ArticlesOral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial
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
References (25)
- et al.
Clinically isolated syndromes
Lancet Neurol
(2012) - et al.
Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study
Lancet
(2001) - et al.
Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial
Lancet
(2004) - et al.
Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial
Lancet Neurol
(2012) - et al.
Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial
Lancet
(2009) - et al.
Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study
Lancet
(2007) - et al.
Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial
Lancet Neurol
(2009) - et al.
Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet Neurol
(2014) Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials
Neurology
(2011)- et al.
Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group
N Engl J Med
(2000)