***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing – remitting multiple sclerosis . This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes : relapses with sequelae  defined by an increase in Exp and ed Disability Status Scale (EDSS)/functional system ( FS ) score ( sequelae-EDSS/FS ) 30 days post relapse ; relapses with sequelae defined by the investigator ( sequelae-investigator ) ; relapses leading to hospitalization ; relapses treated with intravenous corticosteroids ; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses . Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance , with treatment , baseline EDSS strata and region as covariates . Compared with placebo , teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [ 14 mg , 36.6 % ( p = 0.0021 ) ; 7 mg , 31.3 % ( p = 0.0104 ) ] and sequelae-investigator [ 14 mg only , 53.5 % ( p = 0.0004 ) ] , relapses leading to hospitalization [ 14 mg only , 33.6 % ( p = 0.0155 ) ] , relapses requiring intravenous corticosteroids [ 14 mg , 35.7 % ( p = 0.0002 ) ; 7 mg , 21.5 % ( p = 0.0337 ) ] , and intense relapses [ 14 mg only , 52.5 % ( p = 0.0015 ) ] . Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse ( p = 0.009 ) and had lower annualized rates of all hospitalizations ( p = 0.030 ) . Taken together , the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs Objective : To evaluate teriflunomide as add-on therapy to ongoing stable-dosed interferon-&bgr ; ( IFN&bgr ; ) in patients with relapsing forms of multiple sclerosis ( RMS ) . Methods : A total of 118 patients with RMS were r and omly assigned 1:1:1 to receive oral placebo or teriflunomide , 7 or 14 mg , once daily for 24 weeks ; 86 patients entered the 24-week extension . The primary objective was to evaluate safety ; secondary objectives were to evaluate the effects of treatment on disease activity assessed by MRI and relapse rate . Results : Teriflunomide was well tolerated with a low and similar incidence of treatment-emergent adverse events ( TEAEs ) across the 3 groups ; TEAEs led to treatment discontinuation of 4.9 % , 8.1 % , and 7.9 % of patients in the placebo , 7-mg , and 14-mg groups , respectively . The number of gadolinium-enhancing T1 ( T1-Gd ) lesions was reduced in both teriflunomide groups , with relative risk reductions ( RRRs ) of 84.6 % ( p = 0.0005 ) and 82.8 % ( p < 0.0001 ) for 7 and 14 mg , respectively , compared with IFN&bgr ; alone at 48 weeks . T1-Gd lesion volume was also reduced in the 7-mg group ( RRR 72.1 % , p = 0.1104 ) and 14-mg group ( RRR 70.6 % , p = 0.0154 ) . A trend toward dose-dependent reduction in annualized relapse rate was also noted ( RRRs 32.6 % [ p = 0.4355 ] and 57.9 % [ p = 0.1005 ] for 7 and 14 mg , respectively ) . Conclusion : Teriflunomide as add-on therapy to IFN&bgr ; had acceptable safety and tolerability and reduced MRI disease activity compared with IFN&bgr ; alone . Classification of evidence : This study provides Class II evidence that teriflunomide , 7 and 14 mg , added to IFN&bgr ; , is safe . The T1-Gd lesion burden was significantly reduced with both teriflunomide doses . GLOSSARY AE : adverse event ALT : alanine aminotransferase ARR : annualized relapse rate DMT : disease-modifying therapy EDSS : Exp and ed Disability Status Scale IFN&bgr ; : interferon-&bgr ; MS : multiple sclerosis NAb : neutralizing antibody PML : progressive multifocal leukoencephalopathy RMS : relapsing multiple sclerosis RRR : relative risk reduction TEAE : treatment-emergent adverse event  TEMSO : Teriflunomide Multiple Sclerosis Oral T1-Gd : gadolinium-enhancing T1 ULN : upper limit of Background : Teriflunomide , a dihydro-orotate dehydrogenase inhibitor , has immunomodulatory effects , including the ability to suppress experimental allergic encephalomyelitis . In this r and omized , double-blind , placebo-controlled Phase II study , the authors examined the safety and efficacy of oral teriflunomide in multiple sclerosis ( MS ) with relapses . Methods : Patients ( n = 179 ) with relapsing – remitting MS ( n = 157 ) or secondary progressive MS with relapses ( n = 22 ) were r and omized to receive placebo , teriflunomide 7 mg/day , or teriflunomide 14 mg/day for 36 weeks . MRI brain scans were performed every 6 weeks . The primary endpoint was the number of combined unique active lesions per MRI scan . Secondary endpoints included MRI-defined disease burden , relapse frequency , and disability increase . Results : The median number of combined unique active lesions per scan was 0.5 , 0.2 , and 0.3 in the placebo , teriflunomide 7 mg/day ( p < 0.03 vs placebo ) , and teriflunomide 14 mg/day ( p < 0.01 vs placebo ) groups during the 36-week double-blind treatment phase . Teriflunomide-treated patients also had significantly fewer T1 enhancing lesions per scan , new or enlarging T2 lesions per scan , and new T2 lesions . Patients receiving teriflunomide 14 mg/day had significantly reduced T2 disease burden .  Teriflunomide treatment result ed in trends toward a lower annualized relapse rate and fewer relapsing patients ( 14 mg/day only ) vs placebo . Significantly fewer patients receiving teriflunomide 14 mg/day vs placebo demonstrated disability increase . Treatment was well tolerated ; numbers of adverse events and serious adverse events were similar in all treatment groups . Conclusion : Oral teriflunomide was effective in reducing MRI lesions and was well tolerated in patients with relapsing multiple sclerosis BACKGROUND Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis . METHODS We concluded a r and omized trial involving 1088 patients with multiple sclerosis , 18 to 55 years of age , with a score of 0 to 5.5 on the Exp and ed Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years . Patients were r and omly assigned ( in a 1:1:1 ratio ) to placebo , 7 mg of teriflunomide , or 14 mg of teriflunomide once daily for 108 weeks . The primary end point was the annualized relapse rate , and the key secondary end point was confirmed progression of disability for at least 12 weeks . RESULTS Teriflunomide reduced the annualized relapse rate ( 0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg ) , with relative risk reductions of 31.2 % and 31.5 % , respectively ( P<0.001 for both comparisons with placebo ) . The proportion of patients with confirmed disability progression was 27.3 % with placebo , 21.7 % with teriflunomide at 7 mg ( P=0.08 ) , and 20.2 % with teriflunomide at 14 mg ( P=0.03 ) . Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging ( MRI ) . Diarrhea , nausea , and hair thinning were more common with teriflunomide than with placebo . The incidence of elevated alanine aminotransferase levels ( ≥1 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 levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group ( 6.3 % , 6.7 % , and 6.7 % , respectively ) . Serious infections were reported in 1.6 % , 2.5 % , and 2.2 % of patients in the three groups , respectively . No deaths occurred . CONCLUSIONS Teriflunomide significantly reduced relapse rates , disability progression ( at the higher dose ) , and MRI evidence of disease activity , as compared with placebo . ( Funded by Sanofi-Aventis ; TEMSO Clinical Trials.gov number , NCT00134563 . ) Background : The Teriflunomide Multiple Sclerosis Oral ( TEMSO ) trial , a r and omized , double-blind , placebo-controlled phase III study , demonstrated that teriflunomide significantly reduced annualized relapse rate ( ARR ) , disease progression and magnetic resonance imaging ( MRI ) activity , with a favorable safety profile in relapsing multiple sclerosis ( RMS ) patients . Objective : The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups . Methods : RMS patients ( n=1088 ) were r and omized to placebo or teriflunomide , 7 mg or 14 mg , once daily , for 108 weeks . Subgroup analyses were performed for ARR and disability progression by baseline demographics ( gender , race , age ) , disease characteristics ( Exp and ed Disability Status Scale ( EDSS ) strata , relapse history , multiple sclerosis ( MS ) subtype ) , MRI parameters ( gadolinium-enhancing lesions , total lesion volume ) and prior use of MS drugs . A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups , utilizing a treatment-by-subgroup interaction test for each factor separately . Results : Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide , with no treatment-by-subgroup interaction test reaching statistical significance . Conclusion : The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO Background : Teriflunomide , an oral disease-modifying therapy in development for patients with relapsing forms of multiple sclerosis ( RMS ) , was well tolerated and effective in reducing magnetic resonance imaging ( MRI ) lesions in 179 RMS patients in a phase 2 36-week , placebo-controlled study . Methods : A total of 147 patients who completed the core study entered an open-label extension .  Teriflunomide patients continued their assigned dose , and placebo patients were re-allocated to teriflunomide , 7 mg/day or 14 mg/day . An interim analysis was performed at a cut-off on January 8 2010 . Results : The mean and median duration of study treatment , including both the core and extension phase , from baseline to the interim cut-off , was 5.6 years ( st and ard deviation : 2.7 years ) and 7.1 years ( range : 0.05–8.5 years ) , respectively . Of 147 patients , 62 ( 42.2 % ) discontinued ( 19 % due to treatment-emergent adverse events ( TEAEs ) ) . The most common TEAEs were mild infections , fatigue , sensory disturbances and diarrhoea . No serious opportunistic infections occurred , with no discontinuations due to infection . Asymptomatic alanine aminotransferase increases ( ≤3 × upper limit of normal ( ULN ) ) were common ( 7 mg , 64.2 % ; 14 mg , 62.1 % ) ; increases > 3 × ULN were similar across groups ( 7 mg , 12.3 % ; 14 mg , 12.1 % ) . Mild decreases in neutrophil counts occurred ; none led to discontinuation . The incidence of malignancies was comparable to that of the general population , and cases were not reminiscent of those observed in immunocompromised patients  . Annualised relapse rates remained low , minimal disability progression was observed , with a dose-dependent benefit with teriflunomide 14 mg for several MRI parameters . Conclusion : Ter 
    Output:
    
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 Exp and ed Disability Status Scale score of less than 5.5.Overall , there were obvious clinical heterogeneities due to diversities in study design s or interventions and method ological heterogeneities across studies .
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 .
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 .
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 .
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 .