Teriflunomide compared to placebo for multiple sclerosis

Patient or population: people with relapsing multiple sclerosis
Settings: US, Austria, France, Canada, Germany, UK, Sweden, Netherlands, Turkey, Poland, Chile, Ukraine, China, Italy, Australia, etc.
Intervention: teriflunomide at a dose of 14 mg orally once daily
Comparison: placebo

Proportion of participants with at least 1 relapse at 1 year
Follow‐up: 1 year

RR 0.60
(0.48 to 0.75)

761
(1 study)

⊕⊕⊝⊝
low^a

This outcome was considered low, because we considered there were very serious limitation in study design and execution. The bias that influenced the validity of the results for this outcome included: the high risks of bias due to unblinded assessments for relapse and conflicts of interest (sensitivity analysis according to a likely‐case scenario showed a robustness for the results of this outcome, we considered that the high attrition bias did not influence the robustness of the results on relapse). Therefore, we downgraded the quality of evidence for this outcome by 2 levels

The proportion of participants with at least 1 relapse at 2 years
Follow‐up: 2 years

RR 0.80
(0.69 to 0.93)

722
(1 study)

⊕⊕⊝⊝
low^b

This outcome was considered low, because we considered there were very serious limitation in study design and execution. The bias that influenced the validity of the results for this outcome included: the high risks of bias due to unblinded assessments for relapse and conflicts of interest. (Sensitivity analysis according to a likely‐case scenario showed a robustness for the results of this outcome, we considered that the unclear attrition bias did not influence the robustness of the results on relapse.) Therefore, we downgraded the quality of evidence for this outcome by 2 levels

The proportion of participants with disability progression at 1 year
Follow‐up: 1 year

RR 0.55
(0.36 to 0.84)

761
(1 study)

⊕⊝⊝⊝
very low^c,e

This outcome was considered very low based on the following reasons:

• we considered there were very serious limitation in study design and execution. The bias that influenced the validity of the results for this outcome included: the high risks of bias due to the high attrition bias and conflicts of interest. Sensitivity analysis according to a likely‐case scenario showed an unsteadiness for the results of this outcome, we considered that the high attrition bias influenced the robustness of the results on progression disability. Therefore, we downgraded the quality of evidence for this outcome by 2 levels

• This outcome was an indirect outcome because disability progression was confirmed at 3 months of follow‐up. We had serious doubts about directness. Therefore, we downgraded the quality of evidence for this outcome by 1 level

The proportion of participants with disability progression at 2 years
Follow‐up: 2 years

RR 0.74
(0.56 to 0.96)

722
(1 study)

⊕⊝⊝⊝
very low^d,e

This outcome was considered very low based on the following reasons:

• We considered there were very serious limitation in study design and execution. The bias that influenced the validity of the results for this outcome included: the high risks of bias due to unclear attrition bias and conflicts of interest. Sensitivity analysis according to a likely‐case scenario showed an unsteadiness for the results of this outcome, we considered that the unclear attrition bias influenced the robustness of the results on progression disability. Therefore, we downgraded the quality of evidence for this outcome by 2 levels

• This outcome was an indirect outcome because disability progression was confirmed at 3 months of follow‐up. We had serious doubts about directness. Therefore, we downgraded the quality of evidence for this outcome by 1 level

The proportion of participants with diarrhoea at 2 years
Follow‐up: 2 years

RR 2.01
(1.35 to 3.00)

718
(1 study)

⊕⊕⊕⊝
moderate^f

The follow‐up periods were diverse in Confavreux 2014 and O'Connor 2011 (at least 48 weeks (Confavreux 2014) and 108 weeks (O'Connor 2011)). Treatment duration of participants in Confavreux 2014 was variable, ending 48 weeks after the last participant was included (a maximum treatment duration of 173 weeks). Actually, the data on adverse events in Confavreux 2014 were not at 2 years. There was a heterogeneity in follow‐up period between the studies. Therefore, we did not combine the data on adverse events in Confavreux 2014 and O'Connor 2011

The proportion of participants with hair thinning at 2 years
Follow‐up: 2 years

RR 3.94
(2.13 to 7.30)

718
(1 study)

⊕⊕⊕⊝
moderate^f

The follow‐up periods were diverse in Confavreux 2014 and O'Connor 2011 (at least 48 weeks (Confavreux 2014) and 108 weeks (O'Connor 2011)). Treatment duration of participants in Confavreux 2014 was variable, ending 48 weeks after the last participant was included (a maximum treatment duration of 173 weeks). Actually, the data on adverse events in Confavreux 2014 were not at 2 years. There was a heterogeneity in follow‐up period between the studies. Therefore, we did not combine the data on adverse events in Confavreux 2014 and O'Connor 2011

The proportion of participants with elevated ALT levels at 2 years
Follow‐up: 2 years

RR 2.14
(1.35 to 3.39)

718
(1 study)

⊕⊕⊕⊝
moderate^f

The follow‐up periods were diverse in Confavreux 2014 and O'Connor 2011 (at least 48 weeks (Confavreux 2014) and 108 weeks (O'Connor 2011)). Treatment duration of participants in Confavreux 2014 was variable, ending 48 weeks after the last participant was included (a maximum treatment duration of 173 weeks). Actually, the data on adverse events in Confavreux 2014 were not at 2 years. There was a heterogeneity in follow‐up period between the studies. Therefore, we did not combine the data on adverse events in Confavreux 2014 and O'Connor 2011

*The basis for assumed risk is the placebo group risk. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
ALT: alanine aminotransferase; CI: confidence interval; RR: risk ratio.

The assumed risk was defined as placebo group risk because only one study was evaluated.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.