TOPIC

Teriflunomide

TOPIC tested early teriflunomide after a first demyelinating event and delayed a relapse defining clinically definite MS.

Phase: Phase III
Population: First clinical episode suggestive of multiple sclerosis (CIS)
Controlled period: Feb 2008 — Dec 2012

What was compared

RandomizedDouble-blindPlacebo-controlled112 centers

Intervention

Teriflunomide 14 mg

Orally once daily

n=216

Comparator

Placebo

Matching oral tablet once daily

n=197

Additional randomized arm

Teriflunomide 7 mg

Orally once dailyn=205

618 randomizedUp to 108 weeks controlled phase

Primary endpoint

Prespecified outcome

Time to relapse defining clinically definite MS

Up to 108 weeks

Outcome figure

Primary endpoint results

Intervention Comparator or reference

Risk of relapse defining clinically definite MS

Hazard ratio (95% CI)

Up to 108 weeks

Teriflunomide 14 mg vs placebo0.574 (0.379–0.869)

Teriflunomide 7 mg vs placebo0.628 (0.416–0.949)

Risk reductions were significant for 14 mg (P=0.0087) and 7 mg (P=0.0271).

Selected secondary outcomes

Relapse or new MRI lesion

HR 0.651 with 14 mg and 0.686 with 7 mg versus placebo.

Who was studied

Key inclusion criteria

Age 18–55 years
Clinically isolated syndrome: first acute or subacute neurologic event consistent with demyelination
Event within 90 days before randomization
At least 2 characteristic T2 lesions, each at least 3 mm in diameter

Key exclusion criteria

Pregnancy, breastfeeding, or plans to conceive
Clinically relevant coexisting disease
ACTH or systemic corticosteroids within 2 weeks
Previous interferon, cytokine therapy, glatiramer acetate, intravenous immunoglobulin, natalizumab, other immunosuppressants, or leflunomide

Participants at baseline

Characteristic	Teriflunomide 14 mgN=216	Teriflunomide 7 mgN=205	PlaceboN=197
Age, years — mean ± SD	32.8 ± 8.1	31.6 ± 9.0	32.0 ± 8.4
Female sex — n (%)	154 (71%)	130 (63%)	135 (69%)
Time since neurological event, months — mean ± SD	1.80 ± 0.56	1.89 ± 0.56	1.88 ± 0.52
EDSS — mean ± SD	1.80 ± 0.97	1.50 ± 1.02	1.71 ± 1.00
Monofocal onset presentation — n (%)	129 (60%)	122 (60%)	114 (58%)
Gadolinium-enhancing T1 lesions present — n (%)	70 (32%)	66 (32%)	58 (29%)
Previous systemic corticosteroid therapy — n (%)	37 (17%)	21 (10%)	35 (18%)

SD: standard deviation; EDSS: Expanded Disability Status Scale.

Source: Miller et al., Lancet Neurology 2014, Table 1

Safety signal

Liver-enzyme elevation, hair thinning, diarrhea, paresthesia, and upper-respiratory infection were more frequent in at least one teriflunomide group.
Increased alanine aminotransferase (ALT) was the only adverse event leading to permanent treatment discontinuation in more than 2% of participants in any group: 4% with teriflunomide 14 mg, 5% with 7 mg, and 5% with placebo.

Why it mattered

TOPIC showed that oral teriflunomide could delay a second clinical event defining clinically definite MS after a first demyelinating episode. It supported studying treatment early in the disease course, while later diagnostic criteria changed which patients would already qualify for an MS diagnosis at entry.

Important limitation

The conversion endpoint reflects the diagnostic framework of its era; later McDonald criteria may classify some comparable patients as having MS at baseline.