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TERIS

Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial

Year of Publication: 2023

Authors: Christine Lebrun-Frénay, Aksel Siva, Maria Pia Sormani, ..., Daniel Pelletier

Journal: JAMA Neurology

Citation: JAMA Neurol. 2023;80(10):1080-1088

Clinical Question

Does treatment with teriflunomide delay the time to onset of symptoms consistent with multiple sclerosis in patients with radiologically isolated syndrome?

Study Overview

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

Teriflunomide significantly extended time to first clinical MS event
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

Patients per Arm

44 teriflunomide, 45 placebo

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

      

Design

Study Type: Multicenter, double-blind, phase 3, randomized controlled trial

Randomization: 1

Blinding: Double-blind with identical medication, placebo tablets, and packaging

Enrollment Period: September 2017 to October 2020

Follow-up Duration: 96 weeks with optional extension to 144 weeks

Centers: 21

Countries: France, Switzerland, Turkey

Sample Size: 89

Analysis: Intention-to-treat analysis using Cox proportional-hazards regression models; Kaplan-Meier survival curves; SAS software version 9.4 and R version 4.1.3

Inclusion Criteria

Age older than 18 years
Fulfillment of 2009 RIS criteria with structural neuroimaging abnormalities not explained by another disease process
No historical accounts of remitting clinical symptoms consistent with neurologic dysfunction
Written informed consent

Exclusion Criteria

Severe hepatic, kidney, and immune system impairments
Lactating or pregnant women
Previous exposure to immunosuppressive or disease-modifying therapy
Individuals of reproductive potential not meeting teriflunomide use guidelines

Arms

Field	Teriflunomide	Control
Intervention	Oral teriflunomide 14 mg daily up to week 96 or optionally to week 144	Matching placebo tablets daily up to week 96 or optionally to week 144
Duration	96 weeks with optional extension to 144 weeks	96 weeks with optional extension to 144 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to first acute or progressive neurologic event resulting from CNS demyelination, expressed as rate of conversion to clinical MS	Primary	20/45 (44.4%) developed clinical events	8/44 (18.2%) developed clinical events	0.37	0.02
Cumulative number of new/newly enlarging T2 lesions	Secondary	3.04 (95% CI 1.81-5.09)	1.49 (95% CI 0.82-2.69)	Adjusted RR 0.57 (95% CI 0.27-1.20)	0.14
Cumulative number of new gadolinium-enhancing lesions	Secondary	0.50 (95% CI 0.25-1.00)	0.22 (95% CI 0.09-0.55)	Adjusted RR 0.33 (95% CI 0.09-1.37)	0.09
Proportion with new/newly enlarging T2 lesions	Secondary	24/37 (64.9%)	20/34 (58.8%)	Adjusted OR 0.72 (95% CI 0.25-2.06)	0.54
Proportion with new gadolinium-enhancing lesions	Secondary	12/36 (33.3%)	5/33 (15.1%)	Adjusted OR 0.28 (95% CI 0.07-1.13)	0.07
T2 lesion volume (annualized % change, median [range])	Secondary	0.95 (17.121 to 406.6) (n=37)	1.14 (15.0 to 67.3) (n=35)	Unadjusted median difference 0.19	0.94 unadjusted; 0.90 adjusted
Severe COVID-19 infection	Adverse	0	1 (possibly related to drug)		Not specified
Gastrointestinal disorders	Adverse	Not specified	5/44 (11.4%)		Not specified
Dysmenorrhea	Adverse	Not specified	4/44 (9.1%)		Not specified
Benign respiratory infections	Adverse	Not specified	3/44 (6.8%)		Not specified
General disorders/conditions	Adverse	Not specified	3/44 (6.8%)		Not specified
Transient transaminase increase	Adverse	Not specified	2/44 (4.5%)		Not specified
Treatment-ending adverse events	Adverse	Grade 2 diarrhea; Grade 1 scabies	Grade 3 neutropenia		All events resolved after treatment discontinuation

Subgroup Analysis

Adjusted model controlled for sex, age at RIS diagnosis, MS family history, EDSS score, T2-weighted hyperintense lesion volume (log transformed), and presence of gadolinium-enhancing lesions at baseline

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

Funding

Supported by Sanofi, The University Hospital of Nice, University Cote d'Azur, and the Radiologically Isolated Syndrome Consortium

Based on: TERIS (JAMA Neurology, 2023)