± SD | 10.4 ± 8.0 | 10.8 ± 8.2 | 10.6 ± 7.9 |
| EDSS — mean ± SD | 2.4 ± 1.3 | 2.5 ± 1.3 | 2.4 ± 1.3 |
| Relapses in previous 12 months — mean ± SD | 1.4 ± 0.9 | 1.5 ± 1.0 | 1.5 ± 0.9 |
| Previous DMT — n (%) | 264 (74%) | 287 (78%) | 259 (73%) |
| No gadolinium-enhancing lesions — n/N (%) | 218/357 (61%) | 254/367 (69%) | 225/354 (64%) |
SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy.
Source: Calabresi et al., Lancet Neurology 2014, Table 1
Safety signal
- Lymphopenia, liver-enzyme elevation, herpes zoster, hypertension, first-dose bradycardia, and atrioventricular block were more frequent with fingolimod.
- Macular edema was confirmed in 3 participants receiving fingolimod 0.5 mg, 4 receiving 1.25 mg, and 2 receiving placebo.
- Serious adverse events occurred in 15% with fingolimod 0.5 mg and 13% with placebo.
Later safety context
Later FDA warning (2018): severe worsening of disability was reported after fingolimod discontinuation. This post-marketing finding is separate from the controlled-trial safety results above.
FDA, Gilenya label, 2018, section 5.9 ↗Why it mattered
FREEDOMS II reproduced fingolimod’s relapse benefit in a separate, predominantly US population while adding FDA-requested safety assessments. Its nonsignificant disability result highlighted that a reproducible relapse effect does not guarantee a disability benefit in every trial.
Important limitation
The trial did not reproduce a significant disability-progression benefit, emphasizing that consistent relapse efficacy does not guarantee concordant disability results.