Monday, 22 September 2014

Treatment as Onset can slow development of MS

Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, Bauer D, Benamor M, Truffinet P, O'Connor PW; for the TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis(TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 . pii: S1474-4422(14)70191-7

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, 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 (19% 14mg, [17% in 7 mg group vs 14% in the placebo group), hair thinning (12% 14mg/ 6% 7mg/8% placebo), diarrhoea (11%/14%/ vs 6% placebo), 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.

ProfG or NeuroDocG may comment on this further but this trial reports on the effect of giving aubagio (teriflunamide). In this study aubagio was given to people with clinically isolated syndrome and reduced the risk of getting additional attacks and converting to MS by about 40%, The risks were associated with digestive problems and hair thinning. Aubagio is similar in activity to the beta interferons but have the advantage of being a pill. In UK treatment at CIS needs evidence of disease being MS, suvh as with MRI lesions. However, this current study shows that if you treat early then you can have an therapeutic effect, however we can do better. This is not the first study of an oral effective agent in clinically isolated syndrome as movectro, which was temporary available in Australia and Russia was tested and slowed the conversion rate by about 70%. Therefore one may suspect that the "available" DMT that are more effective than aubagio may have greater efficacy however it is up to the manufacturers to prove it.

CoI: None

1 comment:

  1. Thank you MouseDoctor. Despite being the first line oral therapy approved in MS in the UK, I'd like to remind our readers that Avonex (CHAMPS) study achieved a 44% reduction in conversion to clinically definite MS (CDMS), whilst Betaferon (BENEFIT) reduced the risk of CDMS by 41%. Also these are not head to head comparisons!

    MouseDoctor the key here is early treatment and I want be the first or the last neurologist to tout this; we should all stop being 'nancy pansies'. Although approved by NICE and NHS England - Aubagio/terflunomide's achilles heel is the monthly blood tests for the first six months - which is a tall feet in an a cash/resource strapped NHS. Maybe Genzyme can offer something here? cf. JCV testing by Biogen for natalizumab. If we wait longer BG-12 may even receive its NHS England go ahead, and is much easier to institute!


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