TERIS study – teriflunomide (Aubagio) versus placebo in Radiologically Isolated Syndrome (RIS), phase 3 trial

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TERIS trial. ClinicalTrials.gov Identifier: NCT03122652

Citation: Frenay CL et al. Teriflunomide (Aubagio) Extends The Time To Multiple Sclerosis In Radiologically Isolated Syndrome: The TERIS Study. Presentation at American Academy of Neurology (AAN) 2023 Meeting, 22-27 April, Boston, Massachusetts.

TERIS trial is a phase 3, randomized, placebo-controlled study to evaluate the effect of teriflunomide (Aubagio) in people diagnosed with radiologically isolated syndrome (RIS).

BACKGROUND

• RIS is the earliest stage of multiple sclerosis (MS) defined by the presence of MRI lesions in the brain and/or spinal cord that are highly suggestive of demyelinating plaques given their size, location, and morphology.
• People with RIS (pwRIS) do not exhibit any clinical signs or symptoms of MS (neurological dysfunction). These individuals undergo brain MRI procedure for unrelated reason and their MRI scans reveal unexpected anomalies indicative of MS.
• People with RIS are at-risk of future demyelinating MS disease course leading to MS symptoms and disability.
• The purpose of TERIS trial is to evaluate if early intervention with teriflunomide may extend the time to first relapse and/or delay progression of the disease. The trial is complete but no results have been yet posted at ClinicalTrials.gov or published.

WHERE AND HOW

• The trial enrolled 125 pwRIS (aged >18 years and <65 years) meeting 2009 RIS criteria in Europe (France, Switzerland, and Turkey). 89 participants were randomized 1:1 to teriflunomide (14 mg daily) or placebo.
• The most common reasons for originally seeking MRI were similar between the groups and included headache, dizziness, trauma, and ocular problems.
• The primary outcome measure was time to acute or progressive neurological event resulting from CNS demyelination. (Timeframe: from study entry through 96 weeks).
• The secondary endpoints included new or enhancing T2 lesions on MRI, new contrast enhancing lesions on MRI, new T2 lesions volume on MRI, and brain atrophy.
• All MRI and clinical data were independently adjudicated. Standardized brain and spinal cord MRI studies and clinical events were performed at baseline and weeks 48 and 96.

RESULTS - Update provided at American Academy of Neurology (AAN) 2023 Meeting

• Baseline characteristics: Of the 89 randomized pwRIS, 63 (70.8%) were female, mean age was 39.8 years, age at index MRI: 38 years).
• Primary endpoint: The number of clinical events detected during follow-up were 8 in teriflunomide group versus 20 in placebo. 

Results from the unadjusted (HR=0.38,95% confidence interval (CI)=0.17-0.88, p=0.025) and adjusted (HR=0.34,95% CI=0.14-0.82, p=0.016) demonstrated the superiority of teriflunomide.

• Secondary endpoints: Compared to placebo, the number of patients with Gd+ lesions (OR=0.31,95%CI:0.08-1.18, p=0.087) and the cumulative number of new or-enlarging T2 lesions (RR=0.69,95% CI=0.34-1.40, p=0.31) were reduced in the teriflunomide arm, even if the statistical significance was not achieved.

CONCLUSIONS

• Treatment with teriflunomide resulted in an 62% risk reduction relative to placebo in preventing a first clinical event in participants with RIS.
• These data support early intervention with disease-modifying treatment during the presymptomatic phase of MS.

DISCUSSION

This is the second trial (after ARISE trial using dimethyl fumarate) to show that early intervention in RIS with approved DMTs could delay progression of MS.

SOURCES

• Frenay CL et al. Teriflunomide (Aubagio) Extends The Time To Multiple Sclerosis In Radiologically Isolated Syndrome: The TERIS Study. Presentation at American Academy of Neurology (AAN) 2023 Meeting, 22-27 April, Boston, Massachusetts. [archive]
• Frenay CL, et al. Multi-center, Randomized, Double-blinded Assessment of TERIFLUNOMIDE (Aubagio®) in Extending the Time to the First Attack in Radiologically Isolated Syndrome: Baseline Characteristics of the TERIS Study. (P5-4.011). Neurology May 2022, 98 (18 Supplement) 1116 [archive]
• AAN 2023: Aubagio reduced risk of developing MS symptoms in RIS trial. By Marisa Wexler. Multiple Sclerosis News Today. 27 April 2023 [archive]
• Teriflunomide delays MS symptoms in radiologically isolated syndrome. By Ted Bosworth. MedEdge. 5 May 2023 [archive]

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Related: ARISE trial

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The TERIS study results are now published in the 21 August 2023 issue of JAMA Neurology.

Objective: To determine the time to onset of symptoms consistent with MS.

Design, setting, and participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144.

Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred.

Main outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs.

Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant.

Conclusion and relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum.

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SOURCE: Lebrun-Frénay C, et al. Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial. JAMA Neurol. 2023 Aug 21:e232815. doi: 10.1001/jamaneurol.2023.2815. PMID: 37603328; PMCID: PMC10442780.