PDF: TRANSFORMS
(2010)Objective
To compare the efficacy and safety of oral fingolimod with intramuscular interferon beta-1a in patients with relapsing-remitting multiple sclerosis
Study Summary
• No significant difference in disability progression between groups over 12 months
• Two deaths occurred in the 1.25mg group (disseminated varicella zoster and herpes simplex encephalitis)
Intervention
Oral fingolimod 0.5mg or 1.25mg daily vs intramuscular interferon beta-1a 30µg weekly for 12 months
Inclusion Criteria
Age 18-55, relapsing-remitting MS (revised McDonald criteria), EDSS 0-5.5, ≥1 relapse in prior year or ≥2 in prior 2 years
Study Design
Arms: Fingolimod 1.25mg vs Fingolimod 0.5mg vs Interferon beta-1a (1:1:1)
Patients per Arm: Fingolimod 1.25mg: 420, Fingolimod 0.5mg: 429, IFN beta-1a: 431
Outcome
• No significant difference in disability progression (6-8% across groups)
• MRI: Significantly fewer new/enlarged T2 lesions and Gd+ lesions with fingolimod
• Safety: 2 fatal herpesvirus infections in 1.25mg group; bradycardia, macular edema, and skin cancers observed
Bottom Line
Oral fingolimod at both doses (0.5mg and 1.25mg) demonstrated superior efficacy to weekly intramuscular interferon beta-1a in reducing relapse rates (52% and 38% relative reduction) and MRI lesion activity over 12 months. However, no significant differences were seen in disability progression. The 1.25mg dose was associated with two fatal herpesvirus infections, and both doses showed cardiac effects, macular edema, and elevated liver enzymes.
Major Points
- First phase 3 trial comparing oral fingolimod to an active comparator (interferon beta-1a) in relapsing MS
- Fingolimod reduced annualized relapse rate by 52% (0.5mg) and 38% (1.25mg) vs interferon beta-1a
- 89% of patients completed the 12-month study
- MRI outcomes significantly favored fingolimod including fewer Gd+ lesions and less brain volume loss
- No significant difference in confirmed disability progression (6-8% across all groups)
- Two deaths in 1.25mg group: disseminated primary varicella zoster and herpes simplex encephalitis
- Dose-dependent first-dose bradycardia and AV block observed with fingolimod
- Macular edema occurred in 0.5-1% of fingolimod-treated patients
- Annualized relapse rate in interferon group (0.33) was lower than in prior studies (0.61-0.77)
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy; treating neurologist supervised medical management, certified examining neurologist performed EDSS assessments blinded to treatment; patients instructed to cover injection sites and not discuss adverse events with clinical evaluators
- Sample Size
- 1292
- Follow-up
- 12 months
- Centers
- 172
- Countries
- 18 countries
Primary Outcome
Definition: Annualized relapse rate - number of confirmed relapses during 12-month period; relapse defined as new/worsening neurologic symptoms lasting ≥24h without fever, with increase in EDSS functional system scores
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.33 (95% CI 0.26-0.42) | - | - | <0.001 for both fingolimod doses vs interferon |
Limitations & Criticisms
- 12-month duration too short to assess sustained disability progression
- Two deaths from serious herpesvirus infections in 1.25mg group raised safety concerns
- Higher rate of skin cancers in fingolimod groups requires longer follow-up
- Active comparator design limits placebo-adjusted efficacy estimation
- First-dose cardiac monitoring requirements may limit real-world implementation
- Lymphocyte reduction of 73-77% raises immunosuppression concerns
- No dose-response relationship observed for efficacy outcomes
- Breast cancer cases (4 in fingolimod groups) require further investigation
Citation
N Engl J Med 2010;362:402-15