Teriflunomide for multiple sclerosis (Review)

Transcription

1 He D, Xu Z, Dong S, Zhang H, Zhou H, Wang L, Zhang S This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 12

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES APPENDICES HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST INDEX TERMS i

3 [Intervention Review] Teriflunomide for multiple sclerosis Dian He 1, Zhu Xu 1, Shuai Dong 2, Hong Zhang 3, Hongyu Zhou 4, Lu Wang 4, Shihong Zhang 4 1 Department of Neurology, Affiliated Hospital of Guiyang Medical College, Guiyang, China. 2 Department of Neurology, Jinan No. 6 People s Hospital, Jinan, China. 3 Clinical Laboratory, Jinan No. 6 People s Hospital, Jinan, China. 4 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China Contact address: Hongyu Zhou, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, , China. Hyzhou98@yahoo.com. Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group. Publication status and date: New, published in Issue 12, Review content assessed as up-to-date: 7 August Citation: He D, Xu Z, Dong S, Zhang H, Zhou H, Wang L, Zhang S. Teriflunomide for multiple sclerosis. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Disease-modifying therapies (DMTs) for multiple sclerosis aim to specifically reduce inflammation in relapsing multiple sclerosis and promote neuroprotection and neurorepair in progressive multiple sclerosis (MS). Most of the currently available disease-modifying drugs (DMDs) require regular and frequent parenteral administration, which imposes a burden on patients and leads to reduced adherence. Not all MS patients respond adequately to current DMDs and, therefore, alternative MS treatments with less invasive routes of administration and new modes of action are required to expand the current treatment repertoire, increase adherence, and thereby improve ef cacy. As one of the oral DMDs, teriflunomide is a potentially promising new oral agent in the treatment of relapsing MS. It inhibits dihydro-orotate dehydrogenase (DHODH) and the synthesis of pyrimidine and has selective immunosuppressive and immunomodulatory properties. Objectives To explore the potential benefits of teriflunomide and so expand the available DMT options, the effectiveness and safety of teriflunomide, as monotherapy or combination therapy, were assessed versus placebo or approved DMDs (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for modifying disease in patients with MS. Search methods The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (27 June 2012). We checked references in identified trials and manually searched the reports (2004 to June 2012) from neurological associations and MS societies. We also communicated with researchers participating in trials on teriflunomide and contacted Sanofi-Aventis. Selection criteria All randomised, double-blind, controlled, parallel clinical trials (RCTs) with a length of follow-up of at least one year evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or other treatments (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for patients with MS. Titles and abstracts of the citations retrieved by the literature search were screened independently for inclusion or exclusion by two review authors. Any disagreement regarding inclusion was resolved by discussion or by referral to a third assessor if necessary. 1

4 Data collection and analysis Two review authors independently extracted data and assessed trial quality. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation of information. Main results Two studies involving 1204 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFN-β, versus placebo for adult patients with relapsing forms of MS (relapsing-remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)) and an entry Expanded Disability Status Scale (EDSS) score of 5.5. Both studies had high attrition bias (26.8% and 36.4% attrition respectively). Teriflunomide 7 or 14 mg alone had potential benefits on reducing relapse rates, and alone or with add-on IFN-β was safe for patients with relapsing forms of MS in the short term. The most common adverse events included nasopharyngitis, headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, back pain, urinary tract infection, and pain in the arms or legs. Four ongoing trials were identified. Authors conclusions We found low-level evidence for the use of teriflunomide as a disease-modifying therapy for MS, due to the limited quality of the available RCTs. We did not conduct meta-analysis because of the clinical and methodological diversity of the included studies. Shortterm teriflunomide, 7 or 14 mg alone or with add-on IFN-β, was safe for patients with relapsing MS. Both teriflunomide 7 and 14 mg alone had potential benefits for patients with relapsing forms of MS. We are waiting for the publication of ongoing trials. RCTs with high methodological quality and longer periods of observation are needed to assess safety, disability progression, neuroprotection and quality of life. P L A I N L A N G U A G E S U M M A R Y Teriflunomide, a new oral therapy for multiple sclerosis (MS) New disease-modifying therapies (DMTs) with less invasive routes of administration and new modes of action are in development to expand the available DMT options and enhance adherence, thereby improving ef cacy. Teriflunomide is an oral disease-modifying drug with immunosuppressive and immunomodulatory properties.the authors of this review assessed the efficacy and safety of teriflunomide in patients with different forms of MS (relapsing-remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)). They took into account the annualised rate of relapse, the proportion of patients free of disability progression, and the number of brain lesions. Among the pertinent literature, two studies met the inclusion criteria. They involved a total of 1204 patients and evaluated the efficacy and safety of teriflunomide alone or with add-on IFN-β, respectively, versus placebo. The authors were unable to give any clear recommendations for the use of teriflunomide as a DMT for MS because the studies had limited quality, were of short duration and were funded by a pharmaceutical company. As far as safety is concerned, common adverse events included headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, and urinary tract infection. Future studies are needed with higher methodological quality, a better evaluation of the adverse events, and a longer period of teriflunomide administration. B A C K G R O U N D Description of the condition Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) in which autoreactive CD4+ and CD8+ T lymphocytes, B lymphocytes, antibodies, macrophages and cytokines synergize in myelin sheath attack and injury of the underlying axons. It is characterized by recurrent relapses and / or progression, typically striking adults during the primary productive time of their lives and ultimately leading to severe neurological disability. 2

5 (1) The characteristics of MS The overall incidence rate of MS in the world is 3.6 cases per 100,000 person-years in women and 2.0 in men (Alonso 2008). It is estimated to affect 2.1 million people worldwide (National MS Society 2009). There are four clinical phenotypes of MS. Initially, more than 80% of individuals with MS experience a relapsing-remitting disease course (RRMS) characterized by clinical exacerbations of neurologic symptoms followed by complete or incomplete remission (Lublin 1996). After 10 to 20 years, or median age of 39.1 years, about half of them gradually accumulate irreversible neurologic deficits with or without clinical relapses (Confavreux 2006), which is known as secondary progressive MS (SPMS). Another 10% to 20% of individuals with MS are diagnosed with primary progressive MS (PPMS), clinically defined as a disease course without any clinical attacks or remission from onset (Lublin 1996). A significantly rarer form is progressive relapsing MS (PRMS), which initially presents as PPMS however, during the course of the disease, these individuals develop true neurologic exacerbations (Tullman 2004). Growing evidence supports an inflammatory pathology occurring during the early relapsing stage of MS, and neurodegenerative pathology dominates the later progressive stage of the disease.the symptoms of MS can restrict the individual s physical activity and income-earning ability, resulting in a major financial burden on the patient, family, health system and society. Increases in disease severity are associated with both impairment in quality of life and increased costs. Direct medical costs are mainly due to relapses and pharmacological treatments in the earlier stages of disease; indirect costs are mainly due to disability and productivity loss in the later stages (Naci 2010). (2) The endpoints in MS clinical trials The final target of treatments in MS is to prevent the long-term accumulation of irreversible disability, therefore, the efficacy of new therapies should be assessed by measuring their effects on functional impairment and disability. Disease-modifying therapies (DMTs) for MS currently aim to specifically reduce inflammation in relapsing MS (RRMS, SPMS with relapses, and PRMS) and promote neuroprotection and neurorepair in progressive MS (PPMS and SPMS without relapses). For relapsing MS, all immunomodulatory or immunosuppressant drugs as first-line therapy, or under evaluation in clinical trials, aim to reduce disease activity using short-term surrogate endpoints (detection of new lesions on brain magnetic resonance imaging (MRI)) and clinical relapse. Although the changes induced by current therapies on these short-term endpoints correlate with concomitant effects on short-term disability progression at the trial level (Sormani 2010), whether these treatment effects reliably predict the benefit on long-term disability at the individual level is still uncertain. In clinical trials of neuroprotective or reparative strategies in progressive MS, traditional and novel imaging parameters as endpoints should be evaluated in five aspects of performance, pathological specificity, reproducibility, sensitivity to change, clinical relevance, and response to treatment. At present, the three most promising endpoints include changes in whole-brain volume in order to gauge general cerebral atrophy, T1 hypointensity and magnetization transfer ratio to monitor the evolution of lesion damage, and optical coherence tomography findings to evaluate the anterior visual pathway (Barkhof 2009). (3) The disadvantage of current disease-modifying drugs (DMDs) for MS Current DMTs for MS aim to reduce the rate of acute neurological attacks and can delay disability progression. DMTs can positively alter the course of relapsing forms of MS. However, most currently available rst- and second-line DMDs require regular and frequent parenteral administration. The requirement for long-term injections imposes a burden on patients and may in most cases lead to reduced adherence. Furthermore, not all patients respond adequately to current DMDs, suggesting that certain patients require different therapeutic approaches. Therefore, alternative MS treatments with less invasive routes of administration and new modes of action are needed to expand the current treatment repertoire, increase patient satisfaction and adherence, and thereby improve ef cacy. Currently there are two available oral DMDs for MS, fingolimod (Gilenya ) and teriflunomide (Aubagio ). Cladribine (Movectro ), another oral DMD approved and marketed in Russia and Australia in 2010, suffered from withdrawal of applications for marketing authorization in the European Union and discontinuation of development in the United States in 2011 because of an increased risk of cancer. Its manufacturer, Merck Serono, is now withdrawing cladribine from the market in Russia and Australia and the applications in other countries where it was seeking approval (European Medicines Agency 2011; Multiple Sclerosis Association of America 2011). The other two DMDs (laquinimod and BG-12), along with fingolimod and teriflunomide, are still being evaluated in phase III clinical trials. DMTs for MS that are in development are aimed at seeking more effective oral DMDs. (4) The importance of treatment adherence in diseasemodifying therapies (DMTs) for MS Adherence to treatment regimes is essential to ensure patients receive the maximum benefit from their treatment, and also to make sure that treatment is cost-effective. Nonadherence or poor adherence to therapy can lead to poor outcomes or treatment failure and to increased costs (World Health Organization 2003). As MS is a chronic disease that cannot be cured so far, patients are expected to adhere to DMTs indefinitely. Long-term adherence to existing MS therapies is often poor. A multicentre observational study on adherence to DMTs in patients with RRMS showed 3

6 that up to 25% of patients were not adherent to therapy within an average treatment duration of 31 months (Devonshire 2011). Several important barriers contribute to nonadherence to treatment regimens, such as perceived lack of efficacy, adverse event, cognitive impairment and depression, needle phobia and the inconvenience (Patti 2010). Maximizing adherence to MS therapies to improve a patient s chance of gaining the full benefit from his or her treatment is an important therapeutic goal. Currently, all licensed DMDs for MS require parenteral administration weekly or more frequently. The subcutaneous or intramuscular mode of application brings inconvenience and, along with injection-site reactions, impairs quality of life (QoL) requiring long-term acceptance by patients. Perhaps the most important advance in MS treatment that is anticipated to significantly improve adherence to long-term treatment is the availability of orally administered drugs. Oral drugs have a potential advantage over injected therapies in that needle phobia and injection-related adverse events will not be an issue, making treatment available to patients with MS who are unable or unwilling to receive regular injections. Oral immunomodulatory or immunosuppressant drugs characterized by maximum compliance combined with a good safety-benefit ratio would carry the advantage of convenience and greater acceptability, and would then enhance adherence. Description of the intervention Teriflunomide, the active metabolite of leflunomide, is known to possess both anti-proliferative and anti-inflammatory actions but its exact mechanism of action remains unclear. Its ability to noncompetitively and reversibly inhibit the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH), a key cellular enzyme involved in the de novo synthesis of pyrimidine, is believed to be important in its therapeutic effect (Greene 1995; Bruneau 1998). By inhibiting DHODH and diminishing DNA synthesis, teriflunomide has a cytostatic effect on proliferating B and T lymphocytes (Cherwinski 1995). Teriflunomide also inhibits protein tyrosinekinase activity (Xu 1996), resulting in the reduction of T cell proliferation, T cell production of interferon gamma (IFN-γ ) and interleukin 2 (IL2), as well as B cell IgG1 production and inhibition of nuclear factor B (NF B) (Xu 1995; Siemasko 1998; Manna 1999). In addition, teriflunomide diminishes the ability of antigen presenting cells (APC) to activate T cells and for stimulated T cells to activate monocytes in vitro (Zeyda 2005), and inhibits interleukin 1beta, matrix metalloproteinases (Deage 1998) and cyclo-oxygenase-2 activity (Hamilton 1999). Data from human trials of leflunomide in rheumatoid arthritis showed that teriflunomide demonstrated linear pharmacokinetics over a dose range of 5 to 25 mg/day. The mean plasma half-life is 15 to 18 days and teriflunomide is extensively (> 99%) protein bound and exhibits linear protein binding at therapeutic concentrations. Clearance is via biliary and renal routes so administration of cholestyramine can be used to facilitate rapid elimination of teriflunomide from the circulation (Tallantyre 2008). In experimental autoimmune encephalomyelitis, teriflunomide reduces activation of myelin basic protein (MBP)-specific T cells then reduces the production of IFN-γ and chemotaxis. This immunomodulatory potential is clinically relevant and is not exclusively dependent on the depletion of cellular pyrimidine pools (Korn 2004). Teriflunomide delays disease onset, decreases disease severity in a dose-dependent manner and causes inhibition of up to 90% of inflammation, demyelination and axonal loss (Merrill 2009). As an oral DMD, teriflunomide is a new and promising oral agent in the treatment of relapsing MS acting by inhibiting DHODH and the synthesis of pyrimidine with immunosuppressive and immunomodulatory properties. It has been investigated in a lot of clinical trials. How the intervention might work Teriflunomide is an oral agent that has been successfully used in reducing MRI activity and the proportion of patients showing an increase in disability measured on the Expanded Disability Status Scale (EDSS) (Kurtzke 1983) in a randomised, doubleblind, placebo-controlled phase II trial in patients with MS with relapses (O Connor 2006). Recently, a phase III trial (TEMSO) with over 1000 patients with relapsing MS has further demonstrated that teriflunomide monotherapy significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity as compared with placebo (O Connor 2011a). A phase II multicentre, placebo-controlled, double-blind randomised study provides evidence that teriflunomide added to IFN-β is safe and significantly reduces the T1-Gd lesion burden (Freedman 2012). Why it is important to do this review No systematic review currently exists in the peer-reviewed literature that focuses on teriflunomide for patients with MS. A systematic review of all randomised controlled trials is warranted to evaluate the effectiveness and safety of teriflunomide for MS. O B J E C T I V E S To explore the potential benefits of teriflunomide, and expand the available treatment options, by assessing the effectiveness and safety of teriflunomide as monotherapy or combination therapy versus placebo or approved DMDs (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for modifying disease in patients with MS. 4

7 M E T H O D S Criteria for considering studies for this review Types of studies All randomised double-blind, controlled, parallel clinical trials (RCTs) evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or any other treatment for patients with MS. Uncontrolled, nonrandomised or quasi-randomised trials were excluded. Trials with a length of follow-up shorter than one year were excluded. a point in the EDSS score or at least one point in two functional systems (excluding change in sphincteric or cerebral functions). (2) The proportion of patients free of disability progression as assessed by the EDSS (Kurtzke 1983) at two years (or later). Definitions of confirmed disability progression that were reported in the included trials were accepted. Safety The number of patients with adverse effects at one year (or later), number of patients with serious adverse events, and number of patients who withdrew or dropped out from the study because of adverse events. Types of participants Patients aged > 18 years with definite diagnoses of MS according to Poser s (Poser 1983) or Mc Donald s (McDonald 2001; Polman 2005; Polman 2010) criteria, any clinical phenotypes categorized according to the classification of Lublin and Reingold (Lublin 1996), and EDSS scores 6.0 with or without progression were included. Types of interventions Experimental intervention: treatment with oral teriflunomide, as monotherapy or combination therapy, without restrictions regarding dosage, administration frequency and duration of treatment. Control intervention: placebo or other treatments (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for MS. Secondary outcomes We assessed the following secondary outcomes, measured in the treatment phase and at the completion of follow-up versus baseline. (1) The sum of the number of gadolinium-enhancing T1-weighted lesions/the number of patients at one year (or later). Lesions that persisted for more than four weeks were counted more than once. (2) The time to disability progression at two years (or later). (3) Changes in T1 hypointensity and magnetization transfer ratio of lesion damage at two years or later. (4) Mean change in quality of life (QoL).The following scales were accepted: Short Form-36 (SF-36) scores (Ware 1992), MSQoL- 54 questionnaire scores (Vickrey 1995), MSQLI (Fischer 1999) or FAMS (Cella 1996) at two years or later. Types of outcome measures Primary outcomes We assessed the following primary outcomes, measured in the treatment phase and at the completion of follow-up versus baseline. Efficacy (1) The annualised rate of relapse at one year (or later), defined as the mean number of confirmed relapses per patient adjusting for the duration of follow-up to annualise it. Confirmed relapse is defined as the occurrence of new symptoms or worsening of previously stable or improving symptoms and signs not associated with fever or infection that occurs at least 30 days after the onset of a preceding relapse and lasts more than 24 hours. The relapse should be verified by the examining neurologist within seven days after its occurrence and be accompanied by an increase of at least half Search methods for identification of studies No language restrictions were applied to the search. Electronic searches The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (27 June 2012) which, among other sources, contains CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS and PEDRO. The search terms are listed (Appendix 1). In addition, we searched the clinical trials registries ( clinicaltrials.gov). Information on the Trials Register and details of search strategies used to identify trials can be found in the Specialised Register section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group s module. The keywords used to search for trials for this review are listed (Appendix 1). 5

8 Searching other resources 1. We checked the reference lists of published reviews and retrieved articles for additional trials. 2. We handsearched reports (2004 to June 2012) from the neurological associations and MS societies (The Society for Neuroscience, The American Academy of Neurology, The World Federation of Neurology, Federation of European Neuroscience Societies, British Neuroscience Association, National Multiple Sclerosis Society (United States, United Kingdom)). 3. We communicated with investigators participating in trials on teriflunomide. 4. We contacted Sanofi-Aventis ( index.jsp) in an effort to identify further studies. Data collection and analysis Selection of studies Titles and abstracts of the citations retrieved by the literature search were screened independently for inclusion or exclusion by two review authors (He, Xu). The full texts of potentially relevant studies were obtained for further assessment. The eligibility (on the basis of information available in the published data) of these studies was evaluated independently. Papers that did not meet the inclusion criteria were listed in the Characteristic of excluded studies table with the reasons for omission. Any disagreement regarding inclusion was resolved by discussion or by referral to a third assessor (Zhou) if necessary. Data extraction and management Two review authors (He, Xu) independently extracted data from the selected trials using standardised forms. Information about study design, participants, interventions and outcome measures were extracted. Principal investigators of included studies were contacted in order to provide additional data or confirmation of methodological aspects of the study. Disagreements were discussed and resolved by consensus among the review authors. Assessment of risk of bias in included studies The methodological criteria were based on the Cochrane Handbook for Systematic Reviews of Interventions, Version (Higgins 2011). Two review authors (He, Xu) independently evaluated the methodological quality of the studies using the risk of bias tool under the domains of sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome and other biases. Disagreements among the review authors on the methodological quality of the identified studies were discussed and resolved by consensus. Measures of treatment effect We did not enter any data into the RevMan analysis software because the included studies were clinically diverse and at risk of bias, but if data are available in future updates we will analyse them as follows. The pre-set outcomes in this review involved all types of data, including counts and rates, dichotomous and continuous data, ordinal (measurement scales) and time-to-event data. The negative binomial distribution is the optimal distribution for modelling new enhancing lesion counts (van den Elskamp 2009). Negative binomial regression is recommended for the analysis of relapse data in MS clinical trials (Wang 2009). Both the number of relapses and new enhancing lesions are count data. Analyses of counts of rare events (Poisson data) often focus on rates (rates relate the counts to the period of time during which they could have happened). Rate ratio, which compares the rate of events in the two groups by dividing one by the other, will be used to measure the treatment effect on counts of rare events. When measuring the treatment effect on counts of common events, the mean difference will be used to compare the difference in the mean number of events (possibly standardised to a unit time period) experienced by participants in the intervention group compared with the participants in the control group. Both MS relapse and gadoliniumenhancing T1-weighted lesions are common events, therefore the mean difference will be used as the measure of treatment effect. For continuous outcomes, the mean difference or the standardised mean difference (SMD) will be calculated with 95% confidence interval (CI). Standard deviation will be calculated from the CI, or t-tests when it is not reported. Changes in T1 hypointensity and magnetization transfer ratio of lesion damage is a continuous outcome, the mean difference will be used as the measure of treatment effect. For dichotomous outcomes, individual and pooled statistics will be calculated as relative ratios (RR) or odds ratio (OR), the risk difference (RD) (also called the absolute risk reduction) and the number needed to treat (NNT). Both the proportion of patients free of disability progression and the number of patients with adverse effects are dichotomous outcomes and we will used relative ratios (RR) as the measure of treatment effect. Where the ordinal rating scales used in the trials have a reasonably large number of categories, the data will be treated as continuous outcomes arising from a normal distribution. Mean change in QoL belongs to ordinal data. For trials that have used the same rating scale to assess outcome, the mean difference will be used as the measure of treatment effect. Where different rating scales have been used, the measure of the treatment difference is the standardised mean difference. Time-to-event data can be analysed as dichotomous data when the status of all patients in a study is known at a fixed time-point. The time to disability progression belongs to time-to-event data, we will used relative ratios (RR) as the measure of treatment effect. 6

9 Unit of analysis issues Most RCTs on teriflunomide for MS are multi-arm studies with two experimental intervention groups (7 mg/day of teriflunomide and 14 mg/day of teriflunomide) and a common control group, and involving repeated observations on participants. The pre-set outcome measures in this review involve events that may re-occur. If meta-analysis is conducted in future updates, we will combine all relevant experimental intervention groups (7 mg/day of teriflunomide and 14 mg/day of teriflunomide) in the study into a single group, and combine all relevant control intervention groups into a single control group if there is a study with two control intervention groups. Meanwhile, we will perform separate analyses based on the pre-set outcomes in this review and different periods of follow-up. Counts of common events (MS relapse and gadolinium-enhancing T1-weighted lesions) will be treated in the same way as continuous outcome data. Dealing with missing data We did not conduct meta-analysis because of the clinical and methodological diversity across the included studies, so trial authors were not contacted for missing data. If sufficient data are not available from published reports in future updates, the authors will be contacted for further details. For dichotomous outcomes, the missing data will be analysed using an intention-to-treat analysis. For continuous outcomes, sensitivity analyses will be performed to assess the sensitivity of the results to the assumptions that are made. Best- and worst-case scenarios will be considered for taking into account missing data. Assessment of heterogeneity We did not evaluate statistical heterogeneity because of the clinical and methodological heterogeneity across the included studies but in future updates, or if further data become available, we will assess clinical heterogeneity by examining the characteristics of the studies, the similarity between the types of participants, the interventions, and the outcomes as specified in the criteria for included studies.the variability in study design and the risk of bias (methodological heterogeneity) will also be evaluated. When pooling trials in meta-analyses, the I 2 statistic will be calculated to identify heterogeneity across studies. When the I 2 is > 30% there is some level of heterogeneity (Higgins 2011). If tests for heterogeneity are statistically significant and inspection of the individual results suggests that it is still logical to combine results, we will calculate the overall effects using a random-effects model. Assessment of reporting biases The trials included in this review did not permit an assessment of publication bias. If sufficient RCTs are identified in future updates, potential publication bias will be examined using a funnel plot. For continuous outcomes, the standard errors will be used as the vertical axis and the mean differences will be used as the horizontal axis in funnel plots. For dichotomous outcomes, the odds ratios or risk ratios will be plotted on a logarithmic scale as the horizontal axis and the standard errors will be used as the vertical axis. Data synthesis We could not combine the outcome data because of the different trial designs and the risks of bias, we have given a descriptive summary of the results. When clinically and methodologically homogeneous RCTs are identified in future updates and heterogeneity tests suggest an I 2 < 30%, or inspection of the individual results suggests that it still seemed logical to combine results even though tests for heterogeneity are statistically significant, formal metaanalysis using the Review Manager software (Review Manager 2011) will be conducted. Treatment effect estimates for each study and the weighted average of the treatment effects estimated in the individual studies (as a pooled treatment effect estimate) will be calculated, then a random-effects model or fixed-effect model will be selected according to the results of the heterogeneity tests. if it is assumed that each study is estimating exactly the same quantity, a fixed-effect model will be performed, otherwise a randomeffects model will be used. For the outcomes treated as dichotomous data (number of patients free of disability progression, the number of patients with adverse effects, and the time to disability progression), three fixed-effect methods (Mantel-Haenszel, Peto, or inverse variance) and one random-effects method (DerSimonian and Laird) will be selected (the Peto method can only pool odds ratios whilst the other three methods can pool odds ratios, risk ratios, and risk differences). For the outcomes treated as continuous data (relapse, the number of gadolinium-enhancing T1- weighted lesions, changes in T1 hypointensity and magnetization transfer ratio of lesion damage, and mean change in QoL), the inverse-variance fixed-effect model method and the inverse-variance random-effects model method will be selected. Subgroup analysis and investigation of heterogeneity We could not carry out subgroup analysis because of the lack of data, but in future updates and if further data become available we intend to undertake subgroup analyses according to: (1) different therapies (e.g. monotherapy, combined IFN-β therapy or combined glatiramer acetate therapy); (2) different MS patients (e.g. patients with RRMS or patients with progressive MS); (3) duration of follow-up (e.g. 1 year, between 1 and 2 years, more than 2 years); (4) baseline EDSS scores (e.g. 3.5, between 3.5 and 6); (5) dosage level (e.g. 7 mg/day or 14 mg/day); (6) different duration of MS (e.g. 5 years, more than 5 years). Sensitivity analysis 7

10 If a sufficient number of studies had been included, we would have undertaken sensitivity analyses to assess the robustness of our review results. Where possible, we will conduct sensitivity analysis to assess the influence on results of fixed-effect model versus random-effects model assumptions and of including trials at high risk of bias as well as the effects of analysing by intention to treat and the effect size (for dichotomous outcomes, relative ratios versus odds ratio; and for continuous outcomes, the mean difference versus the standardised mean difference). Counts of common events will be treated in the same way as continuous outcome data. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. See: Characteristics of included studies; Characteristics of excluded studies and Characteristics of ongoing studies. Results of the search In total, 54 articles were retrieved by the search strategies. After screening of titles and abstracts, nine articles were selected provisionally and the full papers were obtained for further assessment for eligibility. We excluded seven studies. One study (O Connor 2006) was a randomised, double-blind, placebo-controlled phase study but the length of follow-up was shorter than one year. Three studies (Confavreux 2011; Li 2011; Confavreux 2012) were multiple reports from the same study (O Connor 2006); and a further three studies (Comi 2011; O Connor 2011b; Miller 2012) were multiple reports from the same study (O Connor 2011a). Two studies met the inclusion criteria (O Connor 2011a; Freedman 2012). Four RCTs are currently ongoing (NCT ; NCT ; NCT ; NCT ). Included studies Two studies involving 1204 people were included (O Connor 2011a; Freedman 2012). The O Connor 2011a study evaluated the efficacy and safety of teriflunomide 7 or 14 mg/day versus placebo for adults with relapsing forms of MS (RRMS, SPMS with relapse, and PRMS) (n = 1088). The Freedman 2012 study primarily evaluated the safety and tolerability of teriflunomide 7 or 14 mg/day with add-on IFN-β versus placebo in patients with relapsing MS (RRMS, SPMS with relapse. and PRMS) (n = 116). Characteristics of the study design The study designs of the included studies were diverse. O Connor 2011a was a phase III, randomised, double-blind, placebo-controlled, parallel-group study over 108 weeks. Freedman 2012 was a phase II, multicentre, placebo-controlled, randomised study with a 24-week double-blind study and a 24-week blinded extension. Patients completing 24 weeks of treatment who continued to meet the eligibility criteria could select to enter a 24-week blinded extension during which patients continued to receive their originally assigned treatment regimen. Characteristics of the participants All participants had a diagnosis of definite MS according to Mc- Donald s diagnostic criteria (McDonald 2001; Polman 2005), an age ranging from 18 to 55 years and a relapsing clinical course with or without progression (relapsing-remitting (RR), secondary progressive (SP), or progressive relapsing (PR) MS). All patients had an entry score of 5.5 or lower on the EDSS and no relapse for at least eight weeks before randomisation. The patients in O Connor 2011a had at least two clinical relapses in the previous two years and the patients in Freedman 2012 received a stable dose of IFN-β for at least 26 weeks before screening and had a mean time of 27.1 months since the most recent relapse. All trials reported a baseline comparability of the characteristics of participants between treatment groups, and baseline characteristics of participants were well balanced among the groups. The population entering the 24- week extension in Freedman 2012 had a longer mean time since the most recent relapse compared to patients entering the initial 24-week double-blind study (30.4 months versus 27.1 months). Characteristics of the interventions The interventions in the included studies were diverse. Patients in O Connor 2011a received oral administration of 7 mg/day of teriflunomide or 14 mg/day of teriflunomide or a matching placebo for 108 weeks (7 mg, n = 365; 14 mg, n = 358; placebo, n = 363). Patients in Freedman 2012 received oral administration of 7 mg/ day of teriflunomide added to IFN-β, 14 mg/day of teriflunomide added to IFN-β, or matching placebo added to IFN-β. Initially 116 patients were exposed to the study medication for 24 weeks (placebo, n = 41; 7 mg, n = 37; 14 mg, n = 38); 86 patients entered the 24-week extension phase (placebo, n = 31; 7 mg, n = 28; 14 mg, n = 27). Characteristics of the outcome measures Some of the primary outcomes in the current review were reported, the annualised rate of relapse was reported as a primary endpoint in O Connor 2011a but as a secondary endpoint in Freedman The number of patients with adverse effects, number of patients with serious adverse events and number of patients who withdrew 8

11 or dropped out from the study because of adverse events were reported in both studies. O Connor 2011a reported the proportion of patients with disability progression as assessed by the EDSS at 108 weeks in the secondary outcomes; the proportion of patients free of disability progression could be calculated accordingly. Some of our secondary outcomes were reported: the sum of the number of gadolinium-enhancing T1-weighted lesions were reported both in O Connor 2011a and Freedman 2012; changes in T1 hypointensity of lesion damage was reported in O Connor 2011a. The other secondary outcomes (the time to disability progression, magnetization transfer ratio of lesion damage and mean change in QoL) were not reported in either study. Excluded studies Seven studies were excluded from this review; the reasons for their exclusion are listed in the Characteristics of excluded studies table. Risk of bias in included studies Further details of this assessment are available in the relevant section of the Characteristics of included studies table and are also presented in the Risk of bias graph (Figure 1) and Risk of bias summary (Figure 2). Figure 1. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies. 9

12 Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included study. Allocation In O Connor 2011a, sequence generation and allocation concealment were adequate. In his reply, the principal author indicated use of a randomisation number from a list that was loaded in the database and central randomisation via an interactive voice response system (IVRS). In Freedman 2012, sequence generation and allocation concealment were unclear. The authors described that randomisation was stratified by country and IFN regimen (high- or low-dose), but the specific methods of random sequence generation and allocation concealment were not mentioned. The principal author didn t provide us with any related information in his reply. and only the treating neurologist was aware of any side effects that could potentially be related to active therapy. In his reply the principal author described that the study medication teriflunomide (7 mg and 14 mg) and placebo were supplied as identical tablets. In Freedman 2012, the detailed method of blinding was not described. In particular, the authors didn t report the reasons why some patients were not rolled over into the extension study and the conditions that did not meet the eligibility criteria. It was unclear whether the 24-week extension was single-blind or double-blind. We wrote to the principal author and Sanofi-Aventis but we did not get a reply. Blinding The O Connor 2011a was double-blinded. Both the treating and examining neurologists were unaware of treatment assignments, Incomplete outcome data O Connor 2011a had a high rate of drop-outs (26.8%). The number of and the reasons for dropping out were recorded and bal- 10

13 anced, to a large degree, between groups. The Freedman 2012 study also had a high rate of drop-outs (36.4%) and missing data and the reasons for the missing data were not carefully recorded; they did not balance between groups. Selective reporting All listed outcomes were reported adequately in both studies. Other potential sources of bias Both studies were sponsored by Sanofi-Aventis, conflict of interests may exist. Effects of interventions We did not conduct meta-analysis because of the clinical and methodological diversity of the included studies.treatment effect estimates for each study were not done, but if studies are available for meta-analysis in future updates we will contact trial authors for the missing data. Treatment effects for each study will be estimated using Review Manager software (Review Manager 2011). Primary outcomes Efficacy O Connor 2011a reported that teriflunomide significantly reduced the annualised relapse rate (ARR) (ARR: 0.54 (95% CI 0.47 to 0.62) for placebo, 0.37 (95% CI 0.32 to 0.43) for teriflunomide at 7mg, and 0.37 (95% CI 0.31 to 0.44) for teriflunomide at 14 mg (P < for both comparisons with placebo), with relative risk reductions of 31.2% and 31.5% respectively (P < for both comparisons with placebo) at 108 weeks). For the secondary outcomes, O Connor 2011a reported that the estimated proportions of patients with confirmed progression of disability sustained for at least 12 weeks were 27.3% (95% CI 22.3 to 32.3), 21.7% (95% CI 17.1 to 26.3), and 20.2% (95% CI 15.6 to 24.7) with placebo, teriflunomide at 7 mg, and teriflunomide at 14 mg, respectively. Compared with placebo, the hazard ratios were 0.76 (95% CI 0.56 to 1.05) for teriflunomide at 7 mg and 0.70 (95% CI 0.51 to 0.97) for teriflunomide at 14 mg, representing relative risk reductions as compared with placebo of 23.7% for lower-dose teriflunomide (P = 0.08) and 29.8% for higher-dose teriflunomide (P = 0.03) at 108 weeks. Freedman 2012 reported that 20 patients experienced at least one relapse (placebo, n = 8; 7 mg, n = 7; 14 mg, n = 5), corresponding to an annualised relapse rate (ARR) of per patient-year in the placebo group, in the 7 mg group, and in the 14 mg group. The respective adjusted ARRs were 0.343, 0.231, and 0.144, representing a 32.6% relative decrease in ARR in the 7 mg group (P = ) and a 57.9% (P = ) relative decrease versus placebo in the 14 mg group at 48 weeks. Safety O Connor 2011a reported that similar proportions of patients in the placebo, lower-dose teriflunomide, and higher-dose teriflunomide groups had adverse events (87.5%, 89.1%, and 90.8%, respectively), serious adverse events (12.8%, 14.1%, and 15.9%), and adverse events leading to discontinuation of the study medication (8.1%, 9.8%, and 10.9%). The most common adverse events (crude incidence 10%) with placebo, teriflunomide at 7 mg, and teriflunomide at 14 mg included nasopharyngitis (27.2%, 25.5%, and 26.0%, respectively), headache (17.8%, 22.0%, and 18.7%, respectively), diarrhoea (8.9%, 14.7%, and 17.9%, respectively), fatigue (14.2%, 12.8%, and 14.5%, respectively), elevated alanine aminotransferase levels (6.7%, 12.0%, and 14.2%, respectively), nausea (7.2%, 9.0%, and 13.7%, respectively), hair thinning or decreased hair density (3.3%, 10.3%, and 13.1%, respectively), influenza (10.0%, 9.2%, and 12.0%, respectively), back pain (13.1%, 10.6%, and 11.5%, respectively), urinary tract infection (9.7%, 7.3%, and 10.3%, respectively), and pain in the arms or legs (13.1%, 7.1%, and 9.2%, respectively). The most common adverse events with an increased incidence in the teriflunomide groups (as compared with placebo) that had a dose effect were diarrhoea, nausea, hair thinning or decreased hair density, and elevated alanine aminotransferase levels. These events rarely led to discontinuation of the study medication: discontinuation rate for diarrhoea 0.0%, 0.3%, and 0.3% with placebo, teriflunomide at 7 mg, and teriflunomide at 14 mg, respectively; for nausea 0.0%, 0.3%, and 0.0%; and for hair thinning or decreased hair density 0.0%, 0.5%, and 1.4%. No deaths were reported. The incidence of elevated alanine aminotransferase levels ( one times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of elevations that were at least three times the upper limit of the normal range was similar across study groups (6.3%, 6.7%, and 6.7%, respectively). Mean reductions in neutrophil and lymphocyte counts from baseline values were small in magnitude ( 1.0 x 10 9 per litre and 0.3 x 10 9 per litre, respectively) but were slightly more marked with teriflunomide at 14 mg than with the 7 mg dose or placebo. The reductions occurred during the first three months of treatment and stabilized over time. Moderate neutropenia (defined as a neutrophil count of < 0.9 x 109 per litre) developed in three patients receiving teriflunomide. The neutropenia resolved spontaneously with continued treatment in two of the patients; and in the third patient it resolved after discontinuation of the study drug. The incidence of serious infections was similar across groups (2.2%, 1.6%, and 2.5% with placebo, teriflunomide at 7 mg, and teri- 11

14 flunomide at 14 mg, respectively); no serious opportunistic infections were observed. Eleven pregnancies occurred, leading to four spontaneous abortions (one in the placebo group and three in the higher-dose teriflunomide group), six induced abortions (five in the lowerdose teriflunomide group and one in the higher-dose teriflunomide group). One patient in the higher-dose teriflunomide group (treated for 31 days of the pregnancy) delivered a healthy baby with no reported health concerns after two years. Malignant neoplasms were reported in four patients: three in the placebo group (one each with breast cancer, thyroid cancer, and cervical cancer), and one in the higher-dose teriflunomide group (with cervical carcinoma in situ, reported after 1.5 years of using the drug). The proportion of patients with adverse events related to increased blood pressure was higher with teriflunomide at 7 mg and 14 mg (5.4% and 5.0%, respectively) than with placebo (3.1%). No patient discontinued the study medication because of increased blood pressure. The proportions of patients with hypersensitivity or skin disorders were generally higher with teriflunomide at 7 mg and 14 mg (10.3% and 11.2%, respectively) than with placebo (7.2%). Progressive multifocal leukoencephalopathy was not observed during the trial. Freedman 2012 reported that the overall proportions of patients with adverse events and serious adverse events were slightly higher in the 7 mg group (adverse events 85.4% for placebo group; 94.6% for 7 mg group, and 86.8% for the 14 mg group; serious adverse events 4.9% for placebo group; 10.8% for 7 mg group, and 2.6 for 14 mg group). There was a low and similar incidence of treatment discontinuations in the three groups (4.9% for placebo group; 8.1% for 7 mg group, and 7.9% for the 14 mg group). The most commonly reported adverse events in the placebo, 7 mg, and 14 mg groups were: increased alanine aminotransferase (ALT) (14.6%, 21.6%, and 31.6%, respectively), increased aspartate aminotransferase, diarrhoea (14.6%,10.8%, and 10.5%, respectively), urinary tract infection (17.1%, 10.8%, and 2.6%, respectively), fatigue (9.8%, 5.4%, and 13.2%, respectively), nasopharyngitis (7.3%, 8.1%, and 13.2%, respectively), headache (4.9%, 5.4%, and 15.8%, respectively), decreased lymphocyte count (2.4%, 10.8%, and 13.2%, respectively), decreased white blood cell count (7.3%, 8.1%, and 10.5%, respectively), hypertension (2.4%, 8.1%, and 10.5%, respectively), decreased neutrophil count (2.4%, 2.7%, and 10.5%, respectively), back pain (2.4%, 5.4%, and 10.5%, respectively), nausea (7.3%, 0%, and 13.2%, respectively), and vomiting (4.9%, 2.7%, and 10.5%, respectively). An apparent dose effect after 48 weeks of treatment was noted for ALT increase, hypertension, and decreased lymphocyte count. The serious adverse events included ankle fracture, several occurrences of ALT increase, deep vein thrombosis, musculoskeletal stiffness, pseudarthrosis, an increase in ALT to three to four times the upper limit of normal, lobar pneumonia, cystitis and cholecystitis. There were no events leading to death. The reasons for discontinuing treatment included increases in ALT to three times the upper limit of normal (3 x ULN), hair thinning or decreased hair density, neurodermatitis, diarrhoea, insomnia and fatigue. Secondary outcomes O Connor 2011a reported that patients in both teriflunomide groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (the number of gadolinium-enhancing lesions per T1-weighted scan: 1.33 (95% CI 1.06 to 1.67) for placebo, 0.57 (95% CI 0.43 to 0.75) for teriflunomide at 7 mg, and 0.26 (95% CI 0.17 to 0.41) for teriflunomide at 14 mg (P < for both comparisons with placebo), with a relative risk of 0.43 for teriflunomide at 7 mg versus placebo and 0.20 for teriflunomide at 14 mg versus placebo). Patients on teriflunomide 14 mg had a significantly reduced change in T1 hypointensity of lesion damage from baseline than those in the placebo group (0.53 ± 1.06 for placebo and 0.33 ± 1.0 for teriflunomide at 14 mg, P = 0.02; 0.50 ± 1.15 for teriflunomide at 7 mg versus 0.53 ± 1.06 for placebo, P = 0.19). Freedman 2012 reported a greater reduction in the number of T1-gadolinium lesions per scan at week 48 in both teriflunomide groups compared with the placebo group, with relative risk reductions (RRRs) of 84.6% (P = ) and 82.8% (P < ) in the 7 mg and 14 mg groups, respectively. D I S C U S S I O N Summary of main results This systematic review evaluated the effectiveness and safety of teriflunomide as monotherapy or combination therapy versus placebo or approved DMTs (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for modifying disease in patients with MS. Two studies were included in this review, which targeted adult patients with a relapsing clinical course of MS (RRMS, SPMS with relapse, and PRMS). The O Connor 2011a study was a largescale RCT involving 1088 patients over 108 weeks and primarily evaluated oral teriflunomide 7 mg/day and 14 mg/day versus placebo on relapse, disability progression and safety. The results showed that both teriflunomide at 7 and 14 mg significantly reduced the annualised relapse rate (with relative risk reductions of 31.2% and 31.5% respectively, P < 0.001). The higher-dose teriflunomide significantly reduced the proportion of patients with confirmed disability progression (27.3% with placebo and 20.2% with teriflunomide at 14 mg, P = 0.03). Short-term teriflunomide at both 7 and 14mg was safe and well tolerated by patients with MS. However, the high attrition bias (26.8%) that resulted from the high rate of drop-outs made the results unconvincing. The 12

15 Freedman 2012 study was a RCT, with a 24-week double-blind study and a 24-week blinded extension, which primarily evaluated the safety of oral teriflunomide 7 mg/day and 14mg/day added to IFN-β versus placebo + IFN-β. The results showed that teriflunomide 7 and 14 mg with add-on IFN-β was safe. However, the methodologies for random sequence generation, allocation concealment and blinding were unclear and a high attrition bias existed (36.4%). We did not conduct meta-analysis because of the clinical and methodological diversity of the included studies. Overall completeness and applicability of evidence In this review, it was difficult to answer the question whether teriflunomide alone or with add-on IFN-β was effective for MS. We are unable to give any recommendation for clinical practice and the use of teriflunomide for adult patients with relapsing MS. Two studies with different study designs and relatively poor methodological quality were included. Not all primary outcomes or secondary outcomes were measured and subgroup analysis or sensitivity analyses could not be performed as planned. Quality of the evidence O Connor 2011a was a RCT with a sufficiently large sample size but with a high attrition bias that resulted from the high rate of drop-outs, which made the results unconvincing. Freedman 2012 aimed to evaluate the safety of teriflunomide added to IFN-β. The results were limited because of the study design (24-week study and 24-week extension), a large number of patients did not continue on to the 24-week extension, and a high attrition bias existed. Furthermore, the methodologies on random sequence generation, allocation concealment and blinding were unclear in this trial. of studies for inclusion in this review and extracted data, which minimised the potential for additional bias beyond that detailed in the risk of bias tables. The review authors of this review had no conflicts of interest. Agreements and disagreements with other studies or reviews To the best of our knowledge, teriflunomide for MS has not been systematically reviewed previously. A U T H O R S C O N C L U S I O N S Implications for practice We found low-level evidence for the use of teriflunomide as a disease-modifying therapy for MS due to the limited quality of the available RCTs. However, both teriflunomide 7 mg and 14 mg have potential benefits, alone and with add-on IFN-β, and the review shows it to be safe for patients with relapsing forms of MS in the short term. The most common adverse events included nasopharyngitis, headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, back pain, urinary tract infection, and pain in the arms or legs. Implications for research Randomised controlled trials with high methodological quality and longer periods of observation are needed to assess safety, disability progression, neuroprotection and quality of life. Potential biases in the review process An extensive and comprehensive search was undertaken to limit bias in the review process, however a low number of RCTs were retrieved. The two authors independently assessed the eligibility A C K N O W L E D G E M E N T S We thank the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group editorial team for advice and support. 13

16 R E F E R E N C E S References to studies included in this review Freedman 2012 {published data only} Freedman MS, Wolinsky JS, Wamil B, Confavreux C, Comi G, Kappos L, et al.teriflunomide added to interferonβ in relapsing multiple sclerosis: A randomized phase II trial. Neurology 2012;78(23): O Connor 2011a {published data only} O Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al.randomized trial of oral teriflunomide for relapsing multiple sclerosis. New England Journal of Medicine 2011;365(14): References to studies excluded from this review Comi 2011 {published data only} Comi G, O Connor P, Wolinsky J, Confavreux C, Kappos L, Olsson T, et al.extension of a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses: safety outcomes with up to 4 years of follow-up. Multiple Sclerosis 2011;17:S Confavreux 2011 {published data only} Confavreux C, O Connor P, Freedman M, Benzerdjeb H, Wang D, Bar-Or A. Long term safety and tolerability of teriflunomide in multiple sclerosis: 9-year follow-up of a phase II study. Multiple Sclerosis 2011;17:S Confavreux 2012 {published data only} Confavreux C, Li D, Freedman M, Truffinet P, Benzerdjeb H, Wang D, et al.long-term follow-up of a phase II study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Multiple Sclerosis 2012 Feb 7 [Epub ahead of print]:1 12. Li 2011 {published data only} Li D, O Connor P, Confavreux C, Truffinet P, Wang D, Traboulsee A. Efficacy of teriflunomide in relapsing multiple sclerosis: phase II extension study with 8-year follow-up. Multiple Sclerosis 2011;17:S Miller 2012 {published data only} Miller AE, O Connor P, Wolinsky JS, Confavreux C, Kappos L, Olsson TP, et al.pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Multiple Sclerosis 2012; Vol. 18, issue 11: O Connor 2006 {published data only} O Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, et al.a Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006;66(6): O Connor 2011b {published data only} O Connor P, Wolinsky J, Confavreux C, Comi G, Kappos L, Olsson T, et al.extension of a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses: clinical and MRI data 5 years after initial randomization. Multiple Sclerosis 2011;17:S References to ongoing studies NCT {published and unpublished data} NCT Pilot Study of Teriflunomide as Adjunctive Therapy to Glatiramer Acetate in Subjects With Multiple Sclerosis. clinicaltrials.gov/ct2/show/nct (Accessed 17 June 2011). NCT {published and unpublished data} NCT An Efficacy Study of Teriflunomide in Patients With Relapsing Multiple Sclerosis (TOWER). clinicaltrials.gov/ct2/show/study/nct (Accessed 10 May 2012). NCT {published and unpublished data} NCT Long Term Safety and Efficacy Study of Teriflunomide 7 mg or 14 mg in Patients With Relapsing- Remitting Multiple Sclerosis. clinicaltrials.gov/ct2/show/ study/nct (Accessed 27 March 2012). NCT {published and unpublished data} NCT Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta (TERACLES). clinicaltrials.gov/ct2/ show/study/nct (Accessed 25 July 2012). Additional references Alonso 2008 Alonso A, Hernán MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 2008;71 (2): Barkhof 2009 Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nature Review Neurology 2009;5(5): Bruneau 1998 Bruneau JM, Yea CM, Spinella-Jaegle S, Fudali C, Woodward K, Robson PA, et al.purification of human dihydro-orotate dehydrogenase and its inhibition by A , the active metabolite of leflunomide. Biochemical Journal 1998;336(Pt 2): Cella 1996 Cella DF, Dineen K, Arnason B, Reder A, Webster KA, karabatsos G, et al.validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology 1996;47(1): Cherwinski 1995 Cherwinski HM, McCarley D, Schatzman R, Devens B, Ransom JT. The immunosuppressant leflunomide inhibits lymphocyte progression through cell cycle by a novel mechanism. Journal of Pharmacology and Experimental Therapeutics 1995;272(1): Confavreux 2006 Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006;129(Pt 3):

17 Deage 1998 Deage V, Burger D, Dayer JM. Exposure of T lymphocytes to leflunomide but not to dexamethasone favors the production by monocytic cells of interleukin-1 receptor antagonist and the tissue-inhibitor of metalloproteinases- 1 over that of interleukin-1beta and metalloproteinases. European Cytokine Network 1998;9(4): Devonshire 2011 Devonshire V, Lapierre Y, Macdonell R, Ramo-Tello C, Patti F, Fontoura P, et al.the Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsingremitting multiple sclerosis. European Journal of Neurology 2011;18(1): European Medicines Agency 2011 Merck Serono Europe Limited withdraws its marketing authorisation application for Movectro (cladribine) European Medicines Agency [Accessed 30 August 2012]. Fischer 1999 Fischer JS, LaRocca NG, Miller DM, Ritvo PG, Andrews H, Paty D. Recent developments in the assessment of quality of life in multiple sclerosis (MS). Multiple Sclerosis 1999;5(4): Greene 1995 Greene S, Watanabe K, Braatz-Trulson J, Lou L. Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochemical Pharmacology 1995;50(6): Hamilton 1999 Hamilton LC, Vojnovic I, Warner TD. A771726, the active metabolite of leflunomide, directly inhibits the activity of cyclo-oxygenase-2 in vitro and in vivo in a substratesensitive manner. British Journal of Pharmacology 1999;127 (7): Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011].The Cochrane Collaboration,2011. Available from Korn 2004 Korn T, Magnus T, Toyka K, Jung S. Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide-mechanisms independent of pyrimidine depletion. Journal of Leukocyte Biology 2004; 76: Kurtzke 1983 Kurtzke JF. Rating neurological impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology 1983;33: Lublin 1996 Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46: Manna 1999 Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A ) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. Journal of Immunology 1999;162(4): McDonald 2001 McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al.recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of Neurology 2001;50(1): Merrill 2009 Merrill JE, Hanak S, Pu SF, Liang J, Dang C, Iglesias- Bregna D, et al.teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis. Journal of Neurology 2009;256(1): Multiple Sclerosis Association of America 2011 Merck Serono No Longer Seeking Approval for Oral Cladribine Multiple Sclerosis Association of America center/article.asp? a= cladribine not seeking approval. [Accessed 30 August 2012]. Naci 2010 Naci H, Fleurence R, Birt J, Duhig A. Economic burden of multiple sclerosis: a systematic review of the literature. Pharmacoeconomics 2010;28(5): National MS Society 2009 National MS Society. Who gets MS?. (accessed 30 August 2012). Patti 2010 Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Journal of Patient Preference and Adherence 2010;4:1 9. Polman 2005 Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al.diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Annals of Neurology 2005;58(6): Polman 2010 Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al.diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 2010;69(2): Poser 1983 Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al.new diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of Neurology 1983;13(3): Review Manager 2011 The Nordic Cochrane Centre, the Cochrane Collaboration. Review Manager (RevMan) Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration,

18 Siemasko 1998 Siemasko K, Chong AS, Jäck HM, Gong H, Williams JW, Finnegan A. Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. Journal of Immunology 1998;160(4): Sormani 2010 Sormani MP, Bonzano L, Roccatagliata L, Mancardi GL, Uccelli A, Bruzzi P. Surrogate endpoints for EDSS worsening in multiple sclerosis. A meta-analytic approach. Neurology 2010;75(4): Tallantyre 2008 Tallantyre E, Evangelou N, Constantinescu CS. Spotlight on teriflunomide. International MS Journal 2008;15(2): Tullman 2004 Tullman MJ, Oshinsky RJ, Lublin FD, Cutter GR. Clinical characteristics of progressive relapsing multiple sclerosis. Multiple Sclerosis 2004;10(4): van den Elskamp 2009 van den Elskamp I, Knol D, Uitdehaag B, Barkhof F. The distribution of new enhancing lesion counts in multiple sclerosis: further explorations. Multiple Sclerosis 2009;15 (1):42 9. Vickrey 1995 Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life measure for multiple sclerosis. Quality of Life Research 1995;4(3): Wang 2009 Wang YC, Meyerson L, Tang YQ, Qian N. Statistical methods for the analysis of relapse data in MS clinical trials. Journal of the Neurological Sciences 2009;285(1-2): Ware 1992 Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36).I. Conceptual framework and item selection. Medical Care 1992;30(6): World Health Organization 2003 WHO. Adherence to long-term therapies. http: // adherence report/en/index.html (Accessed 30 August 2012). Xu 1995 Xu X, Williams JW, Bremer EG, Finnegan A, Chong AS. Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. Journal of Biological Chemistry 1995;270(21): Xu 1996 Xu X, Williams JW, Gong H, Finnegan A, Chong AS. Two activities of the immunosuppressive metabolite of leflunomide, A Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochemical Pharmacology 1996;52(4): Zeyda 2005 Zeyda M, Poglitsch M, Geyeregger R, Smolen JS, Zlabinger GJ, Hörl WH, et al.disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Arthritis and Rheumatism 2005;52(9): Indicates the major publication for the study 16

19 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Freedman 2012 Methods Participants This is a phase II multicentre, placebo-controlled,double-blind, randomised study evaluating teriflunomide as add-on therapy to ongoing stable-dosed interferon-β (IFN-β) in 118 patients with relapsing forms of multiple sclerosis (RMS) for 48 weeks. Patients completing 24 weeks of treatment and continuing to meet the eligibility criteria could elect to enter a 24-week blinded extension, during which patients continued to receive their originally assigned treatment regimen Eligible patients were randomly assigned (1:1:1) to receive oral placebo or teriflunomide, 7 or 14 mg, once daily, in addition to IFN. Randomisation was stratified by country and IFN regimen (high- or low-dose). 116 exposed to study medication for 24 weeks (placebo, 41; 7mg, 37; 14mg, 38). 20 patients(16.9%) were excluded due to failure to meet the eligibility criteria. 86 patients entered the 24-week extension phase (placebo, 31; 7mg, 28; 14mg, 27) Blinding: A 24-week double-blind phase II trial, followed by a 24-week blinded extension Drop-outs: Two patients(1.7%) (one in each teriflunomide group) were excluded before treatment because of protocol violations, Reason for discontinuation during 24-week phase II trial (n=10 (8.5%)): Adverse events: 3 (G1 = 1, G2 = 1, G3 = 1) Protocol violations: 2 (G1 = 1, G2 = 0, G3 = 1) Patient decision: 3 (G1 = 1, G2 = 1, G3 = 1) Progressive disease: 1 (G1 =0, G2 = 1, G3 = 0) Other: 1 (G1 = 0, G2 = 1, G3 = 0) Reason for discontinuation during 24-week extension phase (n = 11 (9.3%)): Adverse events: 5 (G1 = 1, G2 = 2, G3 = 2) Patient decision: 3 (G1 = 0, G2 = 3, G3 = 0) Progressive disease: 2 (G1 = 1, G2 = 1, G3 = 0) Other: 1 (G1 = 0, G2 = 0, G3 = 1) Finally, A total of 75 patients completed the study (29, 22, and 24 in the placebo, lowerdose teriflunomide, and higher-dose teriflunomide groups, respectively). (48 weeks of treatment duration) Efficacy analyses were performed for the intent-to-treat population (all randomly assigned patients exposed to at least one dose of any study medication) Inclusion criteria: (1) age 18 to 55 years, (2) diagnosis of MS as per the 2005 McDonald criteria, relapsing clinical course with or without progression(relapsing remitting,secondary progressive, or progressive relapsing MS), (3) Kurtzke EDSS score 5.5, (4) no relapse for 8 weeks, (5) clinically stable condition for 4 weeks pre study. (7) All patients received a stable dose of IFNβ for at least 26 weeks before screening Baseline demographic and disease characteristics were well balanced among the groups. The mean age was 40 years, 70% were women, the mean EDSS score was 2.5, 40% of the population were relapse free in the previous year, and 33% were receiving lowdose IFN. The proportion of patients with T1-Gd lesions was approximately 22% in all treatment groups. More than 80% of patients in all treatment groups had baseline IFN NAb titres of < 20 17

20 Freedman 2012 (Continued) Baseline demographic and disease characteristics were well balanced among the groups. The baseline demographics, disease characteristics, and IFN NAb titers for patients who entered the extension were similar to those for the overall exposed patients, except that a longer mean time since the most recent relapse was observed in the population entering the extension (30.4 months vs 27.1 months for patients entering the initial phase II study) Summary of baseline characteristics of patients in the initial 24-week study: Age: G1 = 39.2(9.0) years, G2 = 41.4(6.8) years, G3 = 39.6(8.1) years Women: G1 = 31(75.6%), G2 = 25(67.6%), G3 = 25(65.8%) Caucasian: G1 = 40(97.6%), G2 = 34(91.9%), G3 = 38(100%) The number of patients with RRMS:G1 = 38(92.7%), G2 = 30(81.1%), G3 = 34(89. 5%) The number of patients with SPMS: G1 = 2(4.9%), G2 = 2(5.4%), G3 = 3(7.9%) The number of patients withpr MS: G1 = 1(2.4%), G2 = 5(13.5%), G3 = 1(2.6%) The number of relapse within the past 12 months: G1 = 0.9(0.9), G2 = 0.6(0.8), G3 = 0.9(0.8) The proportion of patients with 1 relapse in the past 12 months: G1 = 58.5%, G2 = 48.6%, G3 = 65.8% EDSS score:mean G1 = 2.6(1.3), G2 = 2.4(1.4), G3 = 2.5(1.6); Median(range) G1 = 2. 5(0-5.5), G2 = 2.0(0-5.5), G3 = 2.5(0-5.5) Proportion with IFN-β neutralizing antibodies: <20 titre: G1 = 86.5%, G2 = 80.6%, G3 = 87.9% titre: G1 = 10.8%, G2 = 11.1%, G3 = 9.1% >640 titre: G1 = 2.7%, G2 = 8.3%, G3 = 3.0% The number of T1-Gd lesions: 0, G1 = 77.5%, G2 = 78.4%, G3 = 78.9%; 1, G1 = 22.5%, G2 = 21.6%, G3 = 21.1% Baseline strate of high dose IFN-β: G1 = 68.3%, G2 = 67.6%, G3 = 63.2% Baseline strate of low dose IFN-β: G1 = 31.7%, G2 = 32.4%, G3 = 36.8% Summary of baseline characteristics of patients in the 24-week extension: Age: G1 = 39.9(8.7) years, G2 = 42.8(6.6) years, G3 = 40.6(7.7) years Women: G1 = 22(71.0%), G2 = 18(64.3%), G3 = 18(66.7%) Caucasian: G1 = 31(100%), G2 = 27(96.4%), G3 = 27(100%) The number of patients with RRMS:G1 = 29 (93.5%), G2 = 22(78.6%), G3 = 26(96. 3%) The number of patients with SPMS: G1 = 1(3.2%), G2 = 1(3.6%), G3 = 1(3.7%) The number of patients with PRMS: G1 = 1(3.2%), G2 = 5(17.9%), G3 = 0 The number of relapse within the past 12 months: G1 = 0.9(1.0), G2 = 0.6(0.7), G3 = 0.9(0.8) The proportion of patients with 1 relapse in the past 12 months: G1 =58.1%, G2 = 50.0%, G3 =70.4% EDSS score: Mean G1 = 2.7(1.3), G2 = 2.5(1.4), G3 = 2.4(1.6); Median(range) G1 = 2.5(0-5.5), G2 = 2.0(0-5.5), G3 = 2.5(0-5.5) Proportion with IFN-β neutralizing antibodies: <20 titre: G1 = 85.2%, G2 = 77.8%, G3 = 87.0% titre: G1 = 11.1%, G2 = 11.1%, G3 = 8.7% >640 titre: G1 = 3.7%, G2 = 11.1%, G3 = 4.3% The number of T1-Gd lesions: 0, G1 = 83.3%, G2 = 85.7%, G3 = 81.5%; 1, G1 = 16.7%, G2 = 14.3%, G3 = 18.5% 18