Abstract
Background
This is an update of the Cochrane review “Teriflunomide for multiple sclerosis” (first published in The Cochrane Library 2012, Issue 12).
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. It is clinically characterized by recurrent relapses or progression, or both, often leading to severe neurological disability and a serious decline in quality of life. Disease-modifying therapies (DMTs) for MS aim to prevent occurrence of relapses and disability progression. Teriflunomide is a pyrimidine synthesis inhibitor approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a DMT for adults with relapsing-remitting MS (RRMS).
Objectives
To assess the absolute and comparative effectiveness and safety of teriflunomide as monotherapy or combination therapy versus placebo or other disease-modifying drugs (DMDs) (interferon beta (IFNβ), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, dimethyl fumarate, alemtuzumab) for modifying the disease course in people with MS.
Search methods
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Specialised Trials Register (30 September 2015). We checked reference lists of published reviews and retrieved articles and searched reports (2004 to September 2015) from the MS societies in Europe and America. We also communicated with investigators participating in trials of teriflunomide and the pharmaceutical company, Sanofi-Aventis.
Selection criteria
We included randomized, controlled, parallel-group clinical trials with a length of follow-up of one year or greater evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or other approved DMDs for people with MS without restrictions regarding dose, administration frequency and duration of treatment.
Data collection and analysis
We used the standard methodological procedures of Cochrane. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. We contacted the principal investigators of included studies for additional data or confirmation of data.
Main results
Five studies involving 3231 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFNβ, versus placebo or IFNβ-1a for adults with relapsing forms of MS and an entry Expanded Disability Status Scale score of less than 5.5.
Overall, there were obvious clinical heterogeneities due to diversities in study designs or interventions and methodological heterogeneities across studies. All studies had a high risk of detection bias for relapse assessment and a high risk of bias due to conflicts of interest. Among them, three studies additionally had a high risk of attrition bias due to a high dropout rate and two studies had an unclear risk of attrition bias. The studies of combination therapy with IFNβ (650 participants) and the study with IFNβ-1a as controls (324 participants) also had a high risk for performance bias and a lack of power due to the limited sample.
Two studies evaluated the benefit and the safety of teriflunomide as monotherapy versus placebo over a period of one year (1169 participants) or two years (1088 participants). A meta-analysis was not conducted. Compared to placebo, administration of teriflunomide at a dose of 7 mg/day or 14 mg/day as monotherapy reduced the number of participants with at least one relapse over one year (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.59 to 0.87, P value = 0.001 with 7 mg/day and RR 0.60, 95% CI 0.48 to 0.75, P value < 0.00001 with 14 mg/day) or two years (RR 0.85, 95% CI 0.74 to 0.98, P value = 0.03 with 7 mg/day and RR 0.80, 95% CI 0.69 to 0.93, P value = 0.004 with 14 days). Only teriflunomide at a dose of 14 mg/day reduced the number of participants with disability progression over one year (RR 0.55, 95% CI 0.36 to 0.84, P value = 0.006) or two years (RR 0.74, 95% CI 0.56 to 0.96, P value = 0.02). When taking the effect of drop-outs into consideration, the likely-case scenario analyses still showed a benefit in reducing the number of participants with at least one relapse, but not for the number of participants with disability progression. Both doses also reduced the annualized relapse rate and the number of gadolinium-enhancing T1-weighted lesions over two years. Quality of evidence for relapse outcomes at one year or at two years was low, while for disability progression at one year or at two years was very low.
When compared to IFNβ-1a, teriflunomide at a dose of 14 mg/day had a similar efficacy to IFNβ-1a in reducing the proportion of participants with at least one relapse over one year, while teriflunomide at a dose of 7 mg/day was inferior to IFNβ-1a (RR 1.52, 95% CI 0.87 to 2.67, P value = 0.14; 215 participants with 14 mg/day and RR 2.74, 95% CI 1.66 to 4.53, P value < 0.0001; 213 participants with 7 mg/day). However, the quality of evidence was very low.
In terms of safety profile, the most common adverse events associated with teriflunomide were diarrhoea, nausea, hair thinning, elevated alanine aminotransferase, neutropenia and lymphopenia. These adverse events had a dose-related effects and rarely led to treatment discontinuation.
Authors’ conclusions
There was low-quality evidence to support that teriflunomide at a dose of 7 mg/day or 14 mg/day as monotherapy reduces both the number of participants with at least one relapse and the annualized relapse rate over one year or two years of treatment in comparison with placebo. Only teriflunomide at a dose of 14 mg/day reduced the number of participants with disability progression and delayed the progression of disability over one year or two years, but the quality of the evidence was very low. The quality of available data was too low to evaluate the benefit teriflunomide as monotherapy versus IFNβ-1a or as combination therapy with IFNβ. The common adverse effects were diarrhoea, nausea, hair thinning, elevated alanine aminotransferase, neutropenia and lymphopenia. These adverse effects were mostly mild-to-moderate in severity, but had a dose-related effect. New studies of high quality and longer follow-up are needed to evaluate the comparative benefit of teriflunomide on these outcomes and the safety in comparison with other DMTs
Plain language summary
Teriflunomide modifies the disease course in people with multiple sclerosis
Background
Teriflunomide was first used in rheumatoid arthritis, and is known to possess both anti-proliferative (inhibiting cell growth) and anti-inflammatory (counteracting a local response to cellular injury) actions. In 2012, its use was approved for these characteristics by the US Food and Drug Administration for people with relapsing (with recurrent exacerbations of neurological symptoms) forms of multiple sclerosis (MS) and in 2013 also by the European Medicines Agency.
Objectives
To assess the effectiveness and safety of two different doses of teriflunomide, alone or in combination with other medicines, for modifying the course of MS in people with the relapsing forms, with or without progression.
Study characteristics
The review authors considered the effectiveness of teriflunomide mainly in terms of the number of participants with at least one relapse, the number of people with disability progression, the annualized rate of relapse (number of relapses per participant-year) and the time to disability progression. They evaluated safety as the number of participants with side effects, number of participants with serious side effects, and number of participants who withdrew or dropped out from the study because of side effects at one year or two years. Among the pertinent literature, five studies met the inclusion criteria. They involved 3231 participants and evaluated the effectiveness and safety of teriflunomide alone or with another medicine called interferon-β (IFNβ), versus placebo (a pretend medicine) or IFNβ-1a. The evidence is current to September 2015.
Key results
The authors found low-quality evidence that both doses of teriflunomide reduced the occurrence of relapses after one year or two years of treatment, while there is very low-quality evidence showing that the medicine prevented disability progression at one year or two years. High-dose rather than low-dose teriflunomide had a similar efficacy to IFNβ-1a in reducing relapse at one year, but the quality of evidence was very low. As far as safety was concerned, the most commonly reported side effects were diarrhoea (frequent, loose stools), nausea (feeling sick), hair thinning, neutropenia (low levels of white blood cells called neutrophils, which fight off infection) and lymphopenia (low levels of white blood cells called lymphocytes, which fight off infection). In general, these side effects are mild to moderate, and do not usually lead to treatment being stopped, but higher dose is more prone to cause these side effects.
Quality of evidence
The low/very low quality of the results is mainly due to the inadequate blinding of relapse assessment (assessors were aware of which treatment the person had received), the high dropout rate (people left the trial), disability progression confirmed in less than six months, the low number of participants, and the different length of treatments within the studies. The duration of the studies is a key point for a lifetime disease with chances of chronic treatments as MS, also suggesting the need of studies with a longer period of monitoring (follow-up). The five studies included in this review were sponsored by pharmaceutical companies, and this is known as a potential source of conflict of interest and thus of bias.
