Elsevier

The Lancet Neurology

Volume 13, Issue 10, October 2014, Pages 977-986
The Lancet Neurology

Articles
Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1474-4422(14)70191-7Get rights and content

Summary

Background

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis.

Methods

In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18–55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700.

Findings

Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379–0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416–0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515–0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540–0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]).

Interpretation

TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect.

Funding

Genzyme, a Sanofi company.

Introduction

The onset of multiple sclerosis is usually signified by a clinical event, consisting of an episode of neurological symptoms and signs called the clinically isolated syndrome.1 Despite this first clinical recognition of a disease process, many patients with clinically isolated syndrome might have already experienced subclinical disease activity as evident on their first MRI scan, which can show lesions in many areas of the brain or spinal cord. Substantial evidence from clinical studies indicates that early treatment of patients with clinically isolated syndrome with injectable disease-modifying therapy delays the development of a second clinical attack or progression of multiple sclerosis, or what has been referred to as clinically definite multiple sclerosis2, 3, 4, 5, 6, 7, 8, 9 and that, in the longer term, patients benefit from early versus delayed treatment.10, 11, 12, 13, 14 However, to convince patients to receive an injectable therapy after only their first clinical event suggestive of multiple sclerosis can be difficult, and so the availability of an effective oral therapy might offer an advance for the treatment of clinically isolated syndrome.

Teriflunomide is a once-daily oral immunomodulator that is approved for the treatment of relapsing-remitting multiple sclerosis. Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, a key mitochondrial enzyme in the de-novo pyrimidine synthesis pathway needed by rapidly dividing lymphocytes.15 In pivotal phase 3 trials in patients with relapsing forms of multiple sclerosis (TEMSO [ClinicalTrials.gov identifier NCT00134563] and TOWER [ClinicalTrials.gov identifier NCT00751881\]), teriflunomide consistently reduced relapses and disability progression as measured by the Expanded Disability Status Scale (EDSS).16, 17 Teriflunomide was also better than placebo on some MRI parameters.16, 18

We report the results of the TOPIC study, in which we assessed the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis.

Section snippets

Study design and participants

TOPIC was a randomised, double-blind, placebo-controlled, parallel-group study that recruited patients from 112 centres (mostly hospitals) in 20 countries. A full list of the countries is available in the appendix. Eligible patients were 18–55 years of age with clinically isolated syndrome, defined as a first acute or subacute neurological event consistent with demyelination (optic neuritis, spinal cord syndrome, or brainstem or cerebellar syndromes) occurring within 90 days before

Results

We enrolled participants into the trial between Feb 13, 2008, and Aug 22, 2012. Of 846 screened participants, 618 were eligible for inclusion and were randomly assigned, 614 of whom received their assigned treatment and were included in the modified intention-to-treat analysis. Of the other four patients, three were in the screening phase when the study was stopped so directly entered the extension phase, and one other patient did not wish to contiue the trial. 214 patients received

Discussion

The risk of relapse indicating conversion to clinically definite multiple sclerosis was significantly reduced following treatment with teriflunomide. The 14 mg dose had greater efficacy than placebo, and was also associated with a significant reduction in occurrence of relapses or MRI lesions, and a significant reduction in total lesion volume and number of gadolinium-enhancing T1 lesions. These beneficial effects are consistent with the favourable outcomes reported in teriflunomide studies in

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