TOWER
(2014)Objective
To provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis
Study Summary
• Teriflunomide 14mg reduced risk of 12-week sustained disability accumulation by 32% (HR 0.68, P=0.0442)
• Four deaths occurred (none related to study drug); safety profile consistent with TEMSO trial
Intervention
Oral teriflunomide 7mg or 14mg once daily vs placebo until 48 weeks after last patient enrolled
Inclusion Criteria
Age 18-55, relapsing MS (2005 McDonald criteria), EDSS ≤5.5, ≥1 relapse in prior 12 months or ≥2 in prior 24 months, no relapse in prior 30 days
Study Design
Arms: Placebo vs Teriflunomide 7mg vs Teriflunomide 14mg (1:1:1)
Patients per Arm: Placebo: 388, Teriflunomide 7mg: 407, Teriflunomide 14mg: 370
Outcome
• 12-week sustained disability: HR 0.95 (7mg, NS) vs HR 0.68 (14mg, P=0.0442)
• Proportion relapse-free at 48 weeks: 60.6% (placebo) vs 71.9% (7mg) vs 76.3% (14mg)
Bottom Line
Teriflunomide 14mg significantly reduced both annualized relapse rate (36% reduction) and risk of sustained disability accumulation (32% reduction) compared to placebo, confirming the efficacy findings from TEMSO. The 7mg dose showed a significant but smaller effect on relapse rate (22% reduction) without significant effect on disability progression. The safety profile was consistent with previous studies.
Major Points
- Second large phase 3 placebo-controlled trial confirming teriflunomide efficacy in relapsing MS
- Teriflunomide 14mg reduced ARR by 36.3% vs placebo (P=0.0001)
- Teriflunomide 7mg reduced ARR by 22.3% vs placebo (P=0.0183)
- Only 14mg dose showed significant reduction in 12-week sustained disability (HR 0.68, P=0.0442)
- 70% of patients completed the study; 67% completed on study treatment
- No MRI endpoints included (based on robust TEMSO MRI data)
- Four deaths occurred, none considered related to study drug
- Pooled TEMSO+TOWER analysis confirmed significant disability benefit for 14mg dose
- Safety profile consistent with TEMSO: elevated ALT, hair thinning, GI symptoms most common
Study Design
- Study Type
- Phase 3, international, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; treating neurologist responsible for assessment and adverse event recording; examining neurologist certified in Neurostatus assigned EDSS scores
- Sample Size
- 1169
- Follow-up
- Variable; ending 48 weeks after last patient randomized (median 581-588 days)
- Centers
- 189
- Countries
- 26 countries including Western Europe, Tunisia, Eastern Europe, Americas, Asia, Australia
Primary Outcome
Definition: Annualized relapse rate (number of protocol-defined relapses per patient-year); relapse defined as new/worsening symptoms lasting ≥24h with EDSS functional system score increase
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.50 (95% CI 0.43-0.58) | - | - | 0.0183 (7mg), 0.0001 (14mg) vs placebo |
Limitations & Criticisms
- No MRI endpoints included, limiting assessment of subclinical disease activity
- 30% of patients discontinued study treatment before study end
- 7mg dose did not achieve significant disability progression reduction
- Variable treatment duration (dependent on enrollment timing) complicates interpretation
- Protocol-mandated discontinuation for elevated ALT/neutropenia may overestimate true discontinuation rates
- Exclusion of patients with prior natalizumab or immunosuppressant use limits generalizability
- Higher proportion of treatment-naive patients compared to typical clinical practice
- Four deaths occurred (though none attributed to study drug)
Citation
Lancet Neurol 2014;13:247-256