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TEMSO

Teriflunomide Multiple Sclerosis Oral (TEMSO) Trial - Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis

Year of Publication: 2011

Authors: Paul O'Connor, Jerry S. Wolinsky, Christian Confavreux, ..., for the TEMSO Trial Group

Journal: New England Journal of Medicine

Citation: N Engl J Med 2011;365:1293-303

Clinical Question

Does oral teriflunomide reduce relapse rates and disability progression in patients with relapsing multiple sclerosis compared to placebo?

Bottom Line

Teriflunomide at both 7mg and 14mg significantly reduced annualized relapse rate by approximately 31% compared to placebo. The 14mg dose also significantly reduced disability progression by 30%. Both doses improved MRI outcomes with an acceptable safety profile including elevated ALT, hair thinning, and GI symptoms.

        Major Points
        First phase 3 trial demonstrating efficacy of oral teriflunomide in relapsing MS
Both doses (7mg and 14mg) achieved identical 31% reduction in annualized relapse rate (0.37 vs 0.54, P<0.001)
Only the 14mg dose showed significant reduction in 12-week sustained disability progression (HR 0.70, P=0.03)
Significant MRI benefits including 67% reduction in total lesion volume change with 14mg dose
Gadolinium-enhancing lesions reduced by 80% with 14mg dose vs placebo
No deaths occurred during the 108-week study period
Serious infections were similar across groups (1.6-2.5%)
Hair thinning and elevated ALT were more common with teriflunomide but rarely led to discontinuation

      

Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind; treating neurologist aware of potential side effects but not treatment assignment, examining neurologist blinded to all clinical information

Enrollment Period: September 24, 2004 to March 13, 2008

Follow-up Duration: 108 weeks

Centers: 127

Countries: 21 countries including Western Europe, Eastern Europe, Americas

Sample Size: 1088

Analysis: Modified intention-to-treat (patients randomized and exposed to study medication for ≥1 day); Poisson regression for relapse rate; Cox proportional hazards for disability progression; two-sided 5% significance level

Inclusion Criteria

Age 18-55 years
Multiple sclerosis meeting McDonald criteria
Relapsing clinical course (with or without progression)
EDSS score ≤5.5
At least 2 clinical relapses in previous 2 years OR at least 1 relapse in previous year
No relapses in the 60 days before randomization

Exclusion Criteria

Other systemic diseases
Pregnant or planned to conceive during trial period

Arms

Field	Control	Teriflunomide 7mg	Teriflunomide 14mg
Intervention	Oral placebo once daily	Oral teriflunomide 7mg once daily	Oral teriflunomide 14mg once daily
Duration	108 weeks	108 weeks	108 weeks

Outcomes

Outcome	Type	Control	HR / OR / RR	P-value
Annualized relapse rate (number of confirmed relapses per patient-year); relapse defined as new/worsening clinical sign lasting ≥24h without fever, confirmed by EDSS functional system score increase	Primary	0.54 (95% CI 0.47-0.62)		<0.001 for both doses vs placebo
Sustained disability progression (≥12 weeks)	Secondary	27.3%	HR 0.76 (7mg), HR 0.70 (14mg)	0.08 (7mg), 0.03 (14mg)
Patients relapse-free at 108 weeks	Secondary	45.6%	HR 0.76 (7mg), HR 0.72 (14mg)	0.01 (7mg), 0.003 (14mg)
Change in total lesion volume (ml)	Secondary	2.21 ± 7.00		0.03 (7mg), <0.001 (14mg)
Gadolinium-enhancing lesions per scan	Secondary	1.33		<0.001 for both
Absence of Gd-enhancing lesions	Secondary	39.0%		<0.001 for both
Change in FIS score from baseline	Secondary	4.3 ± 1.7		0.39 (7mg), 0.83 (14mg) - NS
Any adverse event	Adverse	87.5%
Serious adverse event	Adverse	12.8%
Discontinuation due to AE	Adverse	8.1%
Diarrhea	Adverse	8.9%
Nausea	Adverse	7.2%
Hair thinning	Adverse	3.3%
Elevated ALT (≥1x ULN)	Adverse	35.9%
Elevated ALT (≥3x ULN)	Adverse	6.7%
Serious infections	Adverse	2.2%

Subgroup Analysis

Rates of relapse were higher for patients who entered the trial early vs late in recruitment; the treatment effect remained consistent across subgroups. No significant difference in fatigue outcomes between groups.

Criticisms

Study population slightly higher disease activity compared to other recent oral DMT trials
No MRI-only outcome as primary endpoint
7mg dose did not achieve significant disability progression reduction
Long-term safety beyond 108 weeks requires extension study data
Higher dropout rate (27%) though similar across groups
Limited diversity in study population (>96% White)
No active comparator arm

Funding

Sanofi-Aventis

Based on: TEMSO (New England Journal of Medicine, 2011)

Authors: Paul O'Connor, Jerry S. Wolinsky, Christian Confavreux, ..., for the TEMSO Trial Group

Citation: N Engl J Med 2011;365:1293-303

Content summarized and formatted by NeuroTrials.ai.

TEMSO

(2011)

Objective

To evaluate the efficacy and safety of teriflunomide in reducing the frequency of relapses and progression of physical disability in patients with relapsing multiple sclerosis

Study Summary

• Teriflunomide 7mg and 14mg both significantly reduced annualized relapse rate by 31% vs placebo (0.37 vs 0.54, P<0.001)
• Teriflunomide 14mg significantly reduced 12-week sustained disability progression by 30% (HR 0.70, P=0.03)
• Both doses showed significant improvement in MRI outcomes with no deaths reported

Intervention

Oral teriflunomide 7mg or 14mg once daily vs placebo for 108 weeks

Inclusion Criteria

Age 18-55, relapsing MS (McDonald criteria), EDSS ≤5.5, ≥1 relapse in prior year or ≥2 in prior 2 years, no relapse within 60 days of randomization

Study Design

Arms: Placebo vs Teriflunomide 7mg vs Teriflunomide 14mg (1:1:1)

Patients per Arm: Placebo: 363, Teriflunomide 7mg: 366, Teriflunomide 14mg: 359

Outcome

• Primary: ARR 0.54 (placebo) vs 0.37 (7mg, 31.2% reduction, P<0.001) vs 0.37 (14mg, 31.5% reduction, P<0.001)
• Disability progression at 12 weeks: 27.3% (placebo) vs 21.7% (7mg, P=0.08) vs 20.2% (14mg, P=0.03)
• Gadolinium-enhancing lesions reduced by 57% (7mg) and 80% (14mg) vs placebo

Bottom Line

Major Points

First phase 3 trial demonstrating efficacy of oral teriflunomide in relapsing MS
Both doses (7mg and 14mg) achieved identical 31% reduction in annualized relapse rate (0.37 vs 0.54, P<0.001)
Only the 14mg dose showed significant reduction in 12-week sustained disability progression (HR 0.70, P=0.03)
Significant MRI benefits including 67% reduction in total lesion volume change with 14mg dose
Gadolinium-enhancing lesions reduced by 80% with 14mg dose vs placebo
No deaths occurred during the 108-week study period
Serious infections were similar across groups (1.6-2.5%)
Hair thinning and elevated ALT were more common with teriflunomide but rarely led to discontinuation

Study Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial
Randomization: Yes
Blinding: Double-blind; treating neurologist aware of potential side effects but not treatment assignment, examining neurologist blinded to all clinical information
Sample Size: 1088
Follow-up: 108 weeks
Centers: 127
Countries: 21 countries including Western Europe, Eastern Europe, Americas

Primary Outcome

Definition: Annualized relapse rate (number of confirmed relapses per patient-year); relapse defined as new/worsening clinical sign lasting ≥24h without fever, confirmed by EDSS functional system score increase

Control	Intervention	HR/OR	P-value
0.54 (95% CI 0.47-0.62)	-	-	<0.001 for both doses vs placebo

Limitations & Criticisms

Study population slightly higher disease activity compared to other recent oral DMT trials
No MRI-only outcome as primary endpoint
7mg dose did not achieve significant disability progression reduction
Long-term safety beyond 108 weeks requires extension study data
Higher dropout rate (27%) though similar across groups
Limited diversity in study population (>96% White)
No active comparator arm

Citation

N Engl J Med 2011;365:1293-303

View Original Publication →

TEMSO

Teriflunomide Multiple Sclerosis Oral (TEMSO) Trial - Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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