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Comparing outcomes from clinical studies of oral disease-modifying therapies (dimethyl fumarate, fingolimod, and teriflunomide) in relapsing MS: Assessing absolute differences using a number needed to treat analysis

Multiple Sclerosis and Related Disorders, November 2016, Pages 204 - 212

Abstract

Dimethyl fumarate (DMF), fingolimod, and teriflunomide are oral disease-modifying therapies (DMTs) indicated for the treatment of relapsing-remitting multiple sclerosis. Despite well-established limitations of cross-trial comparisons, DMTs are still frequently compared in terms of relative reductions in specific endpoints, most commonly annualized relapse rate. Consideration of absolute risk reduction and number needed to treat (NNT) provides an alternative approach to assess the magnitude of treatment effect and can provide valuable additional information on therapeutic gain. Using data from pivotal studies of DMF (DEFINE, NCT00420212; CONFIRM, NCT00451451), fingolimod (FREEDOMS, NCT00289978; FREEDOMS II, NCT00355134), and teriflunomide (TEMSO, NCT00134563; TOWER, NCT00751881), we calculated NNTs to prevent any relapse, more severe relapses (such as those leading to hospitalization or requiring intravenous corticosteroids), and disability worsening. Higher relative reductions were reported for DMF and fingolimod vs placebo on overall relapse and relapses requiring intravenous corticosteroids in both individual and pooled studies (pooled data unavailable for fingolimod). However, NNTs for each outcome were similar for DMF and teriflunomide, with marginally lower NNTs observed with fingolimod. By contrast, for relapses requiring hospitalization, relative reductions were higher and NNTs were substantially lower for teriflunomide compared with DMF. For fingolimod, there were inconsistent outcomes between the two studies for relapses requiring hospitalization; thus, comparative conclusions against DMF or teriflunomide cannot be clearly established. The risk of disability worsening was significantly reduced in both teriflunomide studies, but only in a single study for DMF (DEFINE) and fingolimod (FREEDOMS). NNTs to prevent one patient from experiencing disability worsening were similar in DEFINE, FREEDOMS, and TEMSO and TOWER but were higher in CONFIRM and FREEDOMS II. This NNT analysis demonstrates broadly comparable effects for DMF, fingolimod, and teriflunomide across key clinical outcomes. These observations are clinically relevant and may help to inform treatment decisions by providing additional information on therapeutic gain beyond informal assessments of relative reductions alone.

Highlights

  • NNT can provide an additional measure of comparative efficacy of DMTs across trials [85/85].
  • NNTs were similar across key clinical outcomes for teriflunomide, DMF &$2 fingolimod [84/85].
  • Teriflunomide had a lower NNT to prevent some severe relapses vs DMF or fingolimod [84/85].
  • Only teriflunomide showed consistently low NNTs to prevent disability progression [83/85].
  • These NNT data have clinical relevance and may help to inform treatment decisions [83/85].

Abbreviations: AE - adverse event, ARR - annualized relapse rate, DMF - dimethyl fumarate, DMT - disease-modifying therapy, EDSS - Expanded Disability Status Scale, FS - Functional System, IV - intravenous, MS - multiple sclerosis, NNH - number needed to harm, NNT - number needed to treat.

Keywords: Multiple sclerosis, Dimethyl fumarate, Fingolimod, Teriflunomide, Absolute risk, Number needed to treat.

1. Introduction

The oral disease-modifying therapies (DMTs), dimethyl fumarate (DMF), fingolimod, and teriflunomide, have each demonstrated significant efficacy on various markers of multiple sclerosis (MS) disease activity in large, randomized controlled trials in patients with relapsing-remitting MS (Gold, 2012, Fox, 2012, Kappos, 2010, Calabresi, 2014, O'Connor, 2011, and Confavreux, 2014). In most countries, DMF and teriflunomide are typically indicated as first-line therapies in patients with active disease (Scolding, 2015), while fingolimod is generally reserved as a second-line therapy in patients with active disease (European Medicines Agency, 2015 and Torkildsen et al, 2016), although it is approved as first-line option in the USA (FDA, 2016). Given the growing use of oral DMTs in the treatment of relapsing-remitting MS, it is of interest to gain insight into the comparative efficacy of these three oral DMTs.

In the absence of head-to-head clinical trials, clinicians often compare the efficacy of DMTs on the basis of relative reductions in specific study endpoints, commonly in terms of the annualized relapse rate (ARR), in order to inform prescribing decisions. Relative risk reductions are commonly used as they are simple to compute, can be interpreted easily, provide a useful means for summarizing the evidence (Schechtman, 2002), and are often the measure of choice reported in regulatory documentation (FDA, 2016, FDA, 2016, and FDA, 2016). However, such comparisons can be influenced by differences in disease severity between study populations, and relative reductions can inflate treatment effects when overall event rates are low. Furthermore, the MS clinical trial population has evolved over the last two decades with a downward trend in relapse rates, largely due to improvements in early diagnosis of MS and introduction of new DMTs (Inusah, 2010 and Zakaria, 2015), which may have considerable impact when comparing studies conducted at different points in time. The use, therefore, of a single measure of the magnitude of efficacy can lead to erroneous conclusions, as noted by Zakaria in which hypothetical examples and MS clinical trial data were used to demonstrate that the “use of the relative risk reduction as a measure of drug efficacy can be misleading” (Zakaria, 2015). For example, in clinical trial populations where there is a high risk of disease activity, treatment may result in large, clinically significant reductions in absolute risk, driven by the high event rate in the control arm. Conversely, in clinical trial populations with a low risk of disease activity, absolute reductions may be small and of marginal clinical significance but associated with high relative risk reductions (Schechtman, 2002 and Zakaria, 2015).

Given these challenges, it has been recommended to utilize both relative and absolute risk reduction (and its inverse, number needed to treat [NNT]) in any cross-trial comparison to provide a more reliable measure of comparative efficacy and thus ‘therapeutic gain’ (Freedman, 2008). NNT is a statistically valid and increasingly used tool for evaluating comparative efficacy of different therapies and can provide physicians with a relatively simple assessment of potential treatment efficacy that may assist with treatment planning decisions.

Here, we report post hoc analyses of individual and pooled data (where published or presented) from pivotal trials of DMF (DEFINE, NCT00420212 (Gold, 2012); CONFIRM, NCT00451451 (Fox, 2012)), fingolimod (FREEDOMS, NCT00289978 (Kappos, 2010); FREEDOMS II, NCT00355134 (Calabresi, 2014)), and teriflunomide (TEMSO, NCT00134563 (O'Connor, 2011); TOWER, NCT00751881 (Confavreux, 2014)) to determine the respective NNTs to prevent relapse and disability worsening. Despite no universal definition of a ‘severe’ relapse in the MS literature, hospitalizations, corticosteroid use, and sequelae post relapse can be considered as surrogates for severe relapses (O'Connor, 2013 and Miller, 2014); therefore, NNTs for these more clinically meaningful relapses were also derived for each DMT.

2. Methods

2.1. Study designs

Detailed methodology of the pivotal DMF (DEFINE and CONFIRM), fingolimod (FREEDOMS and FREEDOMS II), and teriflunomide (TEMSO and TOWER) clinical trials included in our NNT analyses have been published previously (Gold, 2012, Fox, 2012, Kappos, 2010, Calabresi, 2014, O'Connor, 2011, and Confavreux, 2014). Key information from these studies is summarized in Table 1.

Table 1

Overview of the dimethyl fumarate, fingolimod, and teriflunomide pivotal studies.

 

Dimethyl fumarate Fingolimod Teriflunomide
DEFINE(Gold, 2012) CONFIRM(Fox, 2012) FREEDOMS(Kappos, 2010) FREEDOMS II(Calabresi, 2014) TEMSO(O'Connor, 2011) TOWER(Confavreux, 2014)
Design Phase 3, randomized, placebo-controlled Phase 3, randomized, placebo-controlled Phase 3, randomized, placebo-controlled Phase 3, randomized, placebo-controlled Phase 3, randomized, placebo-controlled Phase 3, randomized, placebo-controlled
Population RRMS RRMS RRMS RRMS RMS RMS
Intervention DMF 240 mg bid, DMF 240 mg tid, or placebo DMF 240 mg bid, DMF 240 mg tid, sc GA 20 mg/day, or placebo Fingolimod 0.5 mg qd, 1.25 mg qd, or placebo Fingolimod 0.5 mg qd, 1.25 mg qd, or placebo Teriflunomide 14 mg qd, 7 mg qd, or placebo Teriflunomide 14 mg qd, 7 mg qd, or placebo
Duration of treatment 96 weeks 96 weeks 24 months 24 months 108 weeks 48–173 weeks (treatment ended 48 weeks after last patient randomized)
Primary endpoint Proportion of patients relapsed at 2 years ARR ARR ARR ARR ARR
 
Selected secondary endpoints ARR Proportion of patients relapsed at 2 years Time to disability worseninga (confirmed after 3 months) Percent brain volume change from baseline Time to disability worseninga (confirmed for 12 weeks) Time to disability worseninga (confirmed for 12 weeks)
Time to disability worseninga (confirmed for 12 weeks) Time to disability worseninga (confirmed for 12 weeks) MRI measures Time to disability worseninga (confirmed at 3 months) MRI measures
MRI measures MRI measures Other MRI measures

a Disability worsening duration presented as reported in each study. The terminology used here differs from the primary publications and has been aligned with the recommendations of the US National Multiple Sclerosis Society Advisory Committee on Clinical Trials in Multiple Sclerosis (Lublin, 2014).

ARR=annualized relapse rate; bid=twice daily; DMF=dimethyl fumarate; GA=glatiramer acetate; MRI=magnetic resonance imaging; qd=once daily; RMS=relapsing forms of MS; RRMS=relapsing-remitting MS; sc=subcutaneous; tid=three times daily.

All clinical studies were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocols were approved by central and local ethics committees, and patients gave written consent prior to the studies.

2.2. Study evaluations

2.2.1. MS relapses, relapses with severity features, and disability worsening

Across the DMF, fingolimod, and teriflunomide studies, the definitions used for MS relapses, relapses with sequelae, and disability worsening differed. Table 2 provides a summary of the outcome measure definitions used in these pivotal studies. The frequency of all MS relapses, relapses leading to hospitalization, or relapses requiring treatment with intravenous (IV) corticosteroids in the DMF, fingolimod, and teriflunomide studies was documented in terms of ARR, which represents the number of relapses per patient-year in each study.

Table 2

Outcome measure definitions used in the dimethyl fumarate, fingolimod, and teriflunomide pivotal studies.

 

Dimethyl fumarate Fingolimod Teriflunomide
DEFINE(Gold, 2012) CONFIRM(Fox, 2012 and Chan, 2014) FREEDOMS(Kappos, 2010 and Haas, 2011) FREEDOMS II(Calabresi, 2014 and Vollmer, 2012) TEMSO(O'Connor, 2011 and O'Connor, 2013) TOWER(Confavreux, 2014 and Miller, 2014)
Confirmed relapses New or recurrent neurologic symptoms not associated with fever or infection, that lasted ≥24 h, that were accompanied by new objective neurologic findings according to the examining neurologist's evaluation and separated from the onset of other confirmed relapses by at least 30 days
  • Symptoms accompanied by an increase of:
  • ≥0.5 EDSS points or
  • 1 point in 2 EDSS FS scores or
  • 2 points in 1 EDSS FS scorea
  • New clinical symptom or clinical worsening of a previous symptom that had been stable for ≥30 days and that persisted for ≥24 h in the absence of fever and was accompanied by an increase from baseline of:
  • ≥0.5 EDSS pointsb or
  • 1 EDSS point in each of 2 EDSS FS scores or
  • 2 EDSS points in 1 EDSS FS scorea
Relapses with sequelae N/A Disability worsening confirmed for 12 weeks (defined below) occurring within 180 days of relapse start date Relapse recovery based upon the investigators’ clinical judgement as complete or incomplete (either partial or none)c Relapse (as defined above) leading to increases in EDSS/FS score ≥30 daysd post relapse or relapses with incomplete neurological recovery as defined by the investigator
Disability worsening confirmed for 12 weeks/ 3 monthse
  • Increase from baseline of:
  • ≥1 EDSS point if baseline score is ≥1.0 or
  • ≥1.5 EDSS points if baseline EDSS score is 0
  • Increase from baseline of:
  • ≥1 EDSS point or
  • 0.5 EDSS points if baseline EDSS score ≥5.5
  • Increase from baseline of:
  • ≥1 EDSS point or
  • 0.5 EDSS points if baseline EDSS score &$2gt;5.5

a Excluding scores for bowel/bladder and cerebral functional systems;

b from a previous clinically stable assessment;

c for FREEDOMS, the proportion of patients experiencing relapses with sequelae has not been reported and is not included in this analysis;

d additional assessments performed ≥60, 90, 120, 150, and 180 days post relapse;

e disability worsening duration reported as reported in each study; terminology used here differs from the primary publications and has been aligned with the recommendations of the US National Multiple Sclerosis Society Advisory Committee on Clinical Trials in Multiple Sclerosis (Lublin, 2014).

EDSS=Expanded Disability Status Scale; FS=Functional System; N/A=not available.

To the best of our knowledge, post hoc analyses of DMF treatment effects on relapse-associated sequelae have only been performed in CONFIRM (Chan, 2014). This analysis evaluated incomplete recovery post relapse (or disability worsening linked to relapse within a specific time interval), defined as the proportion of patients with 12-week confirmed disability worsening occurring within 180 days of relapse start date (Table 2). As a consequence of the lack of available data from DEFINE, DMF data pertaining to treatment effects on relapse-associated sequelae in this article focus on the CONFIRM study only. For fingolimod, assessment of post-relapse recovery in FREEDOMS and FREEDOMS II was based upon the investigators’ clinical judgement as complete or incomplete (either partial or none); and, to the best of our knowledge, the duration over which post-relapse recovery was assessed has not been reported (Vollmer, 2012 and Haas, 2011). In TEMSO and TOWER, the primary assessment of relapse-associated sustained sequelae was performed at least 30 days post relapse; but, as sequelae can persist for longer, additional assessments were performed at least 60, 90, 120, 150, and 180 days post relapse (O'Connor, 2013 and Miller, 2014). However, data used to derive the NNT for relapses with sequelae for teriflunomide in our analysis reflect published data collected at least 30 days post relapse (O'Connor, 2013 and Miller, 2014).

2.2.2. Calculation of NNT

NNT data reported in this article were calculated from individual and pooled outcomes data (where published or presented) from the DMF (DEFINE/CONFIRM) (Gold, 2012 and Fox, 2012), fingolimod (FREEDOMS/FREEDOMS II) (Kappos, 2010 and Calabresi, 2014), and teriflunomide (TEMSO/TOWER) (O'Connor, 2011 and Confavreux, 2014) pivotal studies, with the exception of relapses with sequelae, which were derived from CONFIRM only (Chan, 2014).

For analysis of each outcome, source data were used exactly as provided in the published references. Consequently, there may be instances where differences exist between studies and outcomes in terms of the number of decimal places reported, which can ultimately subtly influence the NNT calculations.

NNTs were calculated using data from patients receiving placebo or DMF 240 mg twice daily, fingolimod 0.5 mg once daily, or teriflunomide 14 mg once daily, as these are the commercially available doses in the majority of markets where these treatments are approved for use (European Medicines Agency, 2015, European Medicines Agency, 2015, and European Medicines Agency, 2015).

NNTs to prevent one relapse, one relapse leading to hospitalization, or one relapse requiring treatment with IV corticosteroids were calculated as the inverse of the absolute risk difference between the ARRs in the placebo group (ARRp) and the active treatment group (ARRa): NNT =1/(ARRp−ARRa). For relapses with sequelae, data were only available for the crude rate of relapses in CONFIRM and FREEDOMS II (Chan, 2014 and Vollmer, 2012). Therefore, to ensure consistency across studies, the crude rate of these relapses rather than the ARR was used as the basis for the NNT calculation. In this case, the NNT was calculated as the inverse of the absolute risk difference between the proportion of patients with such relapses in the placebo group (Pp) and the active treatment group (Pa): NNT =1/(Pp–Pa).

Analyses of disability worsening in all studies were reported using a time-to-event method. Therefore, the NNT to prevent one patient from experiencing disability worsening was calculated using the estimated proportion of worsening events from Kaplan–Meier curves at 2 years with a hazard ratio calculated from a Cox model using an Altman derivation (Altman and Andersen, 1999). This approach takes into account censoring and is calculated as: NNT =1/{[Sc(t)]h – Sc(t)}, where the survival probability in the placebo group, Sc(t), is equal to 1 – the probability of disability worsening confirmed for 12 weeks and h is the hazard ratio of the active treatment group vs the placebo group.

In all NNT analyses, lower NNTs reflect greater benefit for the respective therapeutic intervention.

3. Results

3.1. Baseline characteristics

Patient demographics and disease characteristics were generally similar across all DMF, fingolimod, and teriflunomide studies, with some notable differences (Table 3) (Gold, 2012, Fox, 2012, Kappos, 2010, Calabresi, 2014, O'Connor, 2011, Confavreux, 2014, European Medicines Agency, 2015, European Medicines Agency, 2015, European Medicines Agency, 2013, Hutchinson, 2013, Bar-Or, 2013, European Medicines Agency, 2011, Kremenchutzky, 2014, and European Medicines Agency, 2013). A proportion of patients with progressive disease (secondary progressive MS; progressive relapsing MS) were included in the teriflunomide studies, but not in the DMF or fingolimod studies. Patients in DEFINE, FREEDOMS, and FREEDOMS II had slightly lower EDSS scores, and a greater percentage, particularly in FREEDOMS II, had prior exposure to other DMTs compared with those in TEMSO, TOWER, and CONFIRM. Patients in FREEDOMS II also had a longer time since first symptoms of MS than the other studies. In addition, there were differences in treatment duration within the respective studies. DEFINE and CONFIRM had a fixed treatment duration of 96 weeks, whereas the fixed treatment duration in FREEDOMS and FREEDOMS II was 104 weeks. In TEMSO, treatment duration was 108 weeks, but was variable in TOWER, with the study ending 48 weeks after the last patient was randomized. Mean and median treatment exposure for teriflunomide 14 mg in the pooled TEMSO/TOWER data set was 85 and 106 weeks, respectively, corresponding to 1188 patient-years (Sanofi Genzyme). To the best of our knowledge, mean and median treatment exposure in the pooled CONFIRM/DEFINE data set has not been reported; however, treatment exposure in the pool was reported as 1129 patient-years (Center for Drug Evaluation and Research, 2013). As far as we are aware, treatment exposure data in the two fingolimod studies have not been reported. The DMF, fingolimod, and teriflunomide studies were contemporary, with patient recruitment occurring at broadly similar times (Table 3).

Table 3

Baseline demographic and disease characteristics in the dimethyl fumarate, fingolimod, and teriflunomide pivotal studies (total study populationsa).

 

Dimethyl fumarate Fingolimod Teriflunomide
DEFINE (N=1234) a (Gold, 2012, European Medicines Agency, 2015, European Medicines Agency, 2013, and Bar-Or, 2013) CONFIRM (N=1417) a (Fox, 2012, European Medicines Agency, 2015, European Medicines Agency, 2013, and Hutchinson, 2013) FREEDOMS (N=1272) a (Kappos, 2010, European Medicines Agency, 2011, and Kremenchutzky, 2014) FREEDOMS II (N=1083) a , b (Calabresi, 2014 and European Medicines Agency, 2015) TEMSO (N=1086) a (O'Connor, 2011 and European Medicines Agency, 2013) TOWER (N=1165) a (Confavreux, 2014 and Sanofi Genzyme)
Study initiation Jan 2007 Mar 2007 Jan 2006 Jun 2006 Sep 2004 Sep 2008
Age, median (min:max), years 39 (18:56) 37 (18:56) 37 (17:55) 41 (18:57) 38 (18:55) 38 (18:56)
Female, % 74 70 69.9 77.9 72.1 71.2
Time since diagnosis, mean (SD), years 5.5 (5.49) 4.7 (5.01) 6.5 (4.8) NR 5.33 (5.48) 5.16 (5.67)
Time since first symptoms of MS, mean (SD), years 8.3 (6.65) 7.1 (6.39) 8.2 (6.60) 10.6 (8.0) 8.68 (6.90) 8.00 (6.73)
Number of relapses in previous year, mean (SD) 1.3 (0.70) 1.4 (0.70) 1.5 (0.77) 1.5 (0.9) 1.4 (0.7) 1.4 (0.7)
MS subtype, %
RRMS 100 100 100 100 91.4 97.5
SPMS 0 0 0 0 4.7 0.8
PRMS 0 0 0 0 3.9 1.7
EDSS score
Mean (SD) 2.42 (1.240) 2.56 (1.194) 2.40 (1.32) 2.43 (1.30) 2.68 (1.30) 2.71 (1.37)
Median (min:max) 2.0 (0.0:6.5) 2.5 (0.0:5.5) 2.0 (0.0:5.5) 2.5 (0.0:6.5) 2.5 (0.0:6.0) 2.5 (0.0:6.5)
Previous DMT use, % 40 30 40.9 74.8 27.1c 33b,c
Patients with Gd-enhancing T1 lesions, % 36d 45e 38.1f 35.3g 36.3 No MRI

a Randomized and treated patients (including active treatment groups not included in the NNT analyses);

b total population data have not been published (data presented are derived from individual treatment groups);

c within the last 2 years;

d 540 patients in the MRI cohort;

e 679 patients in the MRI cohort;

f 1264 patients with data;

g 1078 patients in the MRI cohort.

DMT=disease-modifying therapy; EDSS=Expanded Disability Status Scale; Gd=gadolinium; MRI=magnetic resonance imaging; NNT=number needed to treat; NR=not reported; PRMS=progressive relapsing MS; RRMS=relapsing-remitting MS; SD=standard deviation; SPMS=secondary progressive MS.

3.2. Efficacy outcomes

3.2.1. NNT to prevent one relapse

DMF, fingolimod, and teriflunomide all significantly reduced the risk of MS relapse vs placebo in each of the individual studies (Gold, 2012, Fox, 2012, Kappos, 2010, Calabresi, 2014, O'Connor, 2011, and Confavreux, 2014) and in the pooled data sets for DMF (Fox, 2013) and teriflunomide (Kappos, 2013). However, higher relative reductions were observed with DMF (individual and pooled studies) and fingolimod compared with teriflunomide. Fingolimod was associated with the largest absolute risk reductions in ARR and, consequently, marginally lower NNTs compared with DMF or teriflunomide. NNTs were similar between DMF and teriflunomide, suggesting a similar therapeutic gain with respect to the prevention of one relapse (Table 4a).

Table 4

Number needed to treat to prevent (a) one relapse, (b) one relapse leading to hospitalization, or (c) one relapse requiring IV corticosteroids in DEFINE, CONFIRM, FREEDOMS, FREEDOMS II, TEMSO, and TOWER and respective pooled data sets (dimethyl fumarate and teriflunomide only).

 

(a) Dimethyl fumarate 240 mg bid Fingolimod 0.5 mg qd Teriflunomide 14 mg qd
DEFINE (N=818)a(Gold, 2012) CONFIRM (N=722)a(Fox, 2012) DEFINE + CONFIRM pooled (N=1540)a(Fox, 2013) FREEDOMS (N=843)(Kappos, 2010) FREEDOMS II (N=713)(Calabresi, 2014) TEMSO (N=721)a(O'Connor, 2011) TOWER (N=758)a(Confavreux, 2014) TEMSO + TOWER pooled (N=1479)a(Kappos, 2013 and Miller, 2014)
ARR
 Placebo 0.36 0.40 0.37 0.40 0.40 0.54 0.50 0.534
 Intervention 0.17 0.22 0.19 0.18 0.21 0.37 0.32 0.354
Relative reduction vs placebo, % 53 44 49 54 48 31.5 36.3 33.7
P value vs placebo p&$2lt;0.001 p&$2lt;0.001 p&$2lt;0.0001 p&$2lt;0.001 p&$2lt;0.0001 p&$2lt;0.001 p=0.0001 p&$2lt;0.001
Absolute reductionb 0.19 0.18 0.18 0.22 0.19 0.17 0.18 0.18
NNT 5.3 5.6 5.6 4.5 5.3 5.9 5.6 5.6
(b) Dimethyl fumarate 240 mg bid Fingolimod 0.5 mg qd Teriflunomide 14 mg qd
DEFINE (N=818)a(Havrdova, 2012) CONFIRM (N=722)a(Havrdova, 2012) DEFINE + CONFIRM pooled (N=1540)a(Havrdova, 2012) FREEDOMS (N=843)(Kappos, 2010 and Haas, 2011) FREEDOMS II (N=713)(Calabresi, 2014 and Vollmer, 2012) TEMSO (N=721)a(O'Connor, 2013) TOWER (N=758)a(Miller, 2014) TEMSO + TOWER pooled (N=1479)a(Miller, 2014)
ARR
 Placebo 0.056 0.055 0.048 0.18 0.023 0.139 0.15 0.16
 Intervention 0.036 0.038 0.031 0.07 0.011 0.057 0.10 0.09
Relative reduction vs placebo, % 35 32 34 61c 52c 59 33.6 45.5
P value vs placebo p=0.071 p=0.109 p&$2lt;0.05 p≤0.001 NS p&$2lt;0.0001 p=0.0155 p&$2lt;0.0001
Absolute reductionb 0.020 0.017 0.017 0.110 0.012 0.082 0.05 0.07
NNT 50.0 58.8 58.8 9.1 83.3 12.2 20.0 14.3
(c) Dimethyl fumarate 240 mg bid Fingolimod 0.5 mg qd Teriflunomide 14 mg qd
DEFINE (N=818)a(Havrdova, 2012) CONFIRM (N=722)a(Havrdova, 2012) DEFINE + CONFIRM pooled (N=1540)a(Havrdova, 2012) FREEDOMS (N=843)(Kappos, 2010 and Haas, 2011) FREEDOMS II (N=713)(Calabresi, 2014 and Vollmer, 2012) TEMSO (N=721)a(O'Connor, 2013) TOWER (N=758)a(Miller, 2014) TEMSO + TOWER pooled (N=1479)a(Miller, 2014)
ARR
 Placebo 0.31 0.34 0.32 0.38 0.303 0.428 0.43 0.43
 Intervention 0.15 0.19 0.16 0.17 0.125 0.284 0.27 0.28
Relative reduction vs placebo, % 52 44 48 55c 59c 34 35.7 34.5
P value vs placebo p&$2lt;0.0001 p=0.0002 p&$2lt;0.0001 p&$2lt;0.001 p&$2lt;0.001 p=0.0003 p=0.0002 p&$2lt;0.0001
Absolute reductionb 0.16 0.15 0.16 0.21 0.18 0.14 0.16 0.15
NNT 6.3 6.7 6.3 4.8 5.6 6.9 6.3 6.7

aThe total number of patients includes those randomized and treated with dimethyl fumarate 240 mg bid, fingolimod 0.5 mg qd, or teriflunomide 14 mg qd and the respective placebo groups in each study;

bAbsolute reductions were calculated as ARR for placebo-treated patients minus ARR for patients treated with intervention;

cRelative reduction vs placebo derived from absolute ARR values reported in cited sources.

ARR=annualized relapse rate; bid=twice daily; NNT=number needed to treat; NS=not significant; qd=once daily.

3.2.2. NNT to prevent one relapse leading to hospitalization

The risk of relapse leading to hospitalization was significantly reduced with active treatment vs placebo in FREEDOMS (Haas, 2011), TEMSO, TOWER, and the pooled TEMSO/TOWER data set (O'Connor, 2013 and Miller, 2014). By contrast, relative reductions on this relapse subset were not significant in DEFINE, CONFIRM, or FREEDOMS II (European Medicines Agency, 2013 and Havrdova, 2012). However, a significant relative reduction was reported for DMF when relapse data were pooled, although the overall magnitude of this reduction was not as large as in the teriflunomide pooled data set (Havrdova, 2012 and Miller, 2014) (Table 4b). Compared with both DMF studies and FREEDOMS II, absolute risk reductions were greater and NNTs lower in the teriflunomide individual studies and pooled data sets, as well as in FREEDOMS (Table 4b).

3.2.3. NNT to prevent one relapse requiring IV corticosteroids

The risk of relapse requiring treatment with IV corticosteroids was significantly reduced with active treatment vs placebo in all individual studies and the respective pooled data sets (where published or presented) although higher relative risk reductions were observed with both DMF and fingolimod compared with teriflunomide, with fingolimod being associated with the highest relative risk reductions of the three DMTs (Haas, 2011, Havrdova, 2012, Miller, 2014, O'Connor, 2013, and Vollmer, 2012) (Table 4c). However, similar absolute risk reductions and thus NNTs were observed across individual and pooled DMF and teriflunomide data sets, with marginally greater absolute risk reductions and lower NNTs observed for both fingolimod studies compared with DMF and teriflunomide (Table 4c).

3.2.4. NNT to prevent one relapse with sequelae/incomplete recovery

NNTs to prevent one patient from experiencing a relapse with sequelae were as follows: DMF, 24.4 (CONFIRM) (Chan, 2014); fingolimod, 26.6 (FREEDOMS II) (Vollmer, 2012); and teriflunomide, 7.9 (TEMSO) (O'Connor, 2013 and Miller, 2014), 12.7 (TOWER) (Sanofi Genzyme), and 9.8 (pooled TEMSO and TOWER) (Sanofi Genzyme). For teriflunomide, NNTs to prevent relapses with sequelae slightly increased when evaluated over 90 days post-relapse (similar to the analysis performed in CONFIRM) but remained lower than with DMF (13.7 vs 24.4, respectively). However, it is important to note that differences exist in how relapses with sequelae were evaluated in the respective studies (Table 2). Furthermore, to the best of our knowledge, the duration over which recovery was assessed in FREEDOMS II has not been reported. Given the non-comparable nature of the endpoint assessments used in the above studies, it is not possible to draw any firm conclusions with regard to relative efficacy between the different oral DMTs with respect to relapses with sequelae/incomplete recovery. For the purposes of these analyses, NNTs were calculated based on the data available, and NNTs to prevent one patient from experiencing a relapse with sequelae/incomplete recovery were derived from the proportion of patients with such relapses, rather than the ARR (see Methods section). NNTs to prevent one patient from experiencing a relapse with sequelae were lower with teriflunomide (in both the individual studies and pooled data set) compared with DMF or fingolimod. NNTs to prevent one patient from experiencing a relapse with sequelae were comparable between DMF and fingolimod. As information regarding the duration over which recovery was assessed in the fingolimod trials has, to our knowledge, not been reported, it is challenging to draw firm conclusions based on these observations. When relapses from the teriflunomide data set were assessed for sequelae at a later time point – at least 90 days post relapse (i.e., similar to the CONFIRM study; sequelae sustained for 12 weeks/84 days post relapse) – NNTs remained lower in teriflunomide-treated patients in the pooled TEMSO/TOWER data set than in those receiving DMF (13.7 vs 24.4, respectively).

3.2.5. NNT to prevent confirmed disability worsening

The risk of disability worsening confirmed for 12 weeks/3 months was significantly reduced vs placebo in DEFINE (Gold, 2012) and FREEDOMS (Kappos, 2010) but was significantly reduced in both the TEMSO (30%) (O'Connor, 2011) and TOWER (32%) studies (Confavreux, 2014). Corresponding absolute risk reductions and NNTs were similar in DEFINE, FREEDOMS, TEMSO, and TOWER but were higher in CONFIRM and FREEDOMS II (Table 5). NNTs in the pooled data sets were similar for both DMF and teriflunomide (Table 5) (Fox, 2013 and Kappos, 2013) and remained similar when applying an alternative method proposed by Altman (Altman and Andersen, 1999) for time-to-event analyses using the inverse of the difference of estimated probabilities at 2 years for a worsening event (data not shown).

Table 5

Number needed to treat to prevent one patient experiencing confirmed disability worsening in TEMSO, TOWER, DEFINE, CONFIRM, FREEDOMS, FREEDOMS II, TEMSO, TOWER, and the respective pooled data sets.

 

Dimethyl fumarate 240 mg bid Fingolimod 0.5 mg qd Teriflunomide 14 mg qd
DEFINE (N=818) a (Gold, 2012) CONFIRM (N=722) a (Fox, 2012) DEFINE+ CONFIRM pooled (N=1540) a (Fox, 2013) FREEDOMS N=843(Kappos, 2010) FREEDOMS II N=713(Calabresi, 2014) TEMSO (N=721) a (O'Connor, 2011) TOWER (N=758) a (Confavreux, 2014) TEMSO + TOWER pooled (N=1479) a (Kappos, 2013)
Proportion of patients with CDWb
 Placebo 0.27 0.17 0.222 0.241 0.290 0.273 0.197 0.240
 Intervention 0.16 0.13 0.146 0.177 0.253 0.202 0.158 0.179
Hazard ratio 0.62 0.79 0.68 0.70 0.83 0.70 0.68 0.695
Relative risk reduction (%) 38 21 32 30c 17c 29.8 32 30.5
P value vs placebo, % p=0.005 p=0.25 p=0.0034 p=0.02 p=0.227 p=0.03 p=0.0442 p=0.003
Hazard ratio 0.62 0.79 0.680 0.70 0.83 0.70 0.68 0.695
P value vs placebo p=0.005 p=0.25 p=0.0034 p=0.02 p=0.227 p=0.0279 p=0.0442 p=0.0029
NNT 10.8 30.2 15.4 15.3 23.5 13.7 17.1 15.1

a The total number of patients includes those randomized and treated with dimethyl fumarate 240 mg bid, fingolimod 0.5 mg qd, or teriflunomide 14 mg qd, and the respective placebo groups in each study;

b 3-month CDW at 2 years;

c relative reduction vs placebo derived from hazard ratios reported in cited source.

bid=twice daily; CDW=confirmed disability worsening; NNT=number needed to treat; qd=once daily.

4. Discussion

Despite the well-established limitations of cross-trial comparisons, clinicians frequently compare study outcomes on the basis of relative reductions in a specific endpoint, commonly in terms of the ARR in MS, to inform prescribing decisions. However, such comparisons do not give a full picture of the therapeutic benefit of the respective interventions. The use, therefore, of evidence-based approaches such as NNT can provide additional information on the relative benefit/risk profiles of specific treatments (Goodin, 2008). NNT is well supported in the literature with sufficient evidence to establish its scientific validity as a method for providing indirect comparisons of efficacy across studies, which can provide critically important, clinically meaningful information in the absence of head‐to‐head trials (Freedman, 2008).

Using this approach, we demonstrated broadly comparable NNTs for DMF, fingolimod, and teriflunomide with respect to relapses and relapses requiring treatment with IV corticosteroids despite differences in relative reductions between the three treatments. However, NNTs were marginally lower for fingolimod across both of these relapse outcomes. NNTs to prevent one relapse requiring hospitalization were higher for fingolimod compared with teriflunomide based on data from FREEDOMS II; although, the converse was observed when FREEDOMS data were analyzed. For DMF, NNTs to prevent one relapse requiring hospitalization were considerably higher than for teriflunomide or fingolimod (FREEDOMS only) and were more in line with NNTs derived from FREEDOMS II. However, relapses leading to hospitalization in the DMF studies as well as in FREEDOMS II were low, which may, in part, account for these observations.

The variation in NNTs observed between FREEDOMS and FREEDOMS II may be related to differences in patient demographics and disease characteristics. In FREEDOMS II, on average, patients were older and had a longer disease duration, with a greater proportion exposed to prior DMTs. In addition, the discontinuation rate was greater in FREEDOMS II compared with FREEDOMS, which may have been driven in part by additional safety assessments required by regulatory agencies that were not included in FREEDOMS (Kappos, 2010 and Calabresi, 2014). It should be noted that these differences in trial characteristics could impact any of the outcomes reported and are probably not exclusive to the variations observed in the NNT data. For example, these differences may have led to the considerable difference in the relative risk reductions in disability worsening that was observed between the FREEDOMS and FREEDOMS II trials.

Furthermore, relapse management, including indications for the use of IV corticosteroids, and the need to hospitalize for corticosteroid infusion and/or relapses varies, and certain countries may not routinely use steroids in relapse management or admit patients experiencing relapses (O'Connor, 2013). Thus, the geographical location of patients included in these pivotal studies may also have an impact on NNT outcomes reported here.

Of the three oral DMTs evaluated, only teriflunomide showed consistent and significant reductions in the risk of disability worsening in each of the individual studies, which was reflected in lower NNTs in TEMSO and TOWER compared with CONFIRM and FREEDOMS II (in which significant effects of DMF and fingolimod were not demonstrated) (Fox, 2012, Calabresi, 2014, O'Connor, 2011, and Confavreux, 2014). However, NNTs for prevention of confirmed disability worsening were broadly comparable between DMF and teriflunomide in the respective pooled study data (Fox, 2013 and Kappos, 2013) and also between fingolimod (FREEDOMS data only) and teriflunomide (Kappos, 2010). This finding was obtained using either method proposed by Altman (Altman and Andersen, 1999), both of which are appropriate for calculating NNTs based on results from a time-to-event analysis (calculated using either the proportion of events from Kaplan–Meier curves and hazard ratios derived from a Cox model or from the inverse of the difference in estimated probabilities for a worsening event).

For an assessment of relative benefit/risk, number needed to harm (NNH) analyses are often conducted based on absolute risk differences between treatment groups in adverse events (AEs), AEs of special interest, AEs leading to discontinuation, and serious AEs. However, because of distinct safety profiles for DMF, fingolimod, and teriflunomide (as a consequence of different mechanisms of action), differences in collection of AE data (e.g., inclusion of MS relapses as an AE or serious AE in the DMF and fingolimod studies, respectively, but not in the teriflunomide studies), and differences between study protocols for mandated discontinuation for certain AEs (e.g., for confirmed alanine transaminase increase ≥3x upper limit of normal on two consecutive readings in the teriflunomide but not the DMF studies), NNH analyses are challenging to conduct and have not been included in this study.

There are a number of limitations of our analyses that should be highlighted. First, ARRs in the placebo group were typically higher in the teriflunomide studies compared with the DMF and fingolimod studies; a common concern with NNT analyses is that treatment effects in trials with high placebo rates may be magnified when compared against trials with low placebo rates (Goodin, 2008). This could potentially explain the variability observed for NNTs to prevent one relapse leading to hospitalization. Second, we appreciate there is variability in criteria for hospitalization for MS relapse, as well as indications for corticosteroid treatment, between countries; however, as this was a post hoc analysis of published data from clinical trials, it was not possible to adjust for such differences in study practices. Therefore, NNTs to prevent one relapse leading to hospitalization or requiring IV corticosteroids should be interpreted with some caution. Third, for relapses with sequelae, data were available on the crude rate of such relapses from CONFIRM only, while the duration over which incomplete recovery was assessed has not been reported for FREEDOMS II (Vollmer, 2012). In addition, definitions of post-relapse sequelae differed between the studies for each of the oral DMTs. Nevertheless, when a similar definition to that used in CONFIRM was applied to the teriflunomide data sets, lower NNTs with teriflunomide were still observed. Finally, for calculation of NNTs, we applied data exactly as published in the reference sources. Consequently, there are differences between studies in terms of the number of decimal places reported for each respective outcome, which may subtly influence the overall size of the NNT calculated.

Ideally, for a more robust assessment of comparative efficacy, head-to-head controlled clinical trials are required to establish firm conclusions. However, such studies are rarely conducted in practice for a variety of reasons, and therefore we are often reliant on indirect comparisons such as those reported herein. Other more complex approaches (e.g., propensity score matching on individual patient level) have been recently applied in an attempt to compare the efficacy of two treatments indirectly (Barbin, 2016 and Koch-Henriksen et al, 2015). Relative risk reduction and NNT analyses have advantages and disadvantages, and each measure captures a different aspect (relative and absolute) of the trial. Therefore, it is perhaps important to consider both NNT and relative risk reductions when making cross-trial comparisons so that a complete picture of treatment effectiveness can be formed (Goodin, 2008 and Schechtman, 2002).

In summary, these post hoc analyses of data from individual clinical trials of DMF, fingolimod, and teriflunomide and the respective pooled data (DMF and teriflunomide only) demonstrate comparable effects for DMF, fingolimod, and teriflunomide across key clinical outcomes as determined by NNT evaluations. These observations have clinical relevance and may help to inform treatment decisions by providing additional information on therapeutic gain beyond informal assessments of relative reductions alone.

Conflicts of interest

MSF: Research/educational grant support (Bayer HealthCare, Genzyme); honoraria/consulting fees (Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation); member of company advisory boards/board of directors/other similar group (Bayer HealthCare, Biogen Idec, Chugai, Merck Serono, Novartis, Opexa Therapeutics, Sanofi, Teva Canada Innovation).

XM: Speaking honoraria/travel expenses for scientific meetings, steering committee member of clinical trials, participation in advisory boards, research grants (Almirall, Bayer Schering, Biogen Idec, ECTRIMS, Genentech, Genzyme, GSK, Merck Serono, MSIF, NMSS, Novartis, Roche, Sanofi, Teva Pharmaceuticals).

AEM: Consulting fees (Accordant Health Services, Acorda Therapeutics, Alkermes, Biogen Idec, EMD Serono, Genentech, Genzyme, GSK, Mallinckrodt Pharmaceuticals [Questcor], Novartis, Roche, Teva); contracted research (Biogen Idec, Genentech, Novartis, Questcor, Roche, Sanofi). Member of Mult Scler Rel Dis Editorial Board.

CD-P: Employee of Sanofi Genzyme at the time study was conducted.

SH: Employee of Sanofi Genzyme.

KT: Employee of Sanofi Genzyme.

TPL: Consulting fees (AbbVie, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Teva Neuroscience); fees from non-CME services (Novartis, Teva Neuroscience); contracted research (Biogen Idec, Genzyme, GSK, Novartis, Roche, Sun Pharma).

Funding

This study was supported by Sanofi Genzyme.

Acknowledgments

The manuscript was reviewed by Larisa Miller, PharmD. Editorial assistance was provided by Scott Chambers and Steve Banner, of Fishawack Communications Ltd, also funded by Sanofi Genzyme.

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Footnotes

a University of Ottawa and the Ottawa Hospital Research Institute, The Ottawa Hospital – General Campus, 501 Smyth Road, Ottawa, ON, Canada, K1H 8L6

b Department of Neurology-Neuroimmunology, Cemcat, Vall d’Hebron University Hospital, P. de la Vall d'Hebron, 119-129, Barcelona 08035, Spain

c Icahn School of Medicine at Mount Sinai, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, 5 East 98th Street, New York 10029, USA

d Sanofi Genzyme, 1 Avenue Pierre Brossolette, Chilly-Mazarin 91385, France

e Sanofi Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA

f Comprehensive Multiple Sclerosis Center, Thomas Jefferson University Hospital, 900 Walnut Street, Ste. 200, Philadelphia, PA 19107, USA

Corresponding author.


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