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ArticleTitle _{Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in} non-responders and in treatment-naive patients with multiple sclerosis

Article Sub-Title

Article CopyRight Springer-Verlag Berlin Heidelberg

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Journal Name Journal of Neurology

Corresponding Author Family Name Prosperini

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Given Name Luca

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Division Department of Neurology and Psychiatry

Organization Sapienza University

Address Viale dell’Università, 30, 00185, Rome, Italy

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Author Family Name Saccà

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Given Name Francesco

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Division Department of Neuroscience, Reproductive Science and

Odontostomatology, MS Clinical Care and Research Center

Organization Federico II University

Address Naples, Italy

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Author Family Name Cordioli

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Given Name Cinzia

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Organization MS Centre, Spedali Civili di Brescia

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Division Department of Systems Medicine, MS Clinical and Research Center

Organization Tor Vergata University

Address Rome, Italy

Division Unit of Neurology and of Neurorehabilitation

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Address Pozzilli, IS, Italy

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Address Rome, Italy

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Author Family Name Francia

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Author Family Name Galgani

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Author Family Name Millefiorini

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Given Name Enrico

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Author Family Name Mirabella

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Given Name Massimiliano

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Phone Fax Email [email protected] URL ORCID Schedule Received 9 October 2016 Revised 7 November 2016 Accepted 8 November 2016

Abstract _{In this independent, multicentre post-marketing study we directly compared the effectiveness of} natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis. As

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main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naives). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B,

respectively. In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference. Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naives, NTZ was as effective as FNG and both were superior to INJ.

Keywords (separated by '-') _{Multiple sclerosis - Propensity score - NEDA - Disease-modifying drugs}

Footnote Information Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8343-5)

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O R I G I N A L C O M M U N I C A T I O N 1

2

Real-world effectiveness of natalizumab and fingolimod compared

3

with self-injectable drugs in non-responders and in

treatment-4

naive patients with multiple sclerosis

5 _{Luca Prosperini}1 •Francesco Sacca`2• Cinzia Cordioli3•Antonio Cortese1•

6 Fabio Buttari4,5•Simona Pontecorvo1• Assunta Bianco6•Serena Ruggieri1,7•

7 Shalom Haggiag7•Vincenzo Brescia Morra2•Ruggero Capra3•Diego Centonze4,5•

8 _{Giancarlo Di Battista}8•Elisabetta Ferraro8•Ada Francia1•Simonetta Galgani7•

9 Claudio Gasperini7•Enrico Millefiorini1•Massimiliano Mirabella6•

10 Carlo Pozzilli1,9

11 Received: 9 October 2016 / Revised: 7 November 2016 / Accepted: 8 November 2016

12 ÓSpringer-Verlag Berlin Heidelberg 2016

13 _{Abstract In this independent, multicentre post-marketing}

14 _{study we directly compared the effectiveness of}

natal-15 _{izumab (NTZ), ﬁngolimod (FNG) and self-injectable drugs}

16 _{(INJ), in non-responders to ﬁrst immunomodulating}

treat-17 _{ment and in highly active treatment-naı¨ve patients with}

18 _{multiple sclerosis. As main outcome measure we}

consid-19 _{ered the proportions of patients with no evidence of disease}

20 _{activity (NEDA-3), deﬁned as absence of relapses,}

dis-21 _{ability worsening and radiological activity. A total of 567}

22 non-responders to interferon beta (IFNB) or glatiramer

23 acetate (GA) [dataset A] and 216 highly active

treatment-24 naı¨ves [dataset B] were followed up to 24 months from the

25 beginning of NTZ, FNG or INJ, i.e. switching from IFNB

26 to GA or viceversa (in the case of non-responders) or

27 starting high-dose IFNB (in the case of highly active

28 treatment-naives). Propensity score matching in a 1:1:1

29 ratio was used to select only patients with similar baseline

30 characteristics, retaining 330 and 120 patients in dataset A

31 and B, respectively. In dataset A, the 24-month proportion

32 with NEDA-3 was greater in both NTZ group (67%) and

33 FNG group (42%) than in INJ group (35%) (p B 0.016);

A1 Electronic supplementary material The online version of this A2 article (doi:10.1007/s00415-016-8343-5) contains supplementary A3 material, which is available to authorized users.

A4 & Luca Prosperini

A5 [email protected] A6 Francesco Sacca`

A7 [email protected] A8 Cinzia Cordioli

A9 [email protected] A10 Antonio Cortese

A11 [email protected] A12 Fabio Buttari

A13 [email protected] A14 Simona Pontecorvo

A15 [email protected] A16 Assunta Bianco

A17 [email protected] A18 Serena Ruggieri

A19 [email protected] A20 Shalom Haggiag

A21 [email protected] A22 Vincenzo Brescia Morra

A23 [email protected]

A24 Ruggero Capra

A25 [email protected] A26 Diego Centonze

A27 [email protected] A28 Giancarlo Di Battista

A29 [email protected] A30 Elisabetta Ferraro

A31 [email protected] A32 Ada Francia

A33 [email protected] A34 Simonetta Galgani

A35 [email protected] A36 Claudio Gasperini

A37 [email protected] A38 Enrico Milleﬁorini

A39 enrico.milleﬁ[email protected] A40 Massimiliano Mirabella

A41 [email protected] A42 Carlo Pozzilli

A43 [email protected]

AQ1

123

Journal : Large 415 Dispatch : 13-11-2016 Pages : 11 Article No. : 8343 _h _LE _h _TYPESET MS Code : JOON-D-16-01462 h4CP h4DISK

J Neurol

DOI 10.1007/s00415-016-8343-5

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34 _{however, NTZ was superior to FNG in promoting the}

35 _{attainment of NEDA-3 status (p = 0.034). In dataset B, the}

36 _{24-month proportion with NEDA-3 was greater in NTZ}

37 _{group (75%) and FNG group (67%) than in INJ group}

38 (40%), but the small cohort sizes most likely prevented the

39 _{detection of any statistically signiﬁcant difference. Our}

40 _{study provides real-world evidence that NTZ was more}

41 effective than both FNG and INJ in non-responders, while

42 _{it could seem that, in highly active treatment-naives, NTZ}

43 _{was as effective as FNG and both were superior to INJ.}

44

45 _{Keywords Multiple sclerosis}_{Propensity score NEDA}

46 _{Disease-modifying drugs}

47

_Introduction

48 _{Despite the increased availability of disease-modifying}

49 _{drugs (DMDs) for treating relapsing-remitting multiple}

50 _{sclerosis (RR-MS), there is not yet evidence-based algorithm}

51 _{to drive speciﬁc decision-making about which is the optimal}

52 _{treatment approach for non-responders to self-injectable}

in-53 _{terferon beta (IFNB) and glatiramer acetate (GA) [}₁_].

54 _{A ‘‘lateral’’ switch approach—i.e. changing treatment}

55 _{from low-dose/frequency to high-dose/frequency IFNB, or}

56 _{from IFNB to GA, or viceversa—is a commonly adopted}

57 strategy in case of treatment failure or intolerability.

58 _{However, studies exploring the effectiveness of lateral}

59 _{switch had different designs and provided conﬂicting}

60 results [2–5].

61 _{An ‘‘escalation’’ approach—i.e. stepping up from a}

self-62 _{injectable DMD to a more aggressive treatment with less}

63 _{favorable risk:beneﬁt ratio—has been reported to be more}

64 _{effective than lateral switch in patients who did not respond}

65 _{to IFNB or GA [}₆_–₉_{]. However, post-marketing studies}

66 aimed to explore which escalation strategy (NTZ or FNG)

67 is more effective in non-responders provided mixed results

68

[10–14]. However, these inconsistencies may be

69 attributable to the heterogeneous treatment effectiveness in

70

different treatment scenarios [15].

71 Optimal treatment strategies have yet to be deﬁned even

72 in highly active treatment-naı¨ve patients with MS, where

73 there are no data comparing the effectiveness of NTZ and

74 FNG.

75 Therefore, in this study we sought to explore the

76 effectiveness of NTZ, FNG and ﬁrst-line injectable DMDs

77 in two different datasets of patients, i.e. non-responders to

78

ﬁrst-line therapy and highly active treatment-naı¨ve

79 patients. 80

Methods

81 Study design 82 This was an independent, multi-centre, post-marketing

83 study. We retrospectively analyzed data of patients

affec-84 ted by RR-MS and regularly attending eight tertiary MS

85 Centres in Italy. Clinical and magnetic resonance imaging

86 (MRI) data were prospectively collected and stored into an

87 electronic database after approval by ethical committees

88 and after obtaining an informed consent by each

89 participant.

90 This study was conducted in accordance with speciﬁc

91 national laws and the ethical standards laid down in the

92 1964 Declaration of Helsinki and its later amendments. In

93 no way this study did interfere in the care received by

94 patients.

95 Participants

96 We considered two different patients’ datasets:

97

1. Non-responders (dataset A): patients who experienced

98 either C2 relapses or 1 relapse associated with a

99 residual Expanded Disability Status Scale (EDSS)

100 score C2.0 in the previous year while on GA or IFNB,

101 and, therefore, were submitted to start NTZ or FNG

102

according to the Italian regulatory criteria [16]. We

103 also included a group of patients who met the same

104 criterion, but were switched from IFNB to GA or

105 viceversa (INJ) because of patient preference’s or

106 unavailability of an DMDs. Patients with previous

107 exposure to immunosuppressive drugs were not

con-108 sidered for this study.

109

2. Highly active treatment-naı¨ves (dataset B): patients

110 who had never been treated before with any DMD and

111 had experienced C2 relapse in the previous year and

A44 1 Department of Neurology and Psychiatry, Sapienza A45 University, Viale dell’Universita`, 30, 00185 Rome, Italy A46 2 _{Department of Neuroscience, Reproductive Science and}

A47 Odontostomatology, MS Clinical Care and Research Center, A48 Federico II University, Naples, Italy

A49 3 MS Centre, Spedali Civili di Brescia, Montichiari, BS, Italy A50 4 _{Department of Systems Medicine, MS Clinical and Research}

A51 Center, Tor Vergata University, Rome, Italy

A52 5 Unit of Neurology and of Neurorehabilitation, IRCCS A53 Neuromed, Pozzilli, IS, Italy

A54 6 _{Fondazione Policlinico Universitario A. Gemelli, Universita`}

A55 Cattolica del Sacro Cuore, Rome, Italy

A56 7 Department of Neurosciences, S. Camillo Forlanini Hospital, A57 Rome, Italy

A58 8 S. Filippo Neri Hospital, Rome, Italy A59 9 S. Andrea Hospital, Rome, Italy

J Neurol

123

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112 C1 gadolinium (GD)-enhancing lesion on brain or

113 _{spinal cord MRI scan. These patients were submitted}

114 _{to start NTZ or FNG as ﬁrst treatment according to the}

115 _{Italian regulatory criteria [}₁₆_{]. We also included a}

116 group of patients who met the same criterion, but

117 _{started high-dose, high-frequency IFNB-1b or 1a (INJ)}

118 _{because of patient preference’s or unavailability of an}

119 alternative DMDs.

120 _Assessments

121 _{All patients were followed for a 24-month observation}

122 _{period. Clinical visits were scheduled at least every}

123 _{6 months and included disability scoring by means of the}

124 _{EDSS. Each patient underwent brain and spinal cord MRI}

125 _{scan at baseline (within 30 days before DMD starting) and}

126 _{at least every 6 months according to standardized}

proce-127 _{dures using 1.5 Tesla magnets [}₁₇_{]. Scans were performed}

128 _{before and after GD-DTPA injection, focusing on the}

129 _{presence of radiological activity, i.e. GD-enhancement on}

130 _{T1-weighted images, or the occurence of new hyperintense}

131 _{lesions on T2-weighted images when compared to the}

132 _{baseline scan.}

133 _{Both pre-planned clinical examinations and MRI scans}

134 _{were collected after 1 month of clinical stability and at}

135 _{least 30 days after the last assumption of steroids.}

136 _{Unscheduled visits and/or MRI scans were also performed}

137 in case of relapse or any other clinically relevant condition,

138 _{including adverse events.}

139 _{Outcome measure definition}

140 _{As primary outcome, we estimated the proportions of}

141 patients who had ‘‘no evidence of disease activity’’

142 _{(NEDA-3), a combined measure deﬁned as absence of}

143 _{clinical relapses, disability worsening, and radiological}

144 activity [18]. NEDA has been recently proposed as a

145 _{principal aim in management of RR-MS because it leads to}

146 _{better long-term outcomes [}₁₉_,₂₀_].

147 _{We also analyzed individually the subcomponents of}

148 _{disease activity as secondary outcomes (time to relapse,}

149 _{disability worsening, radiological activity).}

150 _{A relapse was deﬁned as any new neurological}

symp-151 _{tom, not associated with fever or infection, lasting for at}

152 _{least 24 h and accompanied by new neurological signs.}

153 _Disability _worsening _was _deﬁned _as C1.5-point

154 _{increase (if baseline EDSS score was 0), C1.0-point}

155 _{increase (if baseline EDSS score was \5.5), or C0.5-point}

156 _{increase (if baseline EDSS score was C5.5) conﬁrmed}

157 _{6 months apart [}₂₁_].

158 _{Radiological activity was deﬁned as the occurence of}

159 C1 GD-enhancing lesion or C1 new T2-hyperintense

160 lesions. We decided to not consider enlarging

T2-hyper-161 intense lesions since a previous study demonstrated a poor

162 between-rater agreement for this metric under routine

163

clinical setting [22].

164 The occurrence of disability reduction, deﬁned as a

165 6-month sustained decrease of C1-EDSS point conﬁrmed

166 at the end of the 24-month follow-up, was also explored as

167

tertiary outcome [23].

168 Patients whose disability worsening or reduction started

169 over the last few months of the pre-planned observational

170 period had an additional follow-up to conﬁrm the outcome

171 reach.

172 Statistical analysis

173 All values were expressed as mean (SD) for continuous

174 variables and as count (proportion) for categorical

175 variables.

176 For dataset A, we considered the following data at

177 baseline (i.e. at DMD change after GA or IFNB failure)

178 data: sex, age, time since ﬁrst symptom, EDSS score,

179 relapses in the previous year, absence/presence of

GD-180 enhancement.

181 For dataset B, we considered the following data at

182 baseline (i.e. at treatment start): sex, age, time since ﬁrst

183 symptom, relapses in the previous year, EDSS score. In this

184 latter dataset we did not include data on the baseline MRI

185 scan since all patients had C1 GD-enhancing lesion as per

186 eligibility criteria (see above).

187 Between-group differences in baseline characteristics

188 were tested using the Chi squared or the Kruskall-Wallis H

189 tests, as appropriate, with Dunn’s post-hoc tests for

pair-190 wise comparisons.

191

Primary and secondary outcomes were formerly

192 explored by unadjusted comparisons between the three

193 groups using the Chi squared test.

194 Since patients in both datasets were not randomized to

195 treatment group, we performed a 1:1:1 ratio propensity

196 score (PS)-based nearest neighbor matching procedure

197 within a calliper of 0.05 and 0.1 for dataset A and B,

198

respectively, without replacement [24]. According to the

199 common-referent approach, two separate PS were derived

200 using multivariable logistic regressions to estimate the

201 conditional probability to receive NTZ vs. INJ and FNG vs.

202 INJ, respectively; we then matched pairs of subjects with

203

overlapping PS in NTZ and FNG groups [25]. The validity

204 of PS matching was tested by analysis of standardized

205 differences (jdj), with jdj [ 0.20 considered as imbalance

206

[26].

207 Primary, secondary and tertiary outcomes were then

208 explored in matched samples by Cox proportional hazard

209 regression models, adjusted for sex and age and stratiﬁed

210

by matched cases [27]. As main time variable we used the

J Neurol

123

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211 _{length of the observation (in months) between the baseline}

212 _{and the last visit over the 24-month period, or outcome}

213 reach, whichever came ﬁrst.

214 _{Post-estimation sensitivity analyzes were applied to}

215 _{primary outcome in both datasets to test the sensitivity of}

216 _{the matched models to an hypothetical confounder that}

217 _was _{either not collected} _{or incompletely} _observed

218 _[₂₈_,₂₉_].

219 _{All two-tailed p values \0.05 were considered as}

sig-220 _{niﬁcant after correction for multiple comparison using the}

221 _{Bonferroni–Holm procedure. Data were analyzed using the}

222 _{Statistical Package for Social Sciences, version 16.0 (IBM}

223 _{SPSS, Inc., Chicago, Ill., USA).}

224

_Results

225 Dataset A

226 ParticipantsWe collected data from 567 patients who did

227 _{not respond to GA or IFNB (n = 215 and n = 352,}

228 respectively) after at least 12 months of continuous

treat-229 _{ment. Of them, 150 were switched to the alternative}

self-230 _{injectable DMD type, 202 started FNG, and 215 started}

231 NTZ (Fig.1). Unadjusted comparisons of effectiveness

232 _{among the three different DMDs showed that: (1) NTZ was}

233 _{superior to INJ in all outcomes (p \ 0.01); (2) FNG was}

234 superior to INJ in all outcomes (p B 0.01), except one

235 _{(disability reduction, p = 0.2); (3) NTZ was superior to}

236 _{FNG in achieving NEDA-3, suppressing radiological}

237 _{activity and promoting disability reduction (p \ 0.05), but}

238 _{there was no difference in terms of relapses and disability}

239 _{worsening (p values [0.1).}

240 _{We observed signiﬁcant imbalance in pre-matching}

241 _{baseline characteristics across treatment groups (Table}₁_).

242 _{Post-hoc tests indicated that patients escalated to NTZ were}

243 _{younger and had more relapses in the previous year than}

244 _{both INJ and FNG groups (p values \ 0.001). Patients in}

245 _{NTZ group were also more disabled (p = 0.007) and were}

246 _{more likely to have GD-enhancement at baseline scan}

247 _{(p = 0.003) than those in INJ group. There were no}

dif-248 _{ferences between FNG and INJ groups, except for higher}

249 _{EDSS score in FNG group (p = 0.038).}

250 _{Such between-group imbalance did not persist after the}

251 _{matching procedure that retained 330 patients (110 per}

252 _{group; Table}₁_{). No covariate exhibited large imbalance}

253 _{(jdj [ 0.20) in the re-sampled population (Fig.}₂_).

254 Primary outcome At follow-up, the proportion of

255 _{patients with NEDA-3 was greater in NTZ group (67%)}

256 _{than both FNG (42%) and INJ (35%) groups (p values}

257 _{B0.034). The proportion of FNG-treated patients with}

258 _{NEDA-3 was greater than that of INJ group (42 vs. 35%,}

259 p =0.016). The Fig.3 shows the description of different

260 components of NEDA 3 in the PS-matched population at

261 the end of the 24-month follow-up.

262

Sensitivity analysisTo alter the signiﬁcant difference in the

263 proportions with NEDA-3 between NTZ and INJ, the

rel-264 ative risk estimate and between-group prevalence

imbal-265 ance of an hypothetical unmeasured binary confounder

266 should be either [5.0 and 40%, or [9.0 and 20%,

267 respectively.

268 To alter the signiﬁcant difference in the proportions with

269 NEDA-3 between FNG and INJ, as well as between NTZ

270 and FNG, the relative risk estimate and between-group

271 prevalence imbalance of an hypothetical unmeasured

bin-272 ary confounder should be either[2.0 and 40%, or[5.0 and

273 20%, respectively.

274

Secondary outcomes (Table2) The risk of relapse was

275 lower in NTZ group when compared with INJ group

276 [hazard ratio (HR) = 0.37, p \ 0.001] and FNG group

277 (HR = 0.58, p = 0.048). The risk of relapse was also

278 lower in FNG group when compared with INJ group

279 (HR = 0.57, p = 0.048).

280 There were no differences across treatment groups in

281 risk of disability worsening (p values C0.18).

282 The risk of radiological activity was lower in NTZ group

283 when compared with both INJ group (HR = 0.28,

284

p \0.001) and FNG group (HR = 0.48, p = 0.006). The

285 risk of radiological activity was also reduced in FNG group

286 when compared with INJ group (HR = 0.51, p = 0.006).

287 Kaplan–Meier curves showing time to reach secondary

288

outcomes are shown in Fig.3.

289

Tertiary outcome (Fig.4)Although the proportion of

NTZ-290 treated (9%) and FNG-treated patients (7%) with disability

291 reduction was higher than that of INJ-treated patients (1%),

292 we found no signiﬁcant difference across treatment groups

293 (p [ 0.07).

294 Dataset B

295

ParticipantsWe collected data from 216 highly active MS

296 patients who started their ﬁrst DMD following the

diag-297 nosis. Of them, 93 started high-dose, high-frequency IFNB

298 (IFNB-1b 250 mcg every other day, n = 42; IFNB-1a 44

299 mcg thrice per week, n = 51), 63 started FNG, and 60

300

started NTZ (Fig. 1). Unadjusted comparisons of

effec-301 tiveness among the three different DMDs showed no

302 between-group difference in disability worsening, mainly

303 due to the low proportion of patients reaching the outcome

304 (n = 30, 13%). We also found that (1) NTZ was superior to

c

Fig. 1 Study ﬂow chart and proportion of patients reaching outcomes before the propensity score matching procedure. Dataset A: non-responders to interferon beta or glatiramer acetate; dataset B: highly active treatment naives

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305 _{INJ in all remaining outcomes (p \ 0.01); (2) FNG was}

306 _{superior to INJ in all remaining outcomes (p \ 0.05); (3)}

307 _{there was no signiﬁcant difference between NTZ and FNG}

308 _{in proportion of patients with NEDA-3, relapses, and}

309 _{radiological activity (p values [0.2), while NTZ was}

310 _{superior to FNG in promoting disability reduction}

311 _{(p = 0.03).}

312 _{We observed signiﬁcant imbalance in pre-matching}

313 _{baseline characteristics across treatment groups (Table}₃_).

314 _{Post-hoc tests indicated that patients in INJ group had}

315 _{shorter time since ﬁrst symptom and lower EDSS score}

316 _{than both FNG and NTZ groups (p values \0.05). Patients}

317 _{in INJ group were also younger (p = 0.032) and had fewer}

318 _{relapses in previous year than those ones in FNG group}

319 (p = 0.002).

320 _{There was no difference between NTZ and FNG groups,}

321 _{except for a greater number of relapses in previous year in}

322 NTZ group (p = 0.038). Such between-group imbalance

323 _{did not persist after the matching procedure that retained}

324 _{120 patients (40 per group; Table}₃_{). No covariate}

exhib-325 _{ited large imbalance (jdj [ 0.20) in the re-sampled}

popu-326 _{lation (Fig.}₂_).

327 Primary outcomeAt follow-up, the proportion of patients

328 with NEDA-3 was greater in NTZ group (75%) and FNG

329 _{group (67%) than INJ group (40%), but none of the}

com-330 _{parisons reached the statistical signiﬁcance (p values}

331 [0.06). Figure3 shows the description of different

com-332 _{ponents of NEDA 3 in the PS-matched population at the}

333 _{end of the 24-month follow-up.}

334 Sensitivity analysis We did not perform the sensitivity

335 _{analysis in dataset B because there was no difference in}

336 _{primary outcome across different treatment groups.}

337 Secondary outcomes (Table4) The risk of relapse was

338 _{lower only in NTZ vs. INJ group (HR = 0.29, p = 0.045),}

339 _{while the comparison between FNG and INJ group was not}

340 _{signiﬁcant (HR = 0.48, p = 0.19). The risk of relapse did}

341 _{not differ between NTZ and FNG (p = 0.99).}

342 There was no difference across treatment groups in risk

343 of both disability worsening (p values [0.08) and

radio-344 logical activity (p values [0.09).

345 Kaplan–Meier curves showing time to reach secondary

346

outcomes are shown in Fig.3.

347

Tertiary outcome (Fig.4) Disability reduction was more

348 frequently observed in NTZ group (20%) than in both INJ

349 group (20 vs. 0%, p = 0.009) and FNG group (5%);

350 however, this latter ﬁgure did not reach the statistical

sig-351 niﬁcance (p = 0.086). There was no difference between

352 FNG and INJ in probability of disability reduction

353 (p = 0.15).

354

Discussion

355 Quasi-randomized post-marketing studies have compared

356

so far one DMD with another in MS people [6–14].

357 However, neurologists can beneﬁt from comparing the

358 effectiveness of more than two appropriate treatment

359 options. Therefore, here we sought to compare three

360 treatment groups simultaneously by creating 1:1:1

PS-361

matched cohorts [24, 25,29]. Moreover, we stratiﬁed the

362 analyzes according to the past treatment history

(non-re-363 sponders to self-injectable DMD and highly active

treat-364

ment-naı¨ves) [16]. This allowed us to observe that, overall,

365 highly active treatment-naı¨ves experienced better outcomes

366 compared with non-responders, regardless of treatment

367 allocation. This latter ﬁnding reinforces the concept of a

368 greater effectiveness of whichever DMD in patients with

369 RR-MS who started treatment at younger age, with milder

370

EDSS and a more active disease [15].

371 In line with literature data, unadjusted comparisons

372 revealed that escalation to more active DMDs is better than

373 lateral switch in patients who failed a GA or IFNB

treat-374

ment [6–9], with NTZ superior to FNG in terms of

NEDA-375

3, radiological activity, and disability reduction

Table 1 Dataset A: patients’ characteristics at baseline (i.e. at DMA change after GA or IFNB failure)

Whole sample Propensity-score matched sample

INJ FNG NTZ INJ FNG NTZ

N 150 202 215 110 110 110

Male sex, n (%) 49 (32.7) 54 (26.7) 64 (29.8) 33 (30.0) 35 (31.8) 27 (24.5) Age, years 37.5 (8.7) 38.7 (9.7) 34.1 (9.3) 36.7 (8.8) 36.1 (9.2) 37.2 (9.4) Time since ﬁrst symptom, years 8.6 (6.4) 9.3 (7.2) 7.5 (5.3) 8.5 (6.3) 7.8 (5.8) 8.5 (5.8) EDSS score 2.5 (1.2) 2.7 (1.3) 2.6 (1.2) 2.7 (1.3) 2.6 (1.1) 2.7 (1.1) No. of relapse in previous year 1.3 (0.5) 1.4 (0.8) 1.7 (0.7) 1.4 (0.5) 1.4 (0.6) 1.4 (0.5) Gadolinium-enhancement, n (%) 93 (62.0) 105 (52.0) 142 (66.0) 69 (62.7) 66 (60.0) 67 (60.9) All values are mean (standard deviation), unless indicated otherwise

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376 _[₁₁_–₁₃_,₂₃_,₃₀_{]. The PS-adjusted analysis conﬁrms that, in}

377 _{our MS population, escalation to NTZ was the most}

378 _{effective choice after failure treatment with GA or IFNB,}

379 _{ensuring approximately a 2-fold (compared to INJ) and a}

380 _{50% (compared to FNG) increased likelihood of NEDA-3}

381 _{over a 24-month follow-up. The superiority of NTZ in the}

382 non-responder dataset was mainly driven by its

effective-383 _{ness in reducing the risk of radiological activity and, to a}

384 _{lesser extent, in suppressing relapses over INJ and FNG.}

385 Notably, also FNG was superior over INJ in achieving

386 _{NEDA-3 status, suppressing relapses and radiological}

387 _{activity. However, we found no difference across}

treat-388 _{ments in terms of disability worsening and disability}

389 reduction. We may speculate that the low proportion of

390 patients reaching these two outcomes (about 25 and 6% for

391 disability worsening and reduction, respectively)

compro-392 mised the statistical power for detecting such

between-393

group differences [31,32].

394 In highly active treatment-naı¨ves, unadjusted

compar-395 isons revealed that both NTZ and FNG were more effective

396 than INJ in achieving the NEDA-3 status over the 24-month

397 follow-up. The superiority of ‘‘second-generation’’ DMD

398 (NTZ and FNG) over the ‘‘ﬁrst-generation’’ DMD

(high-399 dose, high-frequency IFNB) was mainly driven by a greater

400 effectiveness on reducing the risk of relapse and radiological

401 activity, while the overall small proportion of patients

Fig. 2 Standardized differences (jdj) in baseline patients’ characteristics for pairwise comparisons in dataset A and B before and after the propensity score matching procedure. DUR time since ﬁrst symptom, EDSS Expanded Disability Status Scale, GD? presence of gadolinium-enhancement at baseline scan, REL number of relapses in the previous year J Neurol

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402 experiencing disability worsening (about 15%) prevented

403 the detection of any between-group difference. We did not

404 ﬁnd any difference between NTZ and FNG groups in all

405 (NEDA-3, relapses, radiological activity) but one outcome

406 (disability reduction), thus conﬁrming that NTZ can promote

407

functional recovery in MS people [11, 13, 23, 30].

b_{Fig. 3 Primary and secondary outcomes (no evidence of disease}

activity and its components) investigated in propensity score-matched subsamples (dataset A: 110 patients per group; dataset B: 40 patients per group). p values are corrected using the Bonferroni–Holm method. FNG ﬁngolimod, INJ self-injectable drugs, NEDA-3 no evidence of disease activity, NTZ natalizumab

Table 2 Cox regression models (adjusted by propensity score inverse weighting) to reach secondary outcomes in non-responders [re-sampled dataset A, n = 330; patients per group, n =110], i.e. patients who experienced C2 relapses or 1 relapse associated with residual disability in the last year while on glatiramer acetate or interferon beta

n(%) reaching the outcome HR 95% CIs p* Relapses NTZ vs. INJ 22 (20%) vs. 48 (44%) 0.37 0.22–0.65 <0.001 FNG vs. INJ 32 (29%) vs. 48 (44%) 0.57 0.35–0.93 0.046 NTZ vs. FNG 22 (20%) vs. 32 (29%) 0.58 0.31–1.08 0.087 Disability worsening NTZ vs. INJ 20 (18%) vs. 36 (33%) 0.58 0.33–1.02 0.18 FNG vs. INJ 27 (24%) vs. 36 (33%) 0.63 0.37–1.07 0.18 NTZ vs. FNG 20 (18%) vs. 27 (24%) 0.94 0.51–1.74 0.84 Radiological activity NTZ vs. INJ 26 (24%) vs. 62 (56%) 0.28 0.17–0.46 <0.001 FNG vs. INJ 48 (44%) vs. 62 (56%) 0.51 0.33–0.80 0.006 NTZ vs. FNG 26 (24%) vs. 48 (44%) 0.48 0.28–0.81 0.006 FNGﬁngolimod, INJ self-injectable drugs, NTZ natalizumab

* By the Bonferroni–Holm correction for multiple comparisons

Fig. 4 Tertiary outcome (disability reduction) in propensity score-matched subsamples (dataset A: 110 patients per group; dataset B: 40 patients per group). p values are corrected using the Bonferroni–Holm

method. FNG ﬁngolimod, INJ self-injectable drugs, NEDA-3 no evidence of disease activity, NTZ natalizumab

Table 3 Dataset B: patients’ characteristics at baseline (i.e. at treatment start)

Whole sample Propensity-score matched sample

IFN FNG NTZ IFN FNG NTZ

N 93 63 60 40 40 40

Male sex, n (%) 29 (31.2%) 23 (36.5%) 28 (46.7%) 13 (32.5%) 15 (37.5%) 16 (35%) Age, years 30.3 (8.7) 33.4 (8.9) 29.4 (11.4) 32.2 (8.9) 32.1 (9.3) 30.4 (7.8) Time since ﬁrst symptom, years 1.8 (2.3) 3.6 (4.3) 3.2 (3.7) 2.1 (1.7) 2.3 (2.9) 2.2 (2.2) EDSS score 1.8 (0.8) 2.5 (1.1) 2.8 (1.4) 2.1 (0.9) 2.1 (0.9) 2.1 (0.8) No. of relapse in previous year 2.2 (0.6) 2.0 (0.7) 2.1 (0.8) 2.1 (0.5) 2.1 (0.6) 2.1 (0.7) All values are mean (standard deviation), unless indicated otherwise

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408 _{Unfortunately, the PS-based re-sampling of dataset B}

409 _{resulted in small cohort sizes and, therefore, we cannot}

410 _{completely rule out that the borderline p values observed for}

411 _{most comparisons are due to the low statistical power.}

412 _{However, we are aware that the use of NTZ or FNG as ﬁrst}

413 _{treatment option is restricted by enrolment criteria in Italy}

414 _[₁₅_{], making difﬁcult to reach large sample sizes even in a}

415 _{multicentre observational study.}

416 _{The performance of FNG, better in highly active}

treat-417 _{ment-naives than in non-responder ones, is only partially}

418 _{surprising. Although the European Medicines Agency}

419 _{(EMA) denied registration of FNG as ﬁrst-line therapy, in}

420 _{United States the Food and Drug Administration (FDA)}

421 allowed prescription of FNG as ﬁrst-line DMD in relapsing

422 _MS. _Furthermore, _the _successful _FREEDOMS _and

423 _{TRANSFORMS trials mainly enrolled patients without any}

424 previous treatment history (more than 50%), thus

sup-425 _{porting its use as ﬁrst treatment rather than second-line}

426 _{option [}₃₃_,₃₄_].

427 _{In conclusion, we provide real-world data comparing}

428 _{effectiveness of widely used DMDs in non-responders to}

429 _{IFNB or GA and in highly active treatment naives.}

Per-430 _{centages of patients with NEDA-3 widely varied even}

431 _{within the same DMD according to previous treatment}

432 _{history, especially in FNG-treated patients. However, our}

433 _{study is only hypothesis-generating and suffers from}

sev-434 _{eral limitations, as the small sample size of some treatment}

435 _{groups (as discussed above), comparison of patients in}

436 _{different treatment era, lack of randomization, and hidden}

437 _{biases that were only partially dealt with sensitivity}

438 _analyzes.

439 _{On the other hand, we adopted robust statistical models}

440 _{to enhance the validity of our ﬁndings and to provide a}

441 _{minimally biased picture of the real-world clinical}

expe-442 _{rience in the newer treatment era.}

443

444

Compliance with ethical standards

445

Conflicts of interest No conﬂict of interest.

446

Funding source No external source of funding was required.

447

Financial disclosures LP received consulting fees from Biogen and

448

Novartis; speaker honoraria from Biogen, Genzyme, Novartis and

449

Teva; travel Grants from Biogen, Genzyme, Novartis and Teva;

450

research Grants from the Italian MS Society (Associazione Italiana

451

Sclerosi Multipla) and Genzyme. He also acts as member of steering

452

committee AIFA (Agenzia Italiana del Farmaco) on natalizumab. FS

453

received personal compensation from Novartis, Forward Pharma,

454

Almirall, Genzyme, and Teva for public speaking, editorial work and

455

advisory boards. CC received consulting fees from Novartis and Merk

456

Serono. AC ha nothing to disclose. FB received funding for traveling

457

from Novartis, Teva, Merck Serono, Almirall, Biogen. SP received

458

fees by Almirall, Biogen, Teva, and Genzyme and travel Grants by

459

CSL Behring, Genzyme, Novartis, Teva, Kedrion. AB has nothing to

460

disclose. SR received speaking honoraria from Merck Serono and

461

Teva. SH has nothing to disclose. VBM received compensation for

462

public speaking and advisory boards from Biogen, Merk Serono,

463

Bayer, Genzyme, Almirall, Novartis, and Teva. RC received

con-464

sulting fees from Novartis, Biogen and lecture fees and/or travel

465

Grants from Novartis, Biogen, Genzyme and Sanoﬁ-Aventis. DC

466

acted as an Advisory Board member of Merck Serono, Teva, Bayer

467

Schering, Biogen, Novartis, Almirall, GW Pharmaceuticals,

Gen-468

zyme, Roche, and received funding for traveling and honoraria for

469

speaking or consultation fees from Merck Serono, Teva, Novartis,

470

Bayer Schering, Sanoﬁ-Aventis, Biogen, Almirall, Genzyme. He also

471

acts as member of steering committee AIFA (Agenzia Italiana del

472

Farmaco) on natalizumab. GDB has nothing to disclose. EF has

473

nothing to disclose. AF received honoraria for lecturing and

com-474

pensation for travel expenses from Merck Serono, Teva, Novartis,

475

Bayer Schering, Sanoﬁ-Aventis, and Biogen. SG has received fees as

476

invited speaker or travel expenses for attending meeting from Biogen,

477

Merck Serono, Teva, Almirall, Sanoﬁ-Aventis, Novartis, Genzyme.

478

CG received lecture fees and/or consulting fees from Merck Serono,

479

Biogen, Teva, Bayer Schering and Novartis. EM received funding for

480

traveling and speaking honoraria from Novartis and Teva. MM

481

received honoraria from Biogen, Genzyme, Novartis, Merck Serono,

482

Almirall and Teva. CP has received consulting and/or lecture fees

483

and/or research funding and travel Grant from Almirall, Bayer Table 4 Cox regression models

(adjusted by propensity score inverse weighting) to reach secondary outcomes in highly active treatment-naives [re-sampled dataset B, n = 120; patients per group, n = 40], i.e. patients who were never treated before with any disease-modifying drugs and experienced C1 relapse in the last year and 1C gadolinium-enhancement at brain or spinal cord scan

n(%) reaching the outcome HR 95% CIs p* Relapses NTZ vs. INJ 5 (12%) vs. 17 (42%) 0.29 0.11–0.81 0.045 FNG vs. INJ 8 (20%) vs. 17 (42%) 0.48 0.20–1.12 0.19 NTZ vs. FNG 5 (12%) vs. 8 (20%) 0.99 0.25–3.99 0.99 Disability worsening NTZ vs. INJ 2 (5%) vs. 11 (27%) 0.18 0.04–0.82 0.081 FNG vs. INJ 4 (10%) vs. 11 (27%) 0.39 0.12–1.25 0.22 NTZ vs. FNG 2 (5%) vs. 4 (10%) 0.40 0.08–5.32 0.37 Radiological activity NTZ vs. INJ 9 (22%) vs. 22 (55%) 0.42 0.19–0.93 0.096 FNG vs. INJ 11 (27%) vs. 22 (55%) 0.50 0.24–1.05 0.13 NTZ vs. FNG 9 (22%) vs. 11 (27%) 0.99 0.38–2.57 0.99 FNGﬁngolimod, INJ self-injectable drugs, NTZ natalizumab

* By the Bonferroni–Holm correction for multiple comparisons

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484 _{Schering, Biogen, Genzyme, Merck Serono, Novartis, Roche and} 485 _Teva.

486

487

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