TOWER
Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER) Trial
Clinical Question
Does oral teriflunomide reduce relapse rates and disability accumulation in patients with relapsing multiple sclerosis compared to placebo?
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
Design
Study Type: Phase 3, international, randomized, double-blind, placebo-controlled trial
Randomization: 1
Blinding: Double-blind; treating neurologist responsible for assessment and adverse event recording; examining neurologist certified in Neurostatus assigned EDSS scores
Enrollment Period: September 17, 2008 to February 17, 2011
Follow-up Duration: 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
Sample Size: 1169
Analysis: Modified intention-to-treat (patients receiving ≥1 dose); Poisson regression with robust error variance for ARR; log-rank test for disability progression with Cox proportional hazards for HR estimation; two-sided 5% significance level
Inclusion Criteria
- Age 18-55 years
- Relapsing multiple sclerosis meeting 2005 McDonald criteria
- Disease with or without underlying progression
- EDSS score ≤5.5
- At least 1 relapse in previous 12 months OR at least 2 relapses in previous 24 months
- No relapse in the 30 days before randomization
Exclusion Criteria
- Other relevant diseases
- Pregnant, breastfeeding, or planned to conceive/father a child during study
- Previous or concomitant cytokine therapy, interferon beta, or glatiramer acetate within 3 months of randomization
- Ever used natalizumab or other immunosuppressive agents
Arms
| Field | Control | Teriflunomide 7mg | Teriflunomide 14mg |
|---|---|---|---|
| Intervention | Oral placebo once daily (identical in taste and appearance to active drug) | Oral teriflunomide 7mg once daily | Oral teriflunomide 14mg once daily |
| Duration | Until 48 weeks after last patient randomized (median 581 days) | Until 48 weeks after last patient randomized (median 556 days) | Until 48 weeks after last patient randomized (median 588 days) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| 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 | Primary | 0.50 (95% CI 0.43-0.58) | 0.0183 (7mg), 0.0001 (14mg) vs placebo | ||
| Time to 12-week sustained disability accumulation (key secondary) | Secondary | Reference | See above | 0.7620 (7mg), 0.0442 (14mg) | |
| Proportion relapse-free at 48 weeks | Secondary | 60.6% | HR 0.70 (7mg), HR 0.63 (14mg) | 0.0016 (7mg), <0.0001 (14mg) | |
| Proportion free from sustained disability at 48 weeks | Secondary | 85.8% | |||
| Proportion free from sustained disability at 108 weeks | Secondary | 80.3% | |||
| Change in EDSS score from baseline to week 48 | Secondary | +0.09 | 0.4819 (7mg), 0.0429 (14mg) | ||
| Change in SF-36 mental health summary (last visit) | Secondary | -2.79 | 0.1363 (7mg), 0.0224 (14mg) | ||
| Change in FIS score (last visit) | Secondary | +6.31 | 0.3686 (7mg), 0.0429 (14mg) | ||
| Any adverse event | Adverse | 83% | |||
| Serious adverse event | Adverse | 12% | |||
| Permanent treatment discontinuation due to AE | Adverse | 6% | |||
| Death | Adverse | 1 (<1%) | |||
| ALT increased | Adverse | 8% | |||
| ALT >1x ULN | Adverse | 39% | |||
| ALT >3x ULN | Adverse | 6% | |||
| Hair thinning | Adverse | 4% | |||
| Headache | Adverse | 11% | |||
| Diarrhea | Adverse | 7% | |||
| Neutropenia | Adverse | 3% | |||
| Neutrophil count <1.5x10^9/L | Adverse | 7% | |||
| Any infection | Adverse | 51% | |||
| Serious infection | Adverse | 3% | |||
| Hypertension | Adverse | 2% | |||
| Peripheral neuropathy (confirmed) | Adverse | 1% |
Subgroup Analysis
No detailed subgroup analyses reported in main publication. Pooled TEMSO+TOWER analysis confirmed efficacy of teriflunomide 14mg on both ARR and sustained disability accumulation.
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)
Funding
Genzyme, a Sanofi company
Based on: TOWER (The Lancet Neurology, 2014)
Authors: Christian Confavreux, Paul O'Connor, Giancarlo Comi, ..., for the TOWER Trial Group
Citation: Lancet Neurol 2014;13:247-256
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