TERIS
(2023)Objective
Teriflunomide - To determine the time to onset of symptoms of multiple sclerosis in patients with radiologically isolated syndrome treated with teriflunomide versus placebo
Study Summary
• 63% unadjusted and 72% adjusted risk reduction compared to placebo
• Secondary MRI outcomes showed numerical improvements but not statistically significant
Intervention
Double-blind, randomized 1:1 trial of oral teriflunomide 14mg daily versus placebo in patients with radiologically isolated syndrome, with 96-week follow-up and optional extension to 144 weeks
Inclusion Criteria
Age >18 years, fulfillment of 2009 RIS criteria with structural neuroimaging abnormalities not explained by another disease, no historical accounts of remitting clinical symptoms consistent with neurologic dysfunction
Study Design
Arms: Teriflunomide 14mg daily (n=44) vs Placebo (n=45)
Patients per Arm: 44 teriflunomide, 45 placebo
Outcome
• Adjusted HR 0.28 (95% CI 0.11-0.71, P=0.007)
• 8/44 (18.2%) teriflunomide vs 20/45 (44.4%) placebo developed clinical events
Bottom Line
Treatment with teriflunomide resulted in a 63% unadjusted and 72% adjusted risk reduction in preventing a first clinical demyelinating event in patients with radiologically isolated syndrome compared to placebo, suggesting benefit to early treatment in the MS disease spectrum.
Major Points
- Multicenter, double-blind, phase 3 randomized trial of 89 participants with radiologically isolated syndrome
- Significant extension of time to first clinical event with teriflunomide (HR 0.37, 95% CI 0.16-0.84, P=0.02)
- Adjusted analysis showed even greater benefit (HR 0.28, 95% CI 0.11-0.71, P=0.007)
- 18.2% of teriflunomide patients vs 44.4% of placebo patients developed clinical events
- Secondary MRI outcomes showed numerical improvements but did not reach statistical significance
- 20% dropout rate, balanced between groups, with safety profile consistent with known teriflunomide effects
Study Design
- Study Type
- Multicenter, double-blind, phase 3, randomized controlled trial
- Randomization
- Yes
- Blinding
- Double-blind with identical medication, placebo tablets, and packaging
- Sample Size
- 89
- Follow-up
- 96 weeks with optional extension to 144 weeks
- Centers
- 21
- Countries
- France, Switzerland, Turkey
Primary Outcome
Definition: Time to first acute or progressive neurologic event resulting from CNS demyelination, expressed as rate of conversion to clinical MS
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 20/45 (44.4%) developed clinical events | 8/44 (18.2%) developed clinical events | 0.37 (0.16-0.84) | 0.02 |
Limitations & Criticisms
- Study was prematurely discontinued by sponsor due to slow enrollment and COVID-19 pandemic impact
- Sample size smaller than originally planned (89 vs intended larger cohort)
- Could not stratify at-risk subgroups according to known risk factors due to insufficient power
- Secondary MRI measures did not achieve statistical significance, possibly due to switch-to-treatment effect
- 20% dropout rate, though balanced between groups
- Limited generalizability due to premature termination and enrollment challenges
- Could not analyze impact of oligoclonal bands as not included in statistical analysis plan
Citation
JAMA Neurol. 2023;80(10):1080-1088