PDF: FREEDOMS
(2010)Objective
Fingolimod - To evaluate the efficacy and safety of oral fingolimod (0.5 mg and 1.25 mg daily) versus placebo on relapse rate and disability progression in patients with relapsing-remitting multiple sclerosis over 24 months
Study Summary
• Both doses significantly reduced risk of disability progression by 30-32% (HR 0.70 and 0.68, p=0.02)
• Superior MRI outcomes with both doses including reduced gadolinium-enhancing lesions and brain volume loss (p<0.001)
Intervention
Oral fingolimod capsules at 0.5 mg or 1.25 mg once daily for 24 months
Inclusion Criteria
Relapsing-remitting MS by McDonald criteria, age 18-55 years, EDSS 0-5.5, one or more relapses in previous year or two or more in previous 2 years, neurologically stable for 30 days prior to entry
Study Design
Arms: Three parallel arms: fingolimod 1.25 mg daily (n=429), fingolimod 0.5 mg daily (n=425), placebo (n=418)
Patients per Arm: 429 in 1.25 mg group, 425 in 0.5 mg group, 418 in placebo group
Outcome
• Disability progression confirmed at 3 months: 16.6%, 17.7%, and 24.1% (HR 0.68-0.70, p=0.02)
• Significantly fewer gadolinium-enhancing lesions and reduced brain volume loss with both fingolimod doses
Bottom Line
Oral fingolimod at both 0.5 mg and 1.25 mg daily doses significantly reduced the annualized relapse rate by 54-60%, reduced the risk of disability progression by 30-32%, and improved MRI outcomes compared to placebo in relapsing-remitting MS patients, though potential safety concerns include bradycardia, macular edema, elevated liver enzymes, and infections
Major Points
- This was the first phase III trial to demonstrate efficacy of an oral disease-modifying therapy for relapsing-remitting MS
- Both fingolimod doses significantly reduced annualized relapse rates (0.18 with 0.5 mg, 0.16 with 1.25 mg) compared to placebo (0.40), representing 54% and 60% reductions respectively (p<0.001)
- Disability progression confirmed after 3 months was significantly reduced with both doses (cumulative probability 17.7% with 0.5 mg, 16.6% with 1.25 mg vs 24.1% with placebo; HR 0.70 and 0.68, p=0.02)
- All MRI outcomes favored fingolimod including gadolinium-enhancing lesions, new/enlarged T2 lesions, and brain volume loss
- Brain volume loss was reduced by approximately 30% with fingolimod, detected as early as 6 months
- Both fingolimod doses showed similar efficacy, with potentially better safety profile for 0.5 mg dose
- Key safety concerns included transient bradycardia and AV conduction block at first dose, macular edema (1.6% with 1.25 mg), elevated liver enzymes (8.5-12.5%), mild hypertension, and lower respiratory infections
- Fingolimod acts by preventing lymphocyte egress from lymph nodes, reducing circulating lymphocytes by ~70-75%
- Study completion rate was 81.2%, with fewer discontinuations in the 0.5 mg group (18.8%) versus 1.25 mg (30.5%) or placebo (27.5%)
Study Design
- Study Type
- Phase III, multicenter, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind with independent examining neurologist (unaware of treatment assignment and adverse events) and treating neurologist (managed symptoms and adverse events but not objective assessments)
- Sample Size
- 1272
- Follow-up
- 24 months
- Centers
- 138
- Countries
- Multiple countries including Switzerland, Canada, Netherlands, Germany, United States, Poland
Primary Outcome
Definition: Annualized relapse rate over 24 months, defined as number of confirmed relapses per year. Relapse confirmed by examining neurologist within 7 days with objective changes (≥0.5 point EDSS increase, 1 point increase in two functional systems, or 2 points in one functional system)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | Placebo: 0.40 (95% CI 0.34-0.47) | - | <0.001 for both fingolimod doses vs placebo |
Limitations & Criticisms
- Higher discontinuation rate in 1.25 mg fingolimod group (30.5%) compared to 0.5 mg (18.8%) or placebo (27.5%), potentially affecting long-term interpretability
- Macular edema occurred exclusively in 1.25 mg group (7 patients), raising dose-dependent safety concerns
- Increased liver enzyme elevations with fingolimod (8.5-12.5%) compared to placebo (1.7%), predominantly in men
- Lower respiratory tract infections more common with fingolimod (9.6-11.4%) than placebo (6.0%)
- Bradycardia and AV conduction blocks at first dose required 6-hour monitoring period, limiting practical use
- Mild blood pressure increases with fingolimod (mean systolic 1.9-3.6 mmHg, diastolic 0.7-2.1 mmHg by month 24) of unclear long-term significance
- Peripheral lymphocyte counts reduced by 73-76% with fingolimod, raising theoretical concerns about long-term immunosuppression
- 24-month duration may be insufficient to assess long-term cancer risk with chronic immunomodulation
- Study excluded patients with significant comorbidities (diabetes, active infection, immune suppression), limiting generalizability
- Two doses tested showed similar efficacy, questioning need for higher 1.25 mg dose given potentially worse safety profile
- No active comparator arm (interferon or glatiramer acetate) in this study, though TRANSFORMS addressed this
- Mechanism of reduction in brain volume loss unclear - due to reduced inflammation or direct neuroprotective effects
- Definition of disability progression required only 3-month confirmation, though 6-month analysis also showed benefit
Citation
Kappos L, Radue EW, O'Connor P, et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. N Engl J Med 2010;362:387-401