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Oral Teriflunomide: benefits of an oral disease-modifying therapy for patients with a first clinical episode suggestive of multiple sclerosis


Teriflunomide ( Aubagio ) is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis.

Researchers have assessed the efficacy and safety of Teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis.

In this randomised, double-blind, placebo-controlled, parallel-group study ( TOPIC trial ), 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 were enrolled.

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 greater than or equal to 30 days from a preceding clinical event, present for greater than or equal to 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.

During the period 2008-2012, 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% ] ).

TOPIC is 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. ( Xagena )

Miller AR et al, Lancet Neurology 2014; 13: 977–986

XagenaMedicine_2014



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