ARTICLE CLASS OF EVIDENCE

Siponimod and Cognition in SecondaryProgressive Multiple SclerosisEXPAND Secondary Analyses

Ralph HB Benedict PhD Davorka Tomic MD Bruce A Cree MD Robert Fox MD Gavin Giovannoni MD

Amit Bar-Or MD Ralf Gold MD Patrick Vermersch MD Harald Pohlmann MSc Ian Wright PhD

Goril Karlsson MD Frank Dahlke MD Christian Wolf MD and Ludwig Kappos MD

Neurologyreg 202196e376-e386 doi101212WNL0000000000011275

Correspondence

Dr Benedict

benedictbuffaloedu

AbstractObjectiveTo investigate the effects of siponimod on cognitive processing speed in patients with secondaryprogressive (SP)multiple sclerosis (MS) bymeans of a predefined exploratory and post hoc analysis ofthe Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive MultipleSclerosis (EXPAND) study a randomized controlled trial comparing siponimod and placebo

MethodsEXPAND was a double-blind placebo-controlled phase 3 trial involving 1651 patients withSPMS randomized (21) to either siponimod 2 mgd or placebo Cognitive function wasassessed with the Symbol Digit Modalities Test (SDMT) Paced Auditory Serial Addition Test(PASAT) and Brief Visuospatial Memory TestndashRevised (BVMT-R) administered at baseline6-month intervals and end of treatment

ResultsBetween-group differences in mean change from baseline in SDMT scores were significantlybetter in siponimod- vs placebo-treated patients at month 12 (difference 108 [95 confidenceinterval 023ndash194] p = 00132) month 18 (123 [025ndash221) p = 00135) and month 24 (230[111ndash350] p = 00002) Siponimod-treated patients were at significantly lower risk for havinga 4-point sustained decrease in SDMT score (hazard ratio [HR] 079 [065ndash096] p = 00157)while their chance for having a 4-point sustained increase in SDMT score was higher (HR 128[105ndash155] p = 00131) PASAT and BVMT-R scores did not differ significantly between the 2treatment groups (all p gt 028)

ConclusionSiponimod had a significant benefit on SDMT in patients with SPMS Siponimod-treatedpatients were at significantly lower risk for having a ge4-point decrease in SDMT score and had asignificantly higher chance for having a ge4-point increase in SDMT score a magnitude ofchange accepted as clinically meaningful

ClinicalTrialsgov IdentifierNCT01665144

Classification of EvidenceThis study provides Class II evidence that for patients with SPMS siponimod had a significantbenefit on cognitive processing speed

RELATED ARTICLE

EditorialSiponimod for Cognitionin Secondary ProgressiveMultiple SclerosisThinking Through theEvidence

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Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

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From the Department of Neurology (RHBB) University at Buffalo NY Novartis Pharma AG (DT HP GK FD) Basel Switzerland Weill Institute for Neurosciences (BAC)Department of Neurology University of California San Francisco Mellen Center for Treatment and Research in Multiple Sclerosis (RF) Neurological Institute Cleveland Clinic OHBlizard Institute (GG) Barts and The London School of Medicine and Dentistry Queen Mary University of London UK Department of Neurology (AB-O) Perelman School ofMedicine University of Pennsylvania Philadelphia Department of Neurology (RG) St Josef-HospitalRuhr-University Bochum Germany Department of Neurology (PV) Uni-versity of Lille INSERM U1172 CHU Lille FHU Imminent France Novartis Ireland Ltd (IW) Dublin Lycalis sprl (CW) Brussels Belgium and Neurologic Clinic and Policlinic (GKLK) Departments of Medicine Clinical Research Biomedicine and Biomedical Engineering University Hospital and University of Basel Switzerland

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

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Multiple sclerosis (MS) is an immune-mediated neurode-generative disease affecting cognitive function particularlyamong those with progressive course12 MS neurocognitivedisorder affects driving adherence to medication regimensemployment computer-based purchasing and rehabilitationpotential34 The core deficit lies in the domain of cognitiveprocessing speed (CPS)5 with carryover effects to higher-order cognitive processes6ndash8 Consensus opinion considersthe Symbol Digit Modalities Test (SDMT) the best measureof CPS for MS studies9 It is the only CPS test for which achange score is defined as clinically meaningful10

Siponimod is a modulator of sphingosine-1-phosphate (S1P)receptor function with specificity for the S1P1 and S1P5 sub-types of the S1P receptor11 It readily crosses the blood-brainbarrier12 and may have direct actions in the CNS that limitinflammation and promote remyelination13ndash15 In Exploring theEfficacy and Safety of Siponimod in Patients With SecondaryProgressive Multiple Sclerosis (EXPAND) a multicenter ran-domized double-blind parallel-group placebo-controlled phase3 trial siponimod significantly reduced confirmed disabilityprogression (CDP) in progressiveMS compared with placebo16

Here our objectives are to report results from the prespecifiedexploratory analyses of between-group differences in changefrom baseline at months 12 and 24 and averaged over all visitsfor the cognitive tests used in the EXPAND study and the posthoc responder analyses for SDMT outcomes applying anaccepted threshold for clinically meaningful change10 Wepresent data in the overall population and in subgroups de-fined by their pretreatment characteristics for disease activitydisability status and CPS impairment

MethodsPrimary Research QuestionDoes siponimod improve CPS compared with placebo inpatients with secondary progressive (SP) MS

Standard Protocol Approvals Registrationsand Patient ConsentsThis trial is registered with ClinicalTrialsgov (NCT01665144)The trial protocol was approved by the independent ethics

committee at each trial center All patients provided written in-formed consent The trial adhered to the International Confer-ence on Harmonization Guidelines for Good Clinical Practiceand to the Declaration of Helsinki Institutional review boards orethics committees approved the protocol at all sites All patientsincluded in the analysis gave written informed consent beforestarting the study The studywas funded byNovartis PharmaAG

Study Design and ParticipantsEXPAND was a randomized double-blind placebo-controlledevent- and exposure-driven clinical trial to investigate the effi-cacy safety and tolerability of siponimod in patients with SPMSStudy design and results for the EXPAND study were repor-ted16 In brief 1651 patients with SPMSwere randomized (21)to receive either siponimod 2 mgd or placebo in the double-blind part of the study The double-blind part of the study wasstopped once a predefined number of disability progressionevents were observed and after gt95 of randomized patientswere randomized for at least 1 year During the trial patients withestablished disease progression could switch to open-labelsiponimod as rescue medication or go off treatment (either withor without another disease-modifying therapy) 94 patients inthe placebo group (172) and 116 patients in the siponimodgroup (106) switched to open-label siponimod while 135 and57 patients respectively went off treatment

Eligibility criteria were age of 18 to 60 years diagnosis ofSPMS1718 progression on the Expanded Disability StatusScale (EDSS) in the prior 2 years and an EDSS score of 30 to65 at screening Unlike most neuropsychological studies inMS patients in the EXPAND study were not prescreened andexcluded for factors known to affect the development ofcognitive abilities such a childhood learning disability andneurologic and psychiatric disorders such as traumatic braininjury and bipolar disorder Thus the study is representativeof the general advanced MS population but is also susceptibleto potential biases introduced by including participants withthese factors

The primary objective of EXPAND was to evaluate the effi-cacy of siponimod relative to placebo in delaying the time to3-month CDP as measured by the EDSS Three-month CDPwas defined as an increase from baseline EDSS score sub-sequently confirmed after at least 3 months The study

GlossaryASCEND = A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With SecondaryProgressive Multiple Sclerosis BVMT-R = Brief Visuospatial Memory TestndashRevised CDP = confirmed disability progressionCI = confidence intervalCPS = cognitive processing speedDECIDE = Efficacy and Safety of BIIB019 (DaclizumabHigh YieldProcess) Versus Interferon β 1a in Participants With Relapsing-Remitting Multiple Sclerosis EDSS = Expanded DisabilityStatus Scale EXPAND = Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive MultipleSclerosis Gd = gadolinium HR = hazard ratio IFN-β-1a = interferon beta-1a MS = multiple sclerosis MSOAC = MultipleSclerosis Outcome Assessments Consortium OPERA = A Study of Ocrelizumab in Comparison With Interferon Beta-1a(Rebif) in Participants With Relapsing Multiple Sclerosis PASAT = Paced Auditory Serial Addition Test SDMT = SymbolDigit Modalities Test S1P = sphingosine-1-phosphate SPMS = secondary progressive MS

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showed a benefit of siponimod with an estimated hazard ratio(HR) of 079 (95 confidence interval [CI] 065ndash095) ie arelative risk reduction of 21

MRI scans were performed every 12 months For the pur-poses of this report MRI was used to identify acute diseaseactivity defined by gadolinium (Gd) enhancement at eachtime point The data were analyzed independently at a centralreading site (NeuroRX Research Montreal Quebec Canada)by staff unaware of trial treatment group assignments

Cognitive AssessmentsCognitive outcomes included the SDMT (score range 0ndash110higher score indicates better performance)19 Paced AuditorySerial Addition Test (PASAT score range 0ndash60 higher scoreindicates better performance)2021 and the Brief VisuospatialMemory TestndashRevised (BVMT-R score range 0ndash36 higher

score indicates better performance)22 While the SDMT isregarded as the most sensitive of neurocognitive tests in MSresearch1210 the PASAT and BVMT-R are also widely ac-cepted measures of working memory and episodic memoryrespectively23ndash25

The tests were administered at baseline at 6-month intervalsafter randomization and at the end of treatment or end of thecore part of the study To minimize practice effects theoriginal SDMT and 2 alternative forms shown to be equiva-lent in difficulty were presented in an alternating pattern26

Throughout the study only the oral response administrationof the SDMT was used Likewise 2 PASAT forms (A and B)were used in alternating order (A B A etc) in each successivevisit The BVMT-R has 6 validated equivalent alternativeforms and the total learning score (sum of trials 1 2 and 3)was recorded for the sole BVMT-R outcome measure as per

Table 1 Baseline Characteristics

Characteristic Siponimod (n = 1105) Placebo (n = 546) Total (n = 1651)

Age y 480 (78) 481 (79) 480 (79)

Age gt40 y n () 917 (830) 443 (811) 1360 (824)

Female sex n () 669 (605) 323 (592) 992 (601)

Time since diagnosis of MS y 129 (79) 121 (75) 126 (78)

Time since onset of MS symptoms y 171 (84) 162 (82) 168 (83)

Time since conversion to SPMS y 39 (36) 36 (33) 38 (35)

Time since onset of last relapse y 51 (51) 45 (46) 49 (49)

No relapses in year before screening n () 878 (795) 416 (762) 1294 (784)

No relapses in 2 y before screening n () 712 (644) 343 (628) 1055 (639)

EDSS score median 60 60 60

EDSS score ge6 n () 622 (563) 296 (542) 918 (556)

SDMT raw scorea 389 (139) 396 (133) 391 (138)

Median (minimumndashmaximum) 400 (00ndash830) 420 (00ndash830) 410 (00ndash830)

Baseline SDMT score lt43e n () 616 (557) 283 (518) 899 (545)

PASAT raw scoreb 392 (145) 389 (144) 391 (145)

Median (minimumndashmaximum) 420 (00ndash600) 410 (00ndash600) 420 (00ndash600)

BVMT-R Total Recall scorec 206 (88) 204 (89) 205 (89)

Median (minimumndashmaximum) 210 (00ndash360) 210 (00ndash360) 210 (00ndash360)

BVMT-R Delayed Recall scored 81 (34) 80 (34) 81 (34)

Median (minimumndashmaximum) 90 (00ndash220) 90 (00ndash100) 90 (00ndash220)

Abbreviations BVMT-R = Brief Visuospatial Memory TestndashRevised EDSS = Expanded Disability Status Scale MS multiple sclerosis PASAT = Paced AuditorySerial Addition Test SDMT = Symbol Digit Modalities Test SPMS = secondary progressive multiple sclerosisData are presented as mean (SD) unless otherwise indicateda There were 15 and 5 missing data points for SDMT for siponimod and placebo respectivelyb There were 23 missing data points for PASAT for siponimodc There were 27 and 12 missing data points for BVMT-R for siponimod and placebo respectivelyd There were 36 and 21 missing data points for BVMT-R for siponimod and placebo respectivelye Impairment being defined as a baseline SDMT score lt43 points ie ge2 SD below the mean of healthy population normal

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Brief International Cognitive Assessment for Multiple Scle-rosis guidelines24

Statistical AnalysesThe full analysis set comprising all randomized and treatedpatients was used for the primary and post hoc analysesPatients were analyzed according to the randomized treat-ment assignment following the intention-to-treat principleusing all available assessments of the core part regardless ofthe actual study treatment received As with the analysis of theprimary EXPAND outcome (3-month CDP) the full analysisset was used to determine efficacy on cognition because thisapproach is recommended by International Conference onHarmonization guidance27

Summary statistics were generated for each visit at whichcognitive functions were tested Between-group differences inchange from baseline were analyzed using mixed-modelrepeated-measures methodology with visit as a categoricalfactor and adjustment for treatment and baseline score Thesedifferences were evaluated at months 6 12 18 and 24

Increase (ie improvement) or decrease (ie worsening) inSDMT score by 4 points is accepted as a clinically meaningfulchange10 Cox regression analysis was used to provide anal-yses based on clinical meaningful change ie the time tosustained 4-point decrease and time to sustained 4-point in-crease in SDMT score Sustained change was defined as achange from baseline that continued until the end of follow-up in the core part without ever returning above or below thisthreshold Results are presented as HRs which provide theratio of risk (or chance) for sustained deterioration (im-provement) between siponimod and placebo

With the same Cox regression approach homogeneity ofresults over subgroups was evaluated The subgroup resultsare presented in a forest plot showing the HRs of the sub-group categories in relation to the HR of the overall

population Presenting estimates in forest plots is an appro-priate method for comparing homogeneity of subgroups forwhich p valuendashbased analyses are less meaningful due tomultiplicity and small sample size issues

Cox regression analyses for sustained worsening and sus-tained improvement were done for the following sub-groups (1) patients characterized by the presence orabsence of CPS impairment before entering the EXPANDstudy with impairment being defined as a baseline SDMT oflt43 points ie ge2 SD below the mean of healthy pop-ulation norms28 (2) patients with Gd-enhancingpositiveor Gd-negative lesions (3) patients with relapsingSPMS and nonrelapsing SPMS and (4) SDMT-measuredCPS changes in patients in EXPAND with an EDSS scorelt6 (fully ambulatory) vs patients with an EDSS score ge6(using ambulatory support) before entering the EXPANDstudy

Numbers needed to treat were calculated for the risk (orchance) for sustained 4-point decreases or increases basedon the HRs derived from the Cox proportional hazardsmodels

Data AvailabilityThe data for the analyses described in this article are availableby request from the authors or Novartis Pharma AG

ResultsBaseline CharacteristicsPatient characteristics in the 2 treatment arms were similar(table 1) The majority of patients (639) had not had anyrelapses within 2 years before screening Amajority of patients(556) had an EDSS score ge6 (ie used a walking aid beforestudy entry) Almost half of the patients (467) had animpaired prestudy SDMT score

The core part of the study was completed by 817 ofpatients in the siponimod group and 777 of patients inthe placebo group Median duration of patient participa-tion in the core phase (on double-blind treatment onopen-label siponimod as rescue medication or off treat-ment) was 21 months (range 02ndash37 months) The medianduration of exposure to randomized double-blind study drugwas 18 months (range 0ndash37 months) Further details areavailable in the primary publication16 As a result of theflexible-duration study design in which patients enteredthe study sequentially over a long period but completed thestudy at the same point in time the number of patients withassessments available decreases substantially over time Inaddition exposure to double-blind study medication couldbe discontinued after reaching 6-month CDP

Changes in CPS as Measured by SDMTChange in SDMT score between baseline and month 12 wasevaluable in 1365 patients and between baseline and month

Figure 1 Mean Change from Baseline in SDMT Score

Mean change from baseline in Symbol Digit Modalities Test (SDMT) score atmonths 6 12 18 and 24 Error bars represent the standard error p lt 005p lt 001

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24 in 445 patients Time to sustained changes in SDMT scorewas evaluable in 1627 patients Missing SDMT scores aremostly a result of the variable duration of patientparticipation

The mixed-model repeated-measures model showed thatbetween-group differences in mean change from baseline inSDMT scores were significantly better in siponimod-treatedpatients compared with placebo-treated patients at months12 18 and 24 (figure 1)

Clinically Meaningful Changes in SDMT ScorePatients in the siponimod group were at significantly lowerrisk for having a 4-point sustained decrease in SDMT score(figure 2A) while their chance for having a 4-point sustainedincrease in SDMT score was significantly higher (figure 2B)The Kaplan-Meier graph showed that this difference in riskwas already evident at month 6 (the first postrandomizationtime at which it was evaluated) and continued throughout thecourse of double-blind treatment (figure 2A)

Cox regression analysis found that the chance for sustained im-provement by ge4 points was increased by 275 in the siponi-mod group compared with the placebo group (p = 00131) Theproportions of patients who had a sustained improvement inSDMT score by ge4 points a sustained deterioration in SDMTscore by ge4 points or no sustained changes of a magnitude of ge4points (no sustained change) are shown in figure 2C

A number needed to treat analysis found that 32 patients need tobe treated with siponimod over 12 months to prevent 1 addi-tional event of sustained deterioration (decrease byge4 points) inSDMT while 17 patients need to be treated over 24 months toprevent 1 additional event of sustained deterioration in SDMTWhen 37 patients are treated with placebo instead of siponimodover 12 months there is 1 fewer patient with sustained im-provement (increase by ge4 points) in SDMT score while 16patients need to be treated with placebo over 24 months for 1fewer patient with sustained improvement

Subgroup AnalysesFor all analyzed subgroups the proportion of patients withsustained improvement in SDMT was higher for siponimodvs placebo while the proportion of patients with sustaineddeterioration was lower with siponimod vs placebo Likewisechances to improve and risks to deteriorate favored siponi-mod over placebo in all subgroups (figure 3) The HRs in thesubgroup analysis were relatively similar between subgroupcategories and similar to the HR in the overall population

In patients with or without cognitive impairment at baselinethe proportion of patients with sustained improvement inSDMT score was higher for siponimod vs placebo reachingsignificance for those without impairment (HR 149 [95 CI109ndash204] p = 00126) while the proportion of patients withsustained deterioration was lower with siponimod vs placeboreaching significance for patients with or without cognitiveimpairment (HR 072 [053ndash096] p = 00269 and HR 076[058ndash100] p = 00477 respectively)

In patients with or without Gd-positive lesions at baseline theproportion of patients with sustained deterioration was lowerwith siponimod vs placebo reaching significance for patientswith Gd-positive lesions (HR 056 [036ndash087] p = 00093)

In patients with relapsing SPMS and nonrelapsing SPMSthe proportion of patients with sustained improvement inSDMT was higher for siponimod vs placebo reaching

Figure 2 Participants Evidencing a Sustained Deteriorationor Improvement (Both ge4 Points) in SDMT Score

(A) Kaplan-Meier analysis of the percentage of participants evidencing asustained deterioration in the Symbol Digit Modalities Test (SDMT) score byge4 points Hazard ratio (HR) 079 (95 confidence interval [CI] 065ndash096) p =00157 (B) Kaplan-Meier analysis of the percentage of patients over timewho had a sustained improvement in SDMT score by ge4 points HR 128 (95CI 105ndash155) p = 00131 (C) Cox regression analysis of the proportion ofparticipants improving and worsening is statistically significant (p = 00131)Graph contrasts proportions in siponimod (blue) against placebo (gray) withchange in SDMT score defined by 4 points10

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significance for patients with relapsing SPMS (HR 151[107ndash212] p = 00176)

In patients with a baseline EDSS score lt6 and in those withbaseline EDSS score ge6 before entering the EXPAND studythe proportion of patients with sustained improvement inSDMT was higher for siponimod vs placebo reaching sig-nificance in those with EDSS score ge6 (HR 134 [102ndash177]p = 00358) while the proportion of patients with sustaineddeterioration was lower with siponimod vs placebo againreaching significance in those with EDSS score ge6 (HR 076[058ndash099] p = 00437)

Other Cognitive OutcomesChange in PASAT score between baseline and month 12 wasevaluable in 1337 patients and between baseline and month24 in 580 patients Changes in BVMT-R Total Recall andDelayed Recall scores between baseline and month 12 wereevaluable in 1347 and 1332 patients respectively and be-tween baseline and month 24 in 588 and 582 patientsrespectively

PASAT and BVMT-R scores did not differ significantly be-tween the 2 treatment groups (table 2) There were no sig-nificant effects or trends toward significance in these analyses(all p gt 028)

Adverse EventsAs previously reported16 the safety and tolerability of sipo-nimod in the EXPAND study were comparable to those ofother drugs in the S1P-receptor modular class Adverse eventsmore frequent in patients on siponimod than in patients onplacebo included elevated liver transaminase concentrationsbradycardia at treatment initiation macular edema hyper-tension varicella zoster virus reactivation and convulsions allof which have been described previously for other drugs of theclass Frequencies of infections malignancies or death werenot increased

DiscussionThese phase 3 data from the EXPAND study provide Class IIevidence that patients with SPMS treated with siponimod

Figure 3 Subgroup Analyses for Sustained Deterioration or Improvement (Both ge4 Points) in SDMT Score

Symbol DigitModalities Test (SDMT) subgroup analyses for sustained changes For improvement a hazard ratio (HR) gt10 favors siponimod for deteriorationan HR lt10 favors siponimod Cox proportional hazards model was used with treatment country baseline Expanded Disability Status Scale (EDSS) scorebaseline SDMT-Oral score and secondary progressive multiple sclerosis (SPMS) group (withwithout superimposed relapses baseline definition) as cova-riate CI = confidence interval Gd = gadolinium nNrsquo = number of participants with sustained improvement or deteriorationnumber of participants includedin the analysis (ie with nonmissing covariates) nrSPMS nonrelapsing SPMS rSPMS relapsing SPMS p lt 005 aBaseline SDMT score lt43 bbaseline SDMTscore ge43

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experience significant improvement on the SDMT Pre-planned analyses of between-group differences significantlyfavored siponimod over placebo Post hoc responder analysessuggest that these effects are clinically meaningful10 becausesiponimod-treated patients were also at significantly lowerrisk for having a ge4-point decrease in SDMT score and had asignificantly higher chance for having a ge4-point increase inSDMT score Indeed the 21 risk reduction with siponimodin the proportion of patients with a 4-point sustained wors-ening in SDMT score reported here is in line with the 25 riskreduction reported for 6-month confirmed 4-point worseningin SDMT score29

While patients with less advanced disease (those without base-line cognitive impairment [SDMT score ge43]) appear to have ahigher chance for sustained improvement in SDMT with sipo-nimod vs placebo patients with more advanced disease (thosewith baseline cognitive impairment [SDMT score lt43]) appearto have a lower risk for sustained worsening with siponimod vsplacebo A possible explanation for this is that patients withmoreacute disease activity and less cognitive impairmentmay still havecognitive (ie neurologic) reserve available to turn the benefit ofsiponimod on CPS into improvement while in later-stage moreimpaired patients the benefitmay be a slowing of further declinealthough it is also possible that this might simply be a floor effectIt is also feasible that it might take longer than the mediantreatment duration of 18 months for treatment effect to beobserved in later-stage and more-impaired patients Studies ofpatients treated with siponimod for longer duration are needed

The EXPAND extension study is still ongoing and may deliversuch information

The benefit from siponimod was restricted to cognitivefunction as measured by the SDMT Both SDMT andPASAT are used to assess cognitive function in MS30ndash35

although PASAT is more susceptible to practice effects93637

and is found by patients to be stressful36 SDMT as an ac-cepted marker for clinically meaningful difference10 is lessprone to measurement error28 and has high reliability andsensitivity38 Correlations between SDMT and job loss39

and fluctuations in clinical status during relapse40ndash42 are wellknown Including SDMT as a measure for CPS in EXPANDovercomes earlier shortfalls in most MS phase 3 studies tocapture a wider spectrum of functional deficits (the Efficacyand Safety of BIIB019 [Daclizumab High Yield Process]Versus Interferon β 1a in Participants With Relapsing-Remitting Multiple Sclerosis [DECIDE] study33 is an ex-ception) Past characterizations of functional deficits oftenused only the physically focused EDSS alone or the PASATwith the above-described shortcomings The threshold ap-proach used for the analysis of SDMT data was based onthe consensus perspective of the Multiple Sclerosis Out-come Assessments Consortium (MSOAC)43ndash45 Neuro-psychological studies have shown that 4-point changes inSDMT are often associated with clinically meaningful al-terations in mental status10 Recent studies validate thisthreshold as being associated with quality of life outcomes5

and progression of MS disability746

Table 2 Change from Baseline in PASAT and BVMT-R Scores in the Full Analysis Set

Adjusted Means (SE)

Between-Group Difference (95 CI) p ValueSiponimod Placebo

PASAT n 1011 509

Month 12 225 (0300) 180 (0427) 045 (minus057 to 147) 03869

Month 24 298 (0404) 238 (0579) 059 (minus079 to 198) 04015

Average over all visitsa 230 (0269) 183 (0382) 048 (minus044 to 139) 03088

BVMT-R Total Recall score n 1011 508

Month 12 021 (0223) 056 (0298) minus035 (minus101 to 032) 03070

Month 24 178 (0319) 133 (0452) 045 (minus059 to 149) 03944

Average over all visitsa 067 (0225) 057 (0309) 011 (minus058 to 079) 07605

BVMT-R delayed recall n 1003 498

Month 12 minus011 (0090) 004 (0121) minus015 (minus042 to 012) 02844

Month 24 044 (0134) 043 (0190) 001 (minus043 to 045) 09641

Average over all visitsa 008 (0090) 010 (0124) minus001 (minus029 to 026) 09198

Abbreviations BVMT-R = Brief Visuospatial Memory TestndashRevised CI = confidence interval SE = standard error PASAT = Paced Auditory Serial Addition TestBetween-group differences in change frombaselinewere analyzed usingmixed-model repeated-measuresmethodologywith visit as a categorical factor andadjustment for treatment and baseline score Adjusted mean (SE) refers to the change from baseline in PASAT score or to the change from baseline in TotalDelayed Recall scorea Includes all post-baseline visits through month 30 Statistical significance (2 sided) at the 005 level was used

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We are impressed with the results showing an effect of sipo-nimod on SDMT without any evidence of benefit on thePASAT or BVMT-R As noted by others110 the SDMT issensitive but it is not specific to the CPS domain SDMTinvolves paired-associate learning and visual scanning so themore demanding the task is the more likely it is that it willmeasure the effects of cerebral pathology in general This mayexplain in part the value of the SDMT in clinical and researchapplications as noted in a recent consensus report organizedby the MSOAC10 In further support47 lesion-based whitematter tract disruptions were shown to be much more ex-tensively involved across left and right hemisphere networkscompared with the BVMT-R Moreover siponimod hasshown ex vivo partial restoration of cortical neuronal circuitfunction48 together with a reduction in cortical gray matterand thalamic volume loss in patients with SPMS49 whichcorrelated with the SDMT score Volume of the thalamus ahub for multiple neural networks50 is robustly correlated withSDMT in both cross-sectional51 and longitudinal studies52 ofMS As mentioned PASAT is more susceptible to practiceeffects93637 and thus may be a less sensitive measure duringthe core study The neuroprotective effect of siponimod bypartially restoring cortical neuronal circuit after crossing theblood-brain barrier would appear to be independent of itsperipheral effects on immune cells48

BVMT-R is also a gold standard neuropsychological assess-ment in MS but instead examines new learning and episodicmemory23245354 According to published norms55 44 ofpatients had impaired BVMT-R Total Recall score and 48 ofpatients had impaired BVMT-R Delayed Recall score atbaseline similar to the rate of impairment in CPS based on theSDMT score Since the early work published on the effects ofinterferon beta-1a (IFN-β-1a)56 no disease-modifying ther-apy has shown a statistically significant effect on memory in aphase 3 trial SDMT may be more sensitive to the effects ofdisease-modifying therapy because it involves multiple neuralnetworks57 compared to BVMT-R for example47 SDMTperformance can be related to visualspatial processing andocular motor functions and it involves some incidentallearning of symbol-digit associations

EXPAND included a typical SPMS population Fifty-six per-cent of patients needed walking aids nearly two-thirds had norelapses in the 2 years before study entry Only asymp20 ofpatients had focal inflammatory brain activity at baseline16

Across SPMS trials both EXPAND16 and A Clinical Study ofthe Efficacy of Natalizumab on Reducing Disability Pro-gression in Participants With Secondary Progressive MultipleSclerosis (ASCEND) study of the effects of natalizumab58

enrolled a high proportion of severely disabled patientsCompared with other studies in progressive MS EXPANDrecruited patients with similar or longer mean and mediantimes since onset of progression In this population withestablished physical disabilities and baseline SDMT scoreswell below average significant benefit on SDMT wasobserved

In relapsing-remitting MS a beneficial effect was found inocrelizumab-treated patients vs IFN-β-1a on SDMT score inA Study of Ocrelizumab in ComparisonWith Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis(OPERA) I and OPERA II59 A full report of these data awaitspublication but the main article describes a greater increase inSDMT score from baseline favoring ocrelizumab over IFN-β-1a at week 96 (p = 0023) The only other detailed post hocanalysis of SDMT phase 3 data is found among patients withrelapsing-remitting MS in the DECIDE study of daclizumabvs IFN-β-1a33 In this investigation the same form of SDMTwas administered every 3 months Significantly greater meanimprovement from baseline in SDMT score was observed fordaclizumab and more patients treated with daclizumab had age4-point increase suggesting a clinically meaningful benefitIn general it would appear that the effects of disease-modifying therapies on MS include benefits for cognition asmeasured within the CPS domain using the SDMT in par-ticular Of these recent phase 3 trials only EXPAND includeda test of memory It remains to be seen whether the lack ofimpact on memory reported here is unique to this in-tervention or if the effects of disease-modifying therapies inMS are less impactful in cognitive spheres other than CPS

The behavior of the comparator arm in this study is note-worthy revealing no substantial improvement Again con-sidering this result in the context of the DECIDE and OPERAstudies3359 we note that in EXPAND alternative forms of theSDMT were used to minimize learning effects on the out-come measure In contrast the same numbersymbol com-binations were repeated throughout the OPERA andDECIDE studies3359 The lack of improvement in our studymay reflect better control of learning effects In addition theimprovement in SDMT in the IFN-β-1andashtreated comparatorarms of DECIDE andOPERA observed previously may partlyreflect the effects of IFN-β-1a over and above that of placeboor a less advanced relapsing MS population

There were several limitationsWhile the analyses of between-group differences for change from baseline at months 12 and24 for SDMT PASAT and BVMT-Rwere prespecified in theprotocol responder analyses and analyses for sustainedchanges were planned and done post hoc the study wasdesigned after consensus on a clinically meaningful differencewas derived by the MSOAC43 Another limitation is that wedid not collect demographic data such as education or com-mon MS symptoms such as visual impairment fatigue anddepression because the primary outcome in the phase 3 trialwas neurologic disability Considering the randomizationused it is unlikely that these variables differed across thetreatment groups but these factors may nevertheless havemoderated the impact of siponimod on cognition Educationa proxy for cognitive influences SDMT performance60 asdoes depression61 The time-to-event study design leading tovariable duration of study participation and the protocol-endorsed switch to open-label siponimod for patients withestablished progression of disability encumbered comparisons

NeurologyorgN Neurology | Volume 96 Number 3 | January 19 2021 e383

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

for the protocol-defined time points Although only asymp20(183 randomized to siponimod 223 randomized toplacebo) of patients discontinued the study prematurely atlater time points the number of available assessments wassubstantially reduced due to the flexible study duration perpatient This leads to greater CIs in the treatment effect es-timates but potential bias usually introduced by dropoutrelated to study treatment is limited because most of themissing assessments are due to the study design and are notrelated to study treatment Comparing the number needed totreat values reveals that the effect size in this study is modestas is also appreciated in comparisons of the differences ingroup means at the 12- and 24-month time points Finally thefindings in this study may not be applicable in populations ofpatients who differ from those enrolled in EXPAND as evi-denced by the low deterioration rate seen in the patientsreceiving placebo from the ASCEND study at 2 years

The overall findings from this study in a population withadvanced neurologic disability suggest that treatment withsiponimod beneficially affects cognitive functioning asmeasured by the SDMT a benefit likely to have a highimpact on quality of life and vocational status The benefitsobserved were seen in patients with or without prestudyrelapses in patients with or without cognitive impairmentbefore study entry and in patients with an EDSS score ge6or lt6 Benefits were observed in the time to sustainedchange until the end of follow-up in the core studyTreatment effects observed for clinical and imaging out-comes most notably reduction in brain volume loss as anobjective marker of permanent tissue damage and thuslikely related to cognitive function49 are consistent withthe results reported here

AcknowledgmentThe authors acknowledge the support of Daniela Piani Meier(from Novartis) The authors also thank Farid Khalfi (fromNovartis Ireland Ltd) for technical editing of the outline inaccordance with Good Publication Practice (GPP3) guide-lines (ismpporggpp3) The final responsibility for thecontent lies with the authors

Study FundingThe study was funded by Novartis Pharma AG BaselSwitzerland

DisclosureRHB Benedict reports research support and grants from theNIH National MS Society Biogen Genzyme Mallinkrodtand Genentech He has consulting or speaking relationshipswith EMD Serono Biogen Novartis Sanofi GenzymeVerasci and Roche and he receives royalties from Psycho-logical Assessment Resources Inc B Cree has received per-sonal compensation for consulting from AbbVie Biogen IdecEMD Serono MedImmune Novartis GenzymeSanofiAventis and Teva Neurosciences R Fox has received com-pensation for serving as consultant or speaker from Allozyne

Avanir Biogen Idec Novartis Questcor and Teva Pharma-ceutical Industries He or the institution he works for hasreceived research support from Novartis G Giovannoni is asteering committee member on the daclizumab trials forAbbVie the BG12 and daclizumab trials for Biogen-Idec thefingolimod and siponimod trials for Novartis the laquinimodtrials for Teva and the ocrelizumab trials for Roche He hasalso received consultancy fees for advisory board meetings fororal cladribine trials for Merck-Serono and Genzyme-Sanofiand in relation to Data Safety Monitoring Board activities forSynthon BV as well as honoraria for speaking at the physi-ciansrsquo summit and several medical education meetings He isalso the co-chief editor of Multiple Sclerosis and Related Dis-orders (Elsevier) A Bar-Or has received personal compen-sation for consulting serving on scientific advisory boardsandor speaking activities from Bayer Bayhill TherapeuticsBerlex Biogen Idec BioMS Diogenix Eli Lilly F Hoffmann-La Roche Ltd Genentech GlaxoSmithKline (GSK) Guthy-JacksonGGF Merck Serono Novartis Ono PharmaciaSanofi-Aventis Teva Neuroscience and Wyeth R Gold hasreceived compensation for serving as a consultant or speakerfrom Bayer HealthCare Biogen Idec Merck Serono Novar-tis and Teva Neuroscience and he or the institution he worksfor has received research support from Bayer HealthCareBiogen Idec Merck Serono Novartis and Teva Neurosci-ence he has also received honoraria as a journal editor fromSAGE and Thieme Verlag P Vermersch has received hono-raria and consulting fees from Biogen Genzyme-SanofiRoche Novartis Merck Celgene MedDay and Almirall aswell as research support from Biogen Genzyme-SanofiRoche and Merck L Kappos has received no personalcompensation Ludwig Kapposrsquo institution (University Hos-pital Basel) has received in the last 3 years and used exclusivelyfor research support the following steering committee ad-visory board and consultancy fees from Actelion AddexBayer HealthCare Biogen Idec Biotica Genzyme LillyMerck Mitsubishi Novartis Ono Pharma Pfizer ReceptosSanofi Santhera Siemens Teva UCB and Xenoport speakerfees from Bayer HealthCare Biogen Idec Merck NovartisSanofi and Teva support of educational activities from BayerHealthCare Biogen CSL Behring Genzyme MerckNovartis Sanofi and Teva license fees for Neurostatusproducts and grants from Bayer HealthCare Biogen IdecEuropean Union Innoswiss Merck Novartis Roche Re-search Foundation Swiss MS Society and the Swiss NationalResearch Foundation C Wolf is a partner at Lycalis sprl andreports compensation for his organization for consulting fromNovartis Roche Teva Celgene Mylan Synthon 2BBBICON Immunic and Desitin and for speaking from Mylanand Synthon D Tomic H Pohlmann G Karlsson and FDahlke are employees of Novartis I Wright is a contractorwith Novartis Ireland Ltd Go to NeurologyorgN for fulldisclosures

Publication HistoryReceived by Neurology October 28 2019 Accepted in final formAugust 20 2020

e384 Neurology | Volume 96 Number 3 | January 19 2021 NeurologyorgN

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

References1 Sumowski JF Benedict R Enzinger C et al Cognition in multiple sclerosis state of

the field and priorities for the future Neurology 201890278ndash2882 Benedict RHB DeLuca J Enzinger C Geurts JJG Krupp LB Rao SM Neuropsy-

chology of multiple sclerosis looking back and moving forward J Int NeuropsycholSoc 201723832ndash842

3 Langdon DW Cognition in multiple sclerosis Curr Opin Neurol 201124244ndash2494 Goverover Y Chiaravalloti N DeLuca J Brief International Cognitive Assessment for

Multiple Sclerosis (BICAMS) and performance of everyday life tasks actual realityMult Scler 201622544ndash550

5 Costa SL Genova HM DeLuca J Chiaravalloti ND Information processing speed inmultiple sclerosis past present and future Mult Scler 201723772ndash789

6 Forn C Belenguer A Parcet-Ibars MA Avila C Information-processing speed is theprimary deficit underlying the poor performance of multiple sclerosis patients in thePaced Auditory Serial Addition Test (PASAT) J Clin Exp Neuropsychol 200830789ndash796

7 Genova HM DeLuca J Chiaravalloti N Wylie G The relationship between executivefunctioning processing speed and white matter integrity in multiple sclerosis J ClinExp Neuropsychol 201335631ndash641

8 DeLuca J Chelune GJ Tulsky DS Lengenfelder J Chiaravalloti ND Is speed ofprocessing or working memory the primary information processing deficit in multiplesclerosis J Clin Exp Neuropsychol 200426550ndash562

9 Strober L DeLuca J Benedict RH et al Symbol Digit Modalities Test a valid clinicaltrial endpoint for measuring cognition in multiple sclerosis Mult Scler 2019251781ndash1790

10 Benedict RH DeLuca J Phillips G et al Validity of the Symbol Digit Modalities Testas a cognition performance outcome measure for multiple sclerosis Mult Scler 201723721ndash733

11 Gergely P Nuesslein-Hildesheim B Guerini D et al The selective sphingosine1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and hasspecies-specific effects on heart rate Br J Pharmacol 20121671035ndash1047

12 Aslanis V Faller T Van de Kerkhof E Schubart A Wallstrom E Beyerbach ASiponimod (BAF312) (andor its metabolites) penetrates into the CNS and dis-tributes to white matter areas Mult Scler 201218(suppl)355ndash356

13 Gentile A Musella A Bullitta S et al Siponimod (BAF312) prevents synaptic neu-rodegeneration in experimental multiple sclerosis J Neuroinflammation 201613207

14 Jackson SJ Giovannoni G Baker D Fingolimod modulates microglial activation toaugment markers of remyelination J Neuroinflammation 2011876

15 Mannioui A Vauzanges Q Fini JB et al The Xenopus tadpole an in vivo model toscreen drugs favoring remyelination Mult Scler 2018241421ndash1432

16 Kappos L Bar-Or A Cree BAC et al Siponimod versus placebo in secondary pro-gressive multiple sclerosis (EXPAND) a double-blind randomised phase 3 studyLancet 20183911263ndash1273

17 Lublin FD Reingold SC Defining the clinical course of multiple sclerosis results of aninternational survey National Multiple Sclerosis Society (USA) advisory committeeon clinical trials of new agents in multiple sclerosis Neurology 199646907ndash911

18 Rovaris M Confavreux C Furlan R Kappos L Comi G Filippi M Secondary pro-gressive multiple sclerosis current knowledge and future challenges Lancet Neurol20065343ndash354

19 Smith A Symbol Digit Modalities Test Manual Los Angeles Western PsychologicalServices 1982

20 Fischer JS Rudick RA Cutter GR Reingold SC The Multiple Sclerosis FunctionalComposite Measure (MSFC) an integrated approach to MS clinical outcome as-sessment NationalMS Society Clinical Outcomes Assessment Task Force Mult Scler19995244ndash250

21 Gronwall DM Paced auditory serial-addition task a measure of recovery from con-cussion Percept Mot Skills 197744367ndash373

Appendix Authors

Name Location Contribution

Ralph HBBenedictPhD

Department of NeurologyUniversity at Buffalo NY

Studydesign interpretationof data intellectual contentand critical review of datamajor contribution forauthoring and revisingthe manuscript

DavorkaTomic MD

Novartis Pharma AGBasel Switzerland

Interpretation of dataintellectual content andcritical review of data majorcontributions for authoringand revising the manuscript

Bruce ACree MD

UCSF Weill Institute forNeurosciencesDepartment of NeurologyUniversity of California SanFrancisco

Studydesign interpretationof data intellectual contentand critical review of datarevising and input into themanuscript

Robert FoxMD

Mellen Center forTreatment and Research inMultiple SclerosisNeurologic InstituteCleveland Clinic OH

Study designinterpretation of dataintellectual content andcritical review of datarevising and input into themanuscript

GavinGiovannoniMD

Blizard Institute Barts andThe London School ofMedicine and DentistryQueen Mary University ofLondon UK

Study designinterpretation of dataintellectual content andcritical review of datarevising and input into themanuscript

Amit Bar-OrMD

Department of NeurologyPerelman School ofMedicine University ofPennsylvania Philadelphia

Study design interpretationof data intellectual contentand critical review of datarevising and input into themanuscript

Ralf GoldMD

Department of NeurologySt Josef-HospitalRuhr-University BochumGermany

Study designinterpretation of dataintellectual content andcritical review of datarevising and input into themanuscript

PatrickVermerschMD

Department of NeurologyUniversity of Lille INSERM-U995 CHU Lille FHUImminent France

Study designinterpretation of dataintellectual content andcritical review of datarevising and input into themanuscript

HaraldPohlmannMSc

Novartis Pharma AGBasel Switzerland

Study design statisticalanalysis of the dataInterpretation of dataintellectual contentand critical review of datarevising and input into themanuscript

Ian WrightPhD

Novartis Ireland LtdDublin Ireland

Medical writing support fordrafting and revision ofmanuscript

GorilKarlssonMD

Novartis Pharma AGBasel Switzerland

Interpretation of dataintellectual content andcritical review of datarevising and input intothe manuscript

FrankDahlke MD

Novartis Pharma AGBasel Switzerland

Interpretation of dataintellectual content andcritical review of datarevising and input into themanuscript

Appendix (continued)

Name Location Contribution

ChristianWolf MD

Lycalis sprl BrusselsBelgium

Interpretation of dataintellectual content andcritical review of datamajor contributions forauthoring and revising themanuscript

LudwigKappos MD

Neurologic Clinic andPoliclinic Departments ofMedicine ClinicalResearch Biomedicine andBiomedical EngineeringUniversity Hospital andUniversity of BaselSwitzerland

Study designinterpretation of dataintellectual content andcritical review of datarevising and input into themanuscript

NeurologyorgN Neurology | Volume 96 Number 3 | January 19 2021 e385

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

22 Benedict RHB Schretlen S Groninger L Dobraski M Shpritz B Revision of the briefvisuospatial memory test studies of normal performance reliability and validityPsychol Assess 19968145ndash153

23 Erlanger DM Kaushik T Caruso LS et al Reliability of a cognitive endpoint for use ina multiple sclerosis pharmaceutical trial J Neurol Sci 2014340123ndash129

24 Langdon DW Amato MP Boringa J et al Recommendations for a Brief InternationalCognitive Assessment for Multiple Sclerosis (BICAMS) Mult Scler 201218891ndash898

25 Benedict RHB Fischer JS Archibald CJ et al Minimal neuropsychological assess-ment of MS patients a consensus approach Clin Neuropsychol 200216381ndash397

26 Benedict RH Smerbeck A Parikh R Rodgers J Cadavid D Erlanger D Reliability andequivalence of alternate forms for the Symbol Digit Modalities Test implications formultiple sclerosis clinical trials Mult Scler 2012181320ndash1325

27 European Medicines Agency Guidance Issuing Office Statistical Principles forClinical Trials E9 London ICH 1998

28 Drake ASWeinstock-Guttman BMorrow SA Hojnacki DMunschauer FE BenedictRH Psychometrics and normative data for the multiple sclerosis functional com-posite replacing the PASAT with the Symbol Digit Modalities Test Mult Scler 201016228ndash237

29 Mayzent Summary of Product Characteristics European Medicines Agency Avail-able at httpswwwemaeuropaeuendocumentsproduct-informationmayzent-epar-product-information_enpdf Accessed December 14 2020

30 Riccitelli GC Pagani E Rodegher M et al Imaging patterns of gray and white matterabnormalities associated with PASAT and SDMT performance in relapsing-remittingmultiple sclerosis Mult Scler 201925204ndash216

31 Feys P Moumdjian L Van Halewyck F et al Effects of an individual 12-weekcommunity-located start-to-run program on physical capacity walking fatiguecognitive function brain volumes and structures in persons with multiple sclerosisMult Scler 20192592ndash103

32 Vollmer T Huynh L Kelley C et al Relationship between brain volume loss andcognitive outcomes among patients with multiple sclerosis a systematic literaturereview Neurol Sci 201637165ndash179

33 Benedict RH Cohan S Lynch SG et al Improved cognitive outcomes in patients withrelapsing-remitting multiple sclerosis treated with daclizumab beta results from theDECIDE study Mult Scler 201824795ndash804

34 Johnen A Landmeyer NC Burkner PC Wiendl H Meuth SG Holling H Distinctcognitive impairments in different disease courses of multiple sclerosis a systematicreview and meta-analysis Neurosci Biobehav Rev 201783568ndash578

35 Weinstock-Guttman B Galetta SL Giovannoni G et al Additional efficacy endpointsfrom pivotal natalizumab trials in relapsing-remitting MS J Neurol 2012259898ndash905

36 Tombaugh TN A comprehensive review of the Paced Auditory Serial Addition Test(PASAT) Arch Clin Neuropsychol 20062153ndash76

37 Barker-Collo SLWithin session practice effects on the PASAT in clients with multiplesclerosis Arch Clin Neuropsychol 200520145ndash152

38 Sonder JM Burggraaff J Knol DL Polman CH Uitdehaag BM Comparing long-termresults of PASAT and SDMT scores in relation to neuropsychological testing inmultiple sclerosis Mult Scler 201420481ndash488

39 Morrow SA Drake A Zivadinov R Munschauer F Weinstock-Guttman B BenedictRH Predicting loss of employment over three years in multiple sclerosis clinicallymeaningful cognitive decline Clin Neuropsychol 2010241131ndash1145

40 Benedict RH Morrow S Rodgers J et al Characterizing cognitive function duringrelapse in multiple sclerosis Mult Scler 2014201745ndash1752

41 Morrow SA Jurgensen S Forrestal F Munchauer FE Benedict RH Effects of acuterelapses on neuropsychological status in multiple sclerosis patients J Neurol 20112581603ndash1608

42 Pardini M Uccelli A Grafman J Yaldizli O Mancardi G Roccatagliata L Isolatedcognitive relapses in multiple sclerosis J Neurol Neurosurg Psychiatry 2014851035ndash1037

43 LaRocca NG Hudson LD Rudick R et al The MSOAC approach to developingperformance outcomes to measure and monitor multiple sclerosis disability MultScler 2018241469ndash1484

44 Ontaneda D LaRocca N Coetzee T Rudick R NMSS MSFC Task Force Revisitingthe multiple sclerosis functional composite proceedings from the National MultipleSclerosis Society (NMSS) Task Force on Clinical Disability Measures Mult Scler2012181074ndash1080

45 Cohen JA Reingold SC Polman CH Disability outcome measures in multiplesclerosis clinical trials current status and future prospects Lancet 201211467ndash476

46 Goldman MD LaRocca NG Rudick RA et al Evaluation of multiple sclerosis dis-ability outcome measures using pooled clinical trial data Neurology 201993e1ndashe11

47 Fuchs TA Benedict RHB Bartnik A et al Preserved network functional connectivityunderlies cognitive reserve in multiple sclerosis Hum Brain Mapp 2019405231ndash5241

48 Hundehege P Cerina M Eichler S et al The next-generation sphingosine-1 receptormodulator BAF312 (siponimod) improves cortical network functionality in focalautoimmune encephalomyelitis Neural Regen Res 2019141950ndash1960

49 Arnold DA Fox R Bar-Or A et al Effect of siponimod on cortical grey matter andthalamic volume in patients with secondary progressive multiple sclerosis results ofthe EXPAND study Poster presented at the 35th Congress of the European Com-mittee for Treatment and Research in Multiple Sclerosis September 11ndash13 2019Stockholm Sweden P382 2019

50 Bisecco A Rocca MA Pagani E et al Connectivity-based parcellation of the thalamusin multiple sclerosis and its implications for cognitive impairment a multicenterstudy Hum Brain Mapp 2015362809ndash2825

51 Houtchens MK Benedict RHB Killiany R et al Thalamic atrophy and cognition inmultiple sclerosis Neurology 200769113ndash123

52 Bergsland N Zivadinov R Dwyer MG Weinstock-Guttman B Benedict RH Lo-calized atrophy of the thalamus and slowed cognitive processing speed in MS patientsMult Scler 2016221327ndash1336

53 Benedict RH Krupp L Francis G Rao S LaRocca N Langdon DW Group MCWNINDS Common Data Elements Multiple Sclerosis NeuropsychologyCognitionRecommendations Washington DC National Institute for Neurological Diseasesand Stroke 2012

54 Benedict RH Fischer JS Archibald CJ et al Minimal neuropsychological assessmentof MS patients a consensus approach Clin Neuropsychol 200216381ndash397

55 Parmenter BA Testa SM Schretlen DJ Weinstock-Guttman B Benedict RH Theutility of regression-based norms in interpreting theMinimal Assessment of CognitiveFunction in Multiple Sclerosis (MACFIMS) J Int Neuropsychol Soc 2010166ndash16

56 Fischer JS Priore RL Jacobs LD et al Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis Multiple Sclerosis Collaborative Research GroupAnn Neurol 200048885ndash892

57 Silva PHR Spedo CT Baldassarini CR et al Brain functional and effective connec-tivity underlying the information processing speed assessed by the Symbol DigitModalities Test Neuroimage 2019184761ndash770

58 Kapoor R Ho PR Campbell N et al Effect of natalizumab on disease progression insecondary progressive multiple sclerosis (ASCEND) a phase 3 randomised double-blind placebo-controlled trial with an open-label extension Lancet Neurol 201817405ndash415

59 Hauser SL Bar-Or A Comi G et al Ocrelizumab versus interferon beta-1a in re-lapsing multiple sclerosis N Engl J Med 2017376221ndash234

60 Sumowski JF Chiaravalloti N Wylie G et al Cognitive reserve moderates the neg-ative effect of brain atrophy on cognitive efficiency in multiple sclerosis J Int Neu-ropsychol Soc 200915606ndash612

61 Patel VP Feinstein A The link between depression and performance on the symboldigit Modalities test mechanisms and clinical significance Mult Scler 201925118ndash121

e386 Neurology | Volume 96 Number 3 | January 19 2021 NeurologyorgN

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

DOI 101212WNL0000000000011275202196e376-e386 Published Online before print December 16 2020Neurology Ralph HB Benedict Davorka Tomic Bruce A Cree et al

Secondary AnalysesSiponimod and Cognition in Secondary Progressive Multiple Sclerosis EXPAND

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