Benefit of interferon -1a on MSFC progression in secondary progressive MS

DOI 101212WNL595679200259679-687 Neurology

J A Cohen G R Cutter J S Fischer et al progressive MS-1a on MSFC progression in secondaryβBenefit of interferon

This information is current as of September 10 2002

httpwwwneurologyorgcontent595679fullhtmlthe World Wide Web at

The online version of this article along with updated information and services is located on

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

Benefit of interferon -1a on MSFCprogression in secondary progressive MS

JA Cohen MD GR Cutter PhD JS Fischer PhD AD Goodman MD FR Heidenreich MDMF Kooijmans MD PhD AW Sandrock MD PhD RA Rudick MD JH Simon MD PhDNA Simonian MD EC Tsao PhD and JN Whitaker MDdagger for the IMPACT Investigators

AbstractmdashBackground Interferon -1a (IFN-1a Avonex) is efficacious in relapsing forms of MS Studies of other IFNpreparations in secondary progressive MS (SPMS) yielded conflicting results This study was undertaken to determinewhether IFN-1a slowed disease progression in SP-MS Methods A total of 436 subjects with SPMS and ExpandedDisability Status Scale (EDSS) score 35 to 65 were randomized to receive IFN-1a (60 g) or placebo by weeklyintramuscular injection for 2 years The primary outcome measure used for the first time in a large-scale MS trial wasbaseline to month 24 change in the MS Functional Composite (MSFC) comprising quantitative tests of ambulation (Timed25-Foot Walk) arm function (Nine-Hole Peg Test [9HPT]) and cognition (Paced Auditory Serial Addition Test [PASAT])Results Median MSFC Z-score change was reduced 404 in IFN-1a subjects (0096 vs 0161 in placebo subjects p 0033) an effect driven mainly by the 9HPT and PASAT There was no discernible benefit on the EDSS which in thisrange principally reflects walking ability IFN-1a subjects had 33 fewer relapses (p 0008) There was significantbenefit on eight of 11 MS Quality of Life Inventory subscales New or enlarging T2-hyperintense brain MRI lesions andgadolinium-enhancing lesions were reduced at months 12 and 24 (both p 0001) IFN-1a was well tolerated by themajority of subjects Neutralizing antibodies developed in 33 of IFN-1andashtreated subjects Conclusions IFN-1a dem-onstrated benefit on MSFC progression relapses quality of life and MRI activity in SPMS

NEUROLOGY 200259679ndash687

Interferon -1a (IFN-1a Avonex) has been shownto reduce disease progression relapse rate cognitivedeterioration and MRI activity in relapsing forms ofMS1-3 and to reduce the rate of conversion to clini-cally definite MS and subclinical MRI activity inpatients presenting with an acute monophasic demy-elinating event4 Three previous phase III studies ofother IFN preparations in secondary progressiveMS (SPMS)5-7 showed consistent treatment benefits onrelapse rate and MRI activity but conflicting results onthe primary outcome measure time to progression onthe Kurtzke Expanded Disability Status Scale(EDSS)8 The known lack of sensitivity to change of theEDSS in the range represented by the subjects in thesestudies may account in part for the apparent lack ofeffect on the EDSS score despite treatment benefits on

other outcome measures Alternatively progressivegait impairment may become less responsive to ther-apy in advanced stages of MS

To address the insensitivity and poor reliability ofthe EDSS9 the National MS Societyrsquos Clinical Out-comes Assessment Task Force recommended an al-ternative outcome measure for clinical trials the MSFunctional Composite (MSFC)10-14 Unlike the EDSSwhich is derived from the standard neurologic exam-ination the MSFC is based on quantitative tests ofambulation (Timed 25-foot Walk [T25FW]) armfunction (Nine-Hole Peg Test [9HPT]) and cognition(Paced Auditory Serial Addition Test with a 3-secondinterstimulus interval [PASAT3]) Two studies sup-ported the feasibility of the MSFC and its excellentintra- and interrater reliability1516 MSFC validitywas supported by correlation with the EDSS1216-18

disease course17 patient self-reported symptoms andhealth-related quality of life (HRQOL)1819 and MRI-measured lesion load and cerebral atrophy20-22

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the September 10 issue to find the link for this article

daggerDeceasedSee the Appendix on page 685 for a complete listing of the IMPACT InvestigatorsFrom the Mellen Center for Multiple Sclerosis Treatment and Research Department of Neurology (Drs Cohen Fischer and Rudick) Cleveland ClinicFoundation OH Center for Research Methodology and Biometrics (Dr Cutter) AMC Cancer Center Lakewood CO Department of Neurology (DrGoodman) University of Rochester NY Department of Neurology (Dr Heidenreich) Hannover Medical School Germany Biogen Inc (Drs KooijmansSandrock Simonian and Tsao) Cambridge MA Department of Radiology (Dr Simon) University of Colorado Denver and Department of Neurology (DrWhitaker) University of Alabama at BirminghamBiogen Inc supported this study and development of the MSFC manual which is available through the National MS Society MFK NAS AWS andECT are full-time employees of Biogen Inc None of the other authors has a personal financial investment ownership equity or other financial holdingswith Biogen IncResults presented at the annual meeting of the American Academy of Neurology Philadelphia PA May 8 2001Received October 3 2001 Accepted in final form June 11 2002Address correspondence and reprint requests to Dr Jeffrey A Cohen Mellen CenterndashU10 Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland OH44195 e-mail cohenjccforg

Copyright copy 2002 by AAN Enterprises Inc 679

The current study (International MS SecondaryProgressive Avonex Controlled Trial [IMPACT]) wasdesigned to determine whether IFN-1a by weeklyintramuscular (IM) injection reduces disease pro-gression measured by the MSFC in SPMS EDSSprogression relapse rate MRI and HRQOL alsowere assessed IMPACT was the first clinical trial toutilize MSFC change as the predefined primaryendpoint

Subjects and methods Subjects IMPACT was a ran-domized double-blind placebo-controlled two-arm trialcarried out at 42 centersmdash31 in the United States four inCanada and seven in Europe Inclusion criteria were age18 to 60 years inclusive clinically definite SPMS2324 withor without recent relapses disease progression over theprevious year cranial MRI demonstrating lesions consis-tent with MS and an EDSS score of 35 to 65 inclusiveExclusion criteria included a primary progressive course24

inability to perform the component tests of the MSFC atbaseline and prior treatment with IFN Previous treat-ment with other immunomodulatory agents was permittedwith prespecified washout periods The protocol and con-sent documents were approved by the institutional reviewboards of the participating centers Subjects provided writ-ten informed consent prior to undergoing any study-related procedures

Treatment Subjects were randomized to receiveweekly IM injections of IFN-1a (60 g) or placebo for 24months A minimization procedure25 was used to balancethe treatment groups with respect to baseline EDSS (sevenpossible steps) and the presence or absence of gadolinium(Gd)-enhancing lesions on the baseline MRI The contractresearch organization computer generated two minimiza-tion schemes one for North America and one for Europeand Israel

Sixty micrograms was determined to be the maximumtolerated weekly IM dose of IFN-1a in a pilot study of 65subjects with relapsing-remitting MS (RRMS) or SPMSand moderate-to-severe disability26 To lessen side effectsat the initiation of therapy subjects were administered ahalf dose of study medication for four doses For the first26 weeks of study drug dosing subjects took acetamino-phen ibuprofen or naproxen prior to and for 24 hoursafter study drug administration Subjects experiencing in-tolerable side effects were permitted to reduce the dose ofstudy medication temporarily Therapy with any otherdisease-modifying immunotherapy for MS other than IVmethylprednisolone for acute relapses was prohibited

Study procedures Each study site designated a treat-ing nurse treating neurologist examining technician andexamining neurologist The treating nurse and neurologistwere responsible for clinical management of the subjectsThe examining technician administered the MSFC andthe examining neurologist determined the EDSS during allscheduled study visits Neither the examining techniciannor the examining neurologist was involved with any otheraspect of subject care and neither had access to the resultsof prior examinations or to clinical information that mightcompromise blinding To ensure consistency examiningtechnicians were trained to administer the MSFC and ex-amining neurologists were trained to administer the EDSSat a prestudy investigatorsrsquo meeting1416 To compensate for

anticipated practice effects on the MSFC1516 three pre-baseline testing sessions were performed over 28 days

The MSFC and EDSS were performed at baseline andevery 3 months thereafter On-study relapses were definedas new or recurrent neurologic symptoms not associatedwith fever or infection lasting at least 48 hours and ac-companied by objective change on the examining neurolo-gistrsquos examination at an unscheduled visit correspondingto the reported symptoms T2- and T1-weighted MRIscans unenhanced and following administration of Gdwere performed according to a standard protocol at base-line month 12 and month 24 The scans were evaluated ina blinded fashion at the central reading center The num-ber of new or enlarging (20 increase in diameter forlesions 5 mm and 50 increase for lesions 5 mm)T2-hyperintense lesions and number of Gd-enhancing le-sions were determined by a neuroradiologist The totalvolumes of T2-hyperintense lesions and Gd-enhancing le-sions were determined using semiautomated image analy-sis software and a standardized method14 The MS Qualityof Life Inventory (MSQLI) was administered to English-

Table 1 Demographic and baseline disease characteristics ofstudy subjects

Characteristic Placebo n 219 IFN-1a n 217

Age y mean SD 479 77 472 82

Female sex n () 141 (64) 138 (64)

Disease duration ymean SD

167 90 162 90

MSFC Z-score mean SD 0017 073 0018 076

EDSS mean SD 52 11 52 11

EDSS distribution n ()

35ndash55 113 (52) 113 (52)

60ndash65 106 (48) 104 (48)

No of relapses mean SD

Prior 3 y 13 21 15 21

Prior 1 y 05 09 06 11

Relapse free subjects n ()

Prior 3 y 97 (44) 80 (37)

Prior 1 y 135 (62) 129 (59)

Years since prior relapsemean SD

40 52 34 50

Gd-enhancing MRI lesions

No per scan mean SD 12 29 19 64

Volume per scan mm3mean SD

1004 2745 1659 6965

No of subjects () with

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11)

p 005 for all comparisons

IFN-1a interferon -1a MSFC MS Functional CompositeEDSS Expanded Disability Status Scale Gd gadolinium

680 NEUROLOGY 59 September (1 of 2) 2002

speaking subjects at baseline month 12 and month 24The MSQLI is a comprehensive MS-specific HRQOL as-sessment battery developed by an independent researchgroup sponsored by the Consortium of MS Centers and theNational MS Society2728 The Beck Depression Inventorywas administered to English-speaking subjects at baselineand months 3 6 12 and 24 One hundred sixty-two pla-cebo subjects and 165 IFN-1a subjects were eligible forthe MSQLI and Beck Depression Inventory Routine safetyblood samples were obtained every 3 months Serum wasanalyzed for the presence of anti-IFN neutralizing anti-bodies at baseline and every 6 months thereafter using atwo-step assay29 The incidence of titers 120 the levelassociated with reduced biological activity of IFN-1a29 isreported

The Advisory Committee held monthly conference callsto resolve issues of patient eligibility and trial conduct Anindependent external Data and Safety Monitoring Com-mittee reviewed safety data at three time points duringthe trial and performed a preplanned interim analysis af-ter all subjects had been followed for 15 months Continu-ation of the trial was recommended based on predefinedstopping rules

Statistical analysis The primary outcome measurewas the MSFC change from baseline to month 24 TheMSFC was calculated as the mean of the Z-scores of theT25FW 9HPT and PASAT3 which were calculated basedon the pooled dataset from the IMPACT baseline visit16

Decreases in the Z-scores represented deterioration in neu-rologic function

Based on a difference in mean MSFC change of 0523favoring active treatment with a pooled SD of 1584 in theNational MS Society (NMSS) Task Force dataset12 it wasestimated that 440 subjects would be required to detect abetween-group difference in MSFC change over 24 monthswith a two-sided level of significance of 0029 (to accommo-date an interim analysis) 80 power and 225 dropoutsPrior to the interim analysis the stopping rule waschanged requiring a significance level of 0009 for theinterim analysis and setting the alpha level for the finalanalysis at 0047 based on the OrsquoBrienndashFleming methodfor group sequential analysis

Sample size estimation and statistical analysis planwere based on the assumption that the baseline to month24 change in the MSFC would be normally distributedHowever the observed distributions of the MSFC and thethree components were highly skewed Therefore analysesof between-group differences in MSFC progression wereperformed using a nonparametric analysis of covariance onranks stratified by baseline EDSS score and the presenceor absence of Gd-enhancing lesions on baseline MRI Allrandomized subjects served as the intent-to-treat evalua-tion cohort with missing data points imputed using thelast available observation carried forward Analyses of effi-cacy measured by MSFC and EDSS also were performed inprespecified subgroups based on presence or absence of

Figure 1 Trial profile IFN-1a interferon -1a EDSS Expanded Disability Status Scale

September (1 of 2) 2002 NEUROLOGY 59 681

relapses in the year prior to enrollment baseline EDSS of35 to 55 vs 60 to 65 and presence or absence of Gd-enhancing lesions on the baseline MRI scan

Results Baseline characteristics and follow-up A totalof 436 subjects were enrolled from March through Septem-ber 1998 219 subjects were randomized to placebo and 217to IFN-1a Demographic clinical and MRI features of thetwo treatment groups were well matched at baseline andcharacteristic of a SPMS population (table 1) Twenty-three (11) subjects in the placebo group and 29 (13)subjects in the IFN-1a group failed to complete 24months of follow-up (figure 1) One subject randomized toplacebo discontinued the study prior to receiving studymedication because of suicidal ideation The only between-group difference in reason for study discontinuation wassubject request (six placebo subjects vs 16 IFN-1a sub-jects p 005 Fisherrsquos exact test)

MSFC and EDSS progression The disease progressedin both groups over 24 months as indicated by decreasesin the mean and median MSFC Z-scores (table 2) IFN-1atreatment reduced median MSFC worsening by 404 (p 0033) This overall MSFC benefit was driven predomi-nantly by the 9HPT and to a lesser extent the PASAT3(see tables 2 and 3)

Additional analyses confirmed the statistical robustnessof the MSFC results Imputation of missing data using themonth 24 treatment group median mean or worst valuesor use of the actual data without imputation of missingvalues yielded similar results An unadjusted statisticaltest the Wilcoxonrsquos rank sum test also yielded between-group differences using the last observation carried for-ward (p 0032) and actual data (p 0016) Similarbenefit of IFN-1a treatment on MSFC progression wasseen in subjects with and without prestudy relapses in thelow and high EDSS ranges and with and without Gd-enhancing lesions on the baseline MRI scan (data notshown) Treatment benefit was maintained when the anal-ysis was restricted to subjects without a relapse within 3

months of the final visit (median baseline to month 24change 014 for placebo subjects and 007 for IFN-1asubjects p 004) Comparison of the median MSFC val-ues every 3 months over 2 years showed fluctuation at theinitial visits then consistent benefit favoring IFN-1a (fig-ure 2) Taken together these analyses supported the ro-bustness of the beneficial effect of IFN-1a on slowingMSFC progression in SPMS

In contrast there was no difference between the treat-ment groups in the time to EDSS worsening defined as a10-step increase for baseline EDSS 35 to 55 and 05-stepincrease for baseline EDSS 60 to 65 sustained for 3months (p 090 hazard ratio 0977 95 CI 0679 to1407 Cox proportional hazards model) There was littlechange in the EDSS score from baseline to month 24 ineither group (placebo n 193 mean change 0272 me-dian 0 vs IFN-1a n 186 mean change 0258median 0) and no between-group difference (p 0362analysis of covariance on ranks) There was no differencein the proportions of subjects categorized as stable (591placebo vs 640 IFN-1a) worse (337 placebo vs 285IFN-1a) or better (73 placebo vs 75 IFN-1a) basedon EDSS change from baseline to month 24 (p 056Fisherrsquos exact test) Analyses of the predefined subgroupsfailed to identify a cohort showing significant benefit onthe EDSS

Relapse rate The annual relapse rate (total number ofrelapses divided by total number of subject-years) was 030in the placebo-treated subjects vs 020 in the IFN-1andashtreated subjects representing a 33 reduction (p 0008likelihood ratio test with a Poisson regression model) Inthe intent-to-treat cohort 139 placebo subjects (63) and160 IFN-1a subjects (74) were relapse-free during thestudy (p 0023 Fisherrsquos exact test) The mean annualrate of steroid treatment was 027 courses per year for theplacebo subjects and 019 for the IFN-1a subjects (p 0030 likelihood ratio test with a Poisson regressionmodel)

Table 2 Baseline to month 24 change in the MSFC and component Z-scores

Test Placebo n 219 IFN-1a n 217 p Value

MSFC

Mean SD 0495 158 0362 141

Median (midquartile range) 0161 (0417 to 0028) 0096 (0305 to 0066) 0033

T25FW

Mean SD 1191 313 0979 262


9HPT

Mean SD 0290 0494 0202 0476


PASAT3

Mean SD 0004 0473 0094 0498


Analysis of covariance on ranks stratified on baseline EDSS and gadolinium enhancement on baseline MRI

IFN-1a interferon -1a MSFC MS Functional Composite T25FW Timed 25-Foot Walk 9HPT Nine-Hole Peg TestPASAT3 Paced Auditory Serial Addition Test with a 3-second interstimulus interval


HRQOL The two groups were well matched at base-line on the MSQLI (data not shown) Significant benefitfavoring IFN-1a treatment was observed on eight of 11subscales of the MSQLI with a favorable trend on theremaining three scales (additional material related to thisarticle can be found on the Neurology Web site go to wwwneurologyorg and scroll down the Table of Contents to findthe title link for this article) The IFN-1a group improvedfrom baseline to month 24 on 10 of 11 subscales (all exceptthe Bladder Control Scale) In contrast the placebo groupworsened from baseline to month 24 on 10 of 11 subscalesthe Modified Fatigue Impact Scale being the only subscaleshowing improvement

MRI As shown in table 4 IFN-1a treatment reducedthe number of new or enlarging T2-hyperintense lesions atmonths 12 and 24 (both p 0001 Wilcoxonrsquos rank sumtest) The mean number of new or enlarging lesions wasreduced 529 in the IFN-1a group relative to the placebogroup at month 12 and 456 at month 24 As shown intable 5 the number of Gd-enhancing lesions was reducedat months 12 and 24 in the IFN-1a subjects compared toplacebo (both p 0001 Wilcoxonrsquos rank sum test) The

mean volume of Gd enhancement was decreased in theIFN-1a subjects as compared to the placebo group atmonth 12 (610 2217 vs 866 3647 mm3) and month24 (579 2188 vs 815 5365 mm3 both p 0001Wilcoxonrsquos rank sum test) The proportion of subjects with1 Gd-enhancing lesion demonstrated benefit favoringIFN-1a treatment at month 12 (13 vs 32) and month24 (13 vs 28 both p 0001 Fisherrsquos exact test) Me-dian change from baseline in total T2-hyperintense lesionvolume was reduced in the IFN-1 group compared to theplacebo group by 784 at month 12 and 691 at month24 (both p 0001 nonparametric analysis of covariancestratified by baseline EDSS and the presence or absence ofGd-enhancing lesions)

Safety Weekly IM injection of 60 g of IFN-1a waswell tolerated by the majority of subjects However moreIFN-1a subjects withdrew from the study or discontinued

Figure 2 Median MS Functional Composite change frombaseline every 3 months The trend lines were determinedby linear regression IFN-1a interferon -1a

Table 3 Raw scores of MS Functional Composite (MSFC)component tests

Testvisit Placebo n 219 IFN-1a n 217

T25FW s

Baseline

Mean SD 146 154 144 174

Median (midquartilerange)

91 (65ndash161) 91 (64ndash146)

Month 24

Mean SD 320 530 290 470


119 (73ndash271) 104 (71ndash221)

9HPT s

Baseline

Mean SD 332 300 311 161


275 (232ndash348) 264 (230ndash328)

Month 24

Mean SD 531 903 447 828


296 (238ndash398) 275 (237ndash370)

PASAT3 no correct

Baseline

Mean SD 468 123 471 123


510 (390ndash570) 520 (390ndash570)

Month 24

Mean SD 467 137 483 129


520 (380ndash580) 540 (430ndash580)

IFN-1a interferon -1a T25FW Timed 25-Foot Walk9HPT Nine-Hole Peg Test PASAT3 Paced Auditory SerialAddition Test with a 3-second interstimulus interval

Table 4 New or enlarging T2-hyperintense MRI lesions

Month nono of newor enlarging lesions Placebo IFN-1a p Value

Month 12 195 (100) 190 (100)

0 113 (58) 147 (77)

1 31 (16) 22 (12)

2 14 (7) 9 (5)

3 13 (7) 4 (2)

4 24 (12) 8 (4) 0001

Month 24 180 (100) 176 (100)

0 75 (42) 111 (63)

1 19 (11) 18 (10)

2 22 (12) 20 (11)

3 11 (6) 10 (6)

4 53 (29) 17 (10) 0001

Values are expressed as no of subjects ( of total availablescans)

Wilcoxon rank sum test

IFN-1a interferon -1a


study drug because of adverse events 8 vs 4 or intoler-ance of study drug 6 vs 0 (both p 005 Fisherrsquos exacttest) More placebo subjects discontinued because of per-ceived disease worsening (11 vs 3 p 005 Fisherrsquosexact test) Among the completers the average proportionsof full doses after the initial titration were 92 in theIFN-1a group and 96 in the placebo group

There were no unanticipated adverse effects (additionalmaterial related to this article can be found on the Neurol-ogy Web site go to wwwneurologyorg) The only adverseevents occurring with a 5 greater incidence amongIFN-1andashtreated subjects were flulike syndrome feverchills vomiting and injection site inflammation Depres-sion at any time in the study was equally frequent in thetwo groups either self-reported (22 of placebo subjects vs26 of IFN-1a subjects) or defined as a Beck DepressionInventory score 18 (26 of placebo subjects vs 25 ofIFN-1a subjects) There were two deaths among theIFN-1andashtreated subjects one resulting from complica-tions of acute brainstem infarction in a subject with aprevious infarction before the study and the second fromurosepsis Both subjects were off study drug and neitherdeath was thought to be related to study drug

The incidence of a neutralizing antibody titer 20 atany time during the trial was 33 among IFN-1andashtreated subjects

Discussion This study demonstrated benefit ofIFN-1a 60 g IM weekly on MSFC progression in

SPMS Median baseline to month 24 MSFC worsen-ing the primary outcome measure was reduced404 The statistical robustness of this positivefinding was supported by analyses using differentmissing data imputation methods statistical testsand subject cohorts The benefit observed on MSFCprogression was supported by benefits on relapserate HRQOL and MRI

The benefit of IFN-1a treatment on HRQOL sup-ported the clinical significance of the positive resultson MSFC progression relapses and MRI Numerousstudies have shown that MS negatively affectsHRQOL1830-33 HRQOL is lower in patients withSPMS as compared to those with RRMS34 and insubjects with greater involvement as measured bythe EDSS or MSFC1819 Nevertheless it is clear thatpatient self-reported HRQOL provides informationdistinct from clinician assessment of impairment anddisability35 The results reported here on the MSQLIsupported the benefit of IFN-1a on overall well-being from the subjectsrsquo perspective

Two other IFN preparations have been investi-gated in three large-scale trials in SPMS with mixedresults The European study of IFN-1b5 demon-strated benefit on EDSS progression The NorthAmerican study of the same agent6 and the Second-ary Progressive Efficacy Trial of RecombinantInterferon--1a in MS (SPECTRIMS) study ofIFN-1a by subcutaneous injection7 yielded negativeresults on EDSS progression In all three studiesIFN treatment reduced relapse rate by approxi-mately 30 and decreased MRI activity It has beenhypothesized736 that these discrepant findings weredue to differences in study populations Subjects inthe European study of IFN-1b were younger with ashorter duration of disease and substantially higherpre- and on-study relapse rates It may have beenmore difficult to demonstrate a beneficial treatmenteffect on EDSS progression in the North AmericanIFN-1b study and in the SPECTRIMS trial becausethe subjects were at a more advanced stage of SPMS

The subjects in the IMPACT trial were similar tothose the North American IFN-1b study and SPEC-TRIMS As in those studies there was benefit fromtreatment on relapse rate and MRI activity in IM-PACT but not on EDSS progression However bene-fit on disease progression in SPMS was shown inIMPACT through utilization of the MSFC Thegreater sensitivity of the MSFC relative to the EDSSresults from its high degree of reliability advanta-geous metric properties as a continuous scale andassessment of arm function and cognition in additionto ambulation These attributes allowed the MSFCto detect a beneficial treatment effect when theEDSS failed Other studies have suggested thatquantitative functional measures are more sensitiveto change than the EDSS123738

The MSFC has several potential limitations as anoutcome measure First in IMPACT the distribu-tions of change over time of the MSFC componentswere markedly skewed particularly the T25FW

Table 5 Gadolinium-enhancing MRI lesions

Visitno of gadolinium-enhancing lesions Placebo IFN-1a p Value

Baseline 207 (100) 210 (100)

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11) 0350

Month 12 192 (100) 189 (100)

0 131 (68) 165 (87)

1 26 (14) 14 (7)

2 13 (7) 5 (3)

3 3 (2) 2 (1)

4 19 (10) 3 (2) 0001

Month 24 186 (100) 180 (100)

0 133 (72) 156 (87)

1 20 (11) 17 (9)

2 6 (3) 2 (1)

3 12 (6) 2 (1)

4 15 (8) 3 (2) 0001





which may have impaired the ability to demonstratea treatment effect Alternative methods for handlingMSFC data including transformations may improvethe metric properties of the MSFC Also it is possi-ble that alternative testing methods may be neces-sary at different stages of MS Second the MSFCdoes not directly assess vision an important clinicaldimension in MS Contrast sensitivity has shownpromise as a potential measure of visual function forinclusion in the MSFC39 Finally because of the re-cent introduction of the MSFC clinicians are rela-tively unfamiliar with its interpretation

Despite these potential limitations of the MSFCits validity as a clinical outcome measure is sup-ported by multiple independent studies Four studiesusing distinct datasets comprising a total of 1319subjects1216-18 showed that the MSFC correlated withthe EDSS supporting the convergent validity of theMSFC (correlation with another measure of neuro-logic function) Among the components of the MSFCthe T25FW correlated best with the EDSS As ex-pected correlation between the 9HPT and EDSS wasmoderately strong and correlation between the PA-SAT3 and EDSS was modest This pattern of correla-tion between the MSFC components and the EDSSsupports the divergent validity of the MSFC (mea-surement of aspects of MS not covered by the EDSS)an important source of its greater sensitivity

Validity of the MSFC was further supported bythe observation that it was worse in subjects withSPMS as compared to those with RRMS17 TheMSFC has been shown to correlate more stronglywith T2-hyperintense lesion burden on cranialMRI20-22 and whole-brain atrophy2022 as compared tothe EDSS The clinical relevance of the MSFC wassupported by its correlation with patient self-reported MS symptoms and HRQOL1819

The most important aspect of the validity of anoutcome measure for clinical trials is its ability topredict future disease status (predictive validity)which is particularly relevant when assessing as-pects of a chronic disease that typically worsenslowly such as impairment and disability in SPMSIn a long-term follow-up study22 subjects enrolled inthe phase III study of IFN-1a in RRMS1 were reas-sessed an average of 81 years after randomizationBaseline MSFC and MSFC worsening over 2 years inthe original trial were highly correlated with re-quirement for assistance to walk evolution from anRR to an SP course and severe whole-brain atrophyat follow-up The MSFC correlated with these end-points better than the EDSS

The results of studies employing the MSFC shouldbe interpreted primarily based on the overall com-posite score However one advantage of the MSFC isthat changes in the individual components can bedirectly compared In IMPACT benefit on the MSFCappeared to be driven largely by an effect on armfunction and to a lesser extent cognition One inter-pretation of this observation is that progressive gait

impairment in advanced MS is less responsive toIFN-1a treatment as compared to other neurologicmanifestations Interestingly a previous study oforal methotrexate in progressive MS40 also showedbenefit of treatment on upper extremity function(measured by the 9HPT or Box and Blocks test) andcognition (including the PASAT3) but not ambula-tion (measured by the EDSS or Ambulation Index)

An alternative explanation is that differences inMSFC component tests or how they were analyzedaccounted at least in part for the pattern of theresults The T25FW worsened over 2 years in the ma-jority of subjects suggesting that it was a responsivemeasure There was a trend to greater worsening inthe placebo subjects However the T25FW distributionwas the most skewed of the MSFC components withsubstantially greater within- and between-subject vari-ability owing to some subjects with markedly pro-longed walking times Possible scores on the PASAT3were restricted from 0 to 60 and use of the inverse ofthe 9HPT time reduced the skewness of its distribu-tion Thus further studies will be necessary to deter-mine whether the differential treatment effect on theMSFC components resulted from decreased ability ofIFN-1a to preserve ambulation vs other neurologicdomains in SPMS or whether MSFC analytic methodscan be optimized to better detect treatment effects

AcknowledgmentThe authors thank K Lloyd N Blanchard and J Lull for theirassistance with this study as well as the staff of Covance forstudy monitoring The authors were saddened by the death of JNWhitaker during the preparation of this manuscript

AppendixThe IMPACT Investigators include the following investigationalteams (the site principal investigator is listed first) University ofCalifornia Davis Medical Center Sacramento CA M Agius MDJ Adams RN R Beale D Richman MD N Vijayan MD VWheelock MD University of Maryland School of Medicine Balti-more C Bever MD K Costello RN S Dhib-Jalbut MD KJohnson MD E Katz RN H Panitch MD Minneapolis Clinic ofNeurology Golden Valley G Birnbaum MD I Altafullah MD GChristenson RN K Stillwell University of Washington MedicalCenter Seattle J Bowen MD A Gianas RN E Krause MD EYuen MD Rhode Island HospitalndashBrown University ProvidenceP Calabresi MD L Alderson MD G Johnson MD P Mills RNJ Quinless J Wilterdink MD Mayo Clinic Scottsdale AZJ Carter MD J Buckner R Caselli MD K MacElwee RN KNelson MD J Takata MD Cleveland Clinic Foundation MellenMS Center OH J Cohen MD D Bolibrush C Hara-CleaverRN R Kinkel MD R Rudick MD L Stone MD University ofMedicine and DentistryndashNew Jersey Medical School Newark SCook MD D Cadavid MD A Jotkowitz RN Y Maeda MD JQuinless RN University of Colorado Health Sciences Center Den-ver J Corboy MD J Bainbridge PharmD J LaGuardia MD HNeville MD R Taggart MSN ANP-C R Wright MD GeorgetownUniversity Hospital Washington DCH Crayton MD D BartlettRN S CohanT Gustafson RN J Richert MD C TornatoreMD University of New Mexico Health Science Center Albuquer-que C Ford MD G Graham A Kradochvil J Maldonado MDUniversity of PennsylvaniaPhiladelphia S Galetta MD L Bal-cer MD F Gonzalez-Scarano MD R Grossman MD D KolsonMD PhD G Liu MD M Mills D Pfohl RN A Pruitt MDA-M Rostami MD PhD D Silberberg MD University of Ro-chester NY A Goodman MD Petrie RN E Scheid RN S Sch-wid MD D Shrier MD Yale School of Medicine New Haven CTJ Guarnaccia MD J Hayes S Novella MD H Patwa MD MRizzo MD M Shepard RN T Vollmer MD University of Missis-


sippi Medical Center Jackson R Herndon MD J Corbett MDR Fredericks MD J Pittman PharmD P Reynolds MD MUmberger RN R Wier RN Buffalo General Hospital NY LJacobs MD R Bakshi MD E Gallagher RN S Greenberg MDF Munschauer III MD K Murray MD K Patrick B Weinstock-Guttman MD University of Southern California Los Angeles NKachuk MD L Adobo MA C Cooper R Cowan MD D Ko MDMS Center at Carolinas Medical Center Charlotte NC M Kauf-man MD A Diedrich MD D Lutz R Follmer MD S PutmanMD S Presley Allegheny University of the Health Sciences Phil-adelphia PA F Lublin MD R Elfont MD PhD L Kelly PhDM Weber Oregon Health Sciences University Portland M MassMD D Bourdette MD R Camicioli MD S Cooper-Hanel DGriffiths RN R Whitham MD Indiana University School ofMedicine Indianapolis D Mattson MD PhD J Fleck MD CFlippen MD J Hayes D Jackson RN M Phillips MD Mai-monides Medical Center Brooklyn NY A Miller MD M Brod-bari K Bruining MD E Drexler MD H Elinzano MD MKeilson MD T LaRocca RN BSN L Morgante RN MSN LSciarra RN MSN R Wolintz MD University of California at LosAngeles MS Center L Myers MD R Baumhefner MD S CraigRN R Klutch N Sicotte MD Ohio State University ColumbusK Rammohan MD A Edwards RN D Lynn MD A SlivkaMD Vanderbilt University MS Center Nashville TN S SriramMD S Hunter MD PhD H Moses Jr MD F Niaz MD JSimmons RN K Reece RN MS Center at Shepherd Center At-lanta GA W Stuart MD D Court RN R Gilbert MD EHedaya MD S Morgan D Stuart MD Washington UniversitySt Louis MO J Trotter MD D Cross MD D Derrington MDJ Lauber RN C Martinez LPN University of California at Ir-vine S Van den Noort MD R Babcock RN P Fotinakes MD YQin G Thai MD Yale University New Haven CT T VollmerMD G BlancoJ Guarnaccia MD T Halverson E Kane SMarkovic-Plese MD L Marshall S Novella MD H Patwa MDG Richerson MD M Rizzo MD University of Alabama at Bir-mingham J Whitaker MD K Bashir MD B Layton RN LNabors III MD A Nicholas MD PhD R Slaughter MD KWhikehart University of Texas at Houston Health Science CenterJ Wolinsky MD S Brod MD E Cerreta RN W Lindsey MDC Weisbrodt RN Hopital Notre-Dame Montreal Quebec Can-ada P Duquette MD G Bernier MD P Cossette MD RDubois RN J Poirier Ottawa General Hospital ON Canada MFreedman MD S Christie MD C Freedman BMT (PT) RNelson MD H Rabinovitch MD U Webb RN University ofToronto MS Clinic St Michaels Hospital ON Canada POrsquoConnor MD J Fleming P Fleming RN T Gray MD MHohol MD P Marchotti MD University of Western Ontario Hos-pital London Canada G Rice MD T Bentall BSc G EbersMD M Hopkins RN P Mandalfino MD M Nicolle MS Neuro-logical Center Quellenhof Bad Wildbad Germany A Foit MD RAscheron A Fauser MD J Fernholtz A Immesberger M Riex-inger R Roth Staedtische Kliniken Osnabrueck Germany PHaller MD PhD D Lammers S Stove MD A Terwey MD SWindhagen Medizinische Hochschule Hannover Germany FHeidenreich MD H Becker MD K Fricke R Hilse MD NKoehler MD A Kracke MD R Lindert MD S Maniak MD SMarckmann MD Athens University Greece M Dalakas MD CKilidreas MD A Rombos MD C Taskanikas MD C Voum-vourakis MD Haddassah Hebrew National University Jerusa-lem Israel O Abramsky MD A Askenazi MD A Karmi MDD Karussis MD A Linitsky MD M Mor MD VU ZiekenhuisAmsterdam the Netherlands C Polman MD PhD J CastelijnsMD B Jelles MD N Kalkers MDJ Killestein MD J Meilof TSchweigmann Marianne-Strau-Klinik Milchberg Germany NKoenig MD H Albrecht MD W Feneberg MD C KutschkerMD W Poellmann MD M Starck MD Advisory and Publica-tions Committee J Cohen MD (Chair) A Goodman MD F Hei-denreich MD J Simon MD PhD J Whitaker MD Data andSafety Monitoring Committee J Noseworthy MD (Chair) T Col-ton ScD H-P Hartung MD H McFarland MD L Metz MDMR ReadingAnalysis Center University of Colorado J SimonMD PhD A Cajade-Law MD B Coombs MbChb PhD E EscottMD C Gustafson M Lajaunie MD R Leek M Meyers MS DMiller PhD B Quandt D Singel MSFC Quality Control JFischer PhD J Gellhausen MA A Jak MA Additional Advi-sors G Cutter PhD D Miller PhD R Rudick MD

References1 Jacobs LD Cookfair DL Rudick RA et al Intramuscular in-

terferon beta-1a for disease progression in relapsing multiplesclerosis Ann Neurol 199639285ndash294

2 Simon JH Jacobs LD Campion M et al Magnetic resonancestudies of intramuscular interferon -1a for relapsing multiplesclerosis Ann Neurol 19984379ndash87

3 Fischer JA Priore RL Jacobs LD et al Neuropsychologicaleffects of interferon -1a in relapsing multiple sclerosis AnnNeurol 200048885ndash892

4 Jacobs LD Beck RW Simon JH et al Intramuscular inter-feron beta-1a therapy initiated during a first demyelinatingevent in multiple sclerosis N Engl J Med 2000343898ndash904

5 European Study Group on Interferon -1b in Secondary Pro-gressive MS Placebo-controlled multicentre randomized trialof interferon -1b in treatment of secondary progressive mul-tiple sclerosis Lancet 19983521491ndash1497

6 Goodkin DE the North American Study Group on Interferonbeta-1b in Secondary Progressive MS Interferon beta-1b insecondary progressive MS clinical and MRI results of a 3-yearrandomized controlled trial Neurology 2000542352 Ab-stract

7 Secondary Progressive Efficacy Clinical Trial of RecombinantInterferon-beta-1a in MS (SPECTRIMS) Study Group Ran-domized controlled trial of interferon-beta-1a in secondaryprogressive MS Clinical results Neurology 2001561496 ndash1504

8 Kurtzke JF Rating neurologic impairment in multiple sclero-sis an expanded disability status scale (EDSS) Neurology1983331444ndash1452

9 Whitaker JN McFarland HF Rudge P Reingold SC Out-comes assessment in multiple sclerosis clinical trials a criticalanalysis Mult Scler 1995137ndash47

10 Rudick R Antel J Confavreux C et al Clinical outcomesassessment in multiple sclerosis Ann Neurol 199640469 ndash 479

11 Rudick R Antel J Confavreux C et al Recommendationsfrom the National Multiple Sclerosis Society clinical outcomesassessment task force Ann Neurol 199742379ndash382

12 Cutter GR Baier ML Rudick RA et al Development of amultiple sclerosis functional composite as a clinical trial out-come measure Brain 1999122871ndash882

13 Fischer JS Rudick RA Cutter GR Reingold SC the NationalMS Society Clinical Outcomes Assessment Task Force Themultiple sclerosis functional composite measure (MSFC) anintegrated approach to MS clinical outcome assessment MultScler 19995244ndash250

14 Fischer JS Jak AJ Knicker JE Rudick RA Cutter G Admin-istration and scoring manual for the multiple sclerosis func-tional composite (MSFC) New York Demos 1999

15 Cohen JA Fischer JS Bolibrush DM et al Intrarater andinterrater reliability of the MS functional composite outcomemeasure Neurology 200054802ndash806

16 Cohen JA Cutter GR Fischer JS et al Use of the multiplesclerosis functional composite as an outcome measure in aphase 3 clinical trial Arch Neurol 200158961ndash967

17 Kalkers NF de Groot V Lazeron RHC et al MS functionalcomposite relation to disease phenotype and disability strataNeurology 2000541233ndash1239

18 Miller DM Rudick RA Cutter G Baier M Fischer JS Clini-cal significance of the Multiple Sclerosis Functional Compos-ite Relationship to patient-reported quality of life ArchNeurol 2000571319ndash1324

19 Hoogervorst ELJ van Winsen LML Eikelenboom MJ Kalk-ers NF Uitdehaag BMJ Polman CH Comparisons of patientself-report neurologic examination and functional impair-ment in MS Neurology 200156934ndash937

20 Fisher E Rudick RA Cutter G et al Relationship betweenbrain atrophy and disability an 8-year followup study of mul-tiple sclerosis patients Mult Scler 20006373ndash377

21 Kalkers NF Bergers L de Groot V et al Concurrent validityof the MS Functional Composite using MRI as a biologicaldisease marker Neurology 200156215ndash219

22 Rudick RA Cutter G Baier M et al Use of the multiple


sclerosis functional composite to predict disability in relapsingMS Neurology 2001561324ndash1330

23 Poser C Paty D Scheinberg L et al New diagnostic criteriafor multiple sclerosis guidelines for research protocols AnnNeurol 198313227ndash231

24 Lublin FD Reingold SC Defining the clinical course of multi-ple sclerosis results of an international survey Neurology199646907ndash911

25 Taves DR Minimization a new method of assigning patientsto treatment and control groups Clin Pharmacol Ther 197415443ndash453

26 Simonian N Goodman A Guarnaccia J et al An open-labeltolerability study of interferon beta-1a in combination withsteroids and pentoxyfylline in patients with moderate to se-vere multiple sclerosis Ann Neurol 199844504 Abstract

27 Ritvo PG Fischer JF Miller DM Andrews H Paty D LaRoccaNG Multiple Sclerosis Quality of Life Inventory a userrsquos man-ual New York National Multiple Sclerosis Society 1997

28 Fischer JS LaRocca NG Miller DM Ritvo PG Andrews HPaty D Recent developments in the assessment of quality oflife in multiple sclerosis (MS) Mult Scler 19995251ndash259

29 Rudick RA Simonian NA Alam JA et al Incidence and sig-nificance of neutralizing antibodies to interferon beta-1a inmultiple sclerosis Neurology 1998501266ndash1272

30 Rudick RA Miller D Clough JD Gragg LA Farmer RGQuality of life in multiple sclerosis Comparison with inflam-matory bowel disease and rheumatoid arthritis Arch Neurol1992491237ndash1242

31 Solari A Filippini G Gasco P et al Physical rehabilitationhas a positive effect on disability in multiple sclerosis pa-tients Neurology 19995257ndash62

32 Freeman JA Langdon DW Hobart JC Thompson AJ Inpa-tient rehabilitation in multiple sclerosis do the benefits carryover into the community Neurology 19995250ndash56

33 Nortvedt MW Riise T Myhr KM Nyland HI Performanceof the SF-36 SF-12 and RAND-36 summary scales in amultiple sclerosis population Med Care Res Rev 2000381022ndash1028

34 Janardhan V Bakshi R Quality of life and its relationship tobrain lesions and atrophy on magnetic resonance images in60 patients with multiple sclerosis Arch Neurol 2000571485ndash1491

35 Rothwell PM McDowell Z Wong CK Dorman PJ Doctorsand patients donrsquot agree cross sectional study of patientsrsquo anddoctorsrsquo perceptions and assessments of disability in multiplesclerosis BMJ 19973141580ndash1583

36 McFarland HF Comparative analysis of the outcome of twophase III studies of interferon beta-1b Neurology 2000542352 Abstract

37 Schwid SR Goodman AD Apatoff BR et al Are quantitativefunctional measures more sensitive to worsening MS thantraditional measures Neurology 2000551901ndash1903

38 Syndulko K Tourtellotte WW Baumhefner RW et al Neu-roperformance evaluation of multiple sclerosis disease pro-gression in a clinical trial implications for neurologicaloutcomes J Neurol 19937153ndash176

39 Baier ML Cutter GR Rudick RA et al Performance of avisual function test in a multiple sclerosis cohort Neurology200054(suppl 3)A214 Abstract

40 Goodkin DE Rudick RA Medendorp SV et al Low-dose (75mg) oral methotrexate reduces the rate of progression inchronic progressive multiple sclerosis Ann Neurol 19953730ndash41

ACTIVATE YOUR ONLINE SUBSCRIPTIONAt wwwneurologyorg subscribers can now access the full text of the current issue of Neurology and back issues to 1999Select the ldquoLogin instructionsrdquo link that is provided on the Help screen Here you will be guided through a step-by-step ac-tivation process

Neurology online offersbull Access to journal content in both Adobe Acrobat PDF or HTML formatsbull Links to PubMedbull Extensive search capabilitiesbull Complete online Information for Authorsbull Examinations on designated articles for CME creditbull Access to in-depth supplementary scientific data



J A Cohen G R Cutter J S Fischer et al -1a on MSFC progression in secondary progressive MSβBenefit of interferon


ServicesUpdated Information amp

httpwwwneurologyorgcontent595679fullhtmlincluding high resolution figures can be found at

Supplementary Material

htmlhttpwwwneurologyorgneurologysuppl20020826595679DC1Supplementary material can be found at

References httpwwwneurologyorgcontent595679fullhtmlref-list-1

This article cites 36 articles 18 of which you can access for free at

Citations httpwwwneurologyorgcontent595679fullhtmlotherarticles

This article has been cited by 48 HighWire-hosted articles

Subspecialty Collections

httpwwwneurologyorgcgicollectionquality_of_lifeQuality of life

httpwwwneurologyorgcgicollectionmultiple_sclerosisMultiple sclerosis

controlled_consort_agreementhttpwwwneurologyorgcgicollectionclinical_trials_randomized_Clinical trials Randomized controlled (CONSORT agreement)following collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgmiscaboutxhtmlpermissionsin its entirety can be found online atInformation about reproducing this article in parts (figurestables) or

Reprints

httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Benefit of interferon -1a on MSFCprogression in secondary progressive MS

JA Cohen MD GR Cutter PhD JS Fischer PhD AD Goodman MD FR Heidenreich MDMF Kooijmans MD PhD AW Sandrock MD PhD RA Rudick MD JH Simon MD PhDNA Simonian MD EC Tsao PhD and JN Whitaker MDdagger for the IMPACT Investigators

AbstractmdashBackground Interferon -1a (IFN-1a Avonex) is efficacious in relapsing forms of MS Studies of other IFNpreparations in secondary progressive MS (SPMS) yielded conflicting results This study was undertaken to determinewhether IFN-1a slowed disease progression in SP-MS Methods A total of 436 subjects with SPMS and ExpandedDisability Status Scale (EDSS) score 35 to 65 were randomized to receive IFN-1a (60 g) or placebo by weeklyintramuscular injection for 2 years The primary outcome measure used for the first time in a large-scale MS trial wasbaseline to month 24 change in the MS Functional Composite (MSFC) comprising quantitative tests of ambulation (Timed25-Foot Walk) arm function (Nine-Hole Peg Test [9HPT]) and cognition (Paced Auditory Serial Addition Test [PASAT])Results Median MSFC Z-score change was reduced 404 in IFN-1a subjects (0096 vs 0161 in placebo subjects p 0033) an effect driven mainly by the 9HPT and PASAT There was no discernible benefit on the EDSS which in thisrange principally reflects walking ability IFN-1a subjects had 33 fewer relapses (p 0008) There was significantbenefit on eight of 11 MS Quality of Life Inventory subscales New or enlarging T2-hyperintense brain MRI lesions andgadolinium-enhancing lesions were reduced at months 12 and 24 (both p 0001) IFN-1a was well tolerated by themajority of subjects Neutralizing antibodies developed in 33 of IFN-1andashtreated subjects Conclusions IFN-1a dem-onstrated benefit on MSFC progression relapses quality of life and MRI activity in SPMS

NEUROLOGY 200259679ndash687

Interferon -1a (IFN-1a Avonex) has been shownto reduce disease progression relapse rate cognitivedeterioration and MRI activity in relapsing forms ofMS1-3 and to reduce the rate of conversion to clini-cally definite MS and subclinical MRI activity inpatients presenting with an acute monophasic demy-elinating event4 Three previous phase III studies ofother IFN preparations in secondary progressiveMS (SPMS)5-7 showed consistent treatment benefits onrelapse rate and MRI activity but conflicting results onthe primary outcome measure time to progression onthe Kurtzke Expanded Disability Status Scale(EDSS)8 The known lack of sensitivity to change of theEDSS in the range represented by the subjects in thesestudies may account in part for the apparent lack ofeffect on the EDSS score despite treatment benefits on

other outcome measures Alternatively progressivegait impairment may become less responsive to ther-apy in advanced stages of MS

To address the insensitivity and poor reliability ofthe EDSS9 the National MS Societyrsquos Clinical Out-comes Assessment Task Force recommended an al-ternative outcome measure for clinical trials the MSFunctional Composite (MSFC)10-14 Unlike the EDSSwhich is derived from the standard neurologic exam-ination the MSFC is based on quantitative tests ofambulation (Timed 25-foot Walk [T25FW]) armfunction (Nine-Hole Peg Test [9HPT]) and cognition(Paced Auditory Serial Addition Test with a 3-secondinterstimulus interval [PASAT3]) Two studies sup-ported the feasibility of the MSFC and its excellentintra- and interrater reliability1516 MSFC validitywas supported by correlation with the EDSS1216-18

disease course17 patient self-reported symptoms andhealth-related quality of life (HRQOL)1819 and MRI-measured lesion load and cerebral atrophy20-22

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the September 10 issue to find the link for this article

daggerDeceasedSee the Appendix on page 685 for a complete listing of the IMPACT InvestigatorsFrom the Mellen Center for Multiple Sclerosis Treatment and Research Department of Neurology (Drs Cohen Fischer and Rudick) Cleveland ClinicFoundation OH Center for Research Methodology and Biometrics (Dr Cutter) AMC Cancer Center Lakewood CO Department of Neurology (DrGoodman) University of Rochester NY Department of Neurology (Dr Heidenreich) Hannover Medical School Germany Biogen Inc (Drs KooijmansSandrock Simonian and Tsao) Cambridge MA Department of Radiology (Dr Simon) University of Colorado Denver and Department of Neurology (DrWhitaker) University of Alabama at BirminghamBiogen Inc supported this study and development of the MSFC manual which is available through the National MS Society MFK NAS AWS andECT are full-time employees of Biogen Inc None of the other authors has a personal financial investment ownership equity or other financial holdingswith Biogen IncResults presented at the annual meeting of the American Academy of Neurology Philadelphia PA May 8 2001Received October 3 2001 Accepted in final form June 11 2002Address correspondence and reprint requests to Dr Jeffrey A Cohen Mellen CenterndashU10 Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland OH44195 e-mail cohenjccforg

Copyright copy 2002 by AAN Enterprises Inc 679











Age y mean SD 479 77 472 82

Female sex n () 141 (64) 138 (64)


167 90 162 90




35ndash55 113 (52) 113 (52)

60ndash65 106 (48) 104 (48)


Prior 3 y 13 21 15 21

Prior 1 y 05 09 06 11


Prior 3 y 97 (44) 80 (37)

Prior 1 y 135 (62) 129 (59)


40 52 34 50




1004 2745 1659 6965


0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11)





















MSFC

Mean SD 0495 158 0362 141


T25FW

Mean SD 1191 313 0979 262


9HPT

Mean SD 0290 0494 0202 0476


PASAT3

Mean SD 0004 0473 0094 0498












T25FW s

Baseline

Mean SD 146 154 144 174


91 (65ndash161) 91 (64ndash146)

Month 24

Mean SD 320 530 290 470


119 (73ndash271) 104 (71ndash221)

9HPT s

Baseline

Mean SD 332 300 311 161


275 (232ndash348) 264 (230ndash328)

Month 24

Mean SD 531 903 447 828


296 (238ndash398) 275 (237ndash370)

PASAT3 no correct

Baseline

Mean SD 468 123 471 123


510 (390ndash570) 520 (390ndash570)

Month 24

Mean SD 467 137 483 129


520 (380ndash580) 540 (430ndash580)




Month 12 195 (100) 190 (100)

0 113 (58) 147 (77)

1 31 (16) 22 (12)

2 14 (7) 9 (5)

3 13 (7) 4 (2)

4 24 (12) 8 (4) 0001

Month 24 180 (100) 176 (100)

0 75 (42) 111 (63)

1 19 (11) 18 (10)

2 22 (12) 20 (11)

3 11 (6) 10 (6)

4 53 (29) 17 (10) 0001
















Baseline 207 (100) 210 (100)

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11) 0350

Month 12 192 (100) 189 (100)

0 131 (68) 165 (87)

1 26 (14) 14 (7)

2 13 (7) 5 (3)

3 3 (2) 2 (1)

4 19 (10) 3 (2) 0001

Month 24 186 (100) 180 (100)

0 133 (72) 156 (87)

1 20 (11) 17 (9)

2 6 (3) 2 (1)

3 12 (6) 2 (1)

4 15 (8) 3 (2) 0001















































































Reprints












Age y mean SD 479 77 472 82

Female sex n () 141 (64) 138 (64)


167 90 162 90




35ndash55 113 (52) 113 (52)

60ndash65 106 (48) 104 (48)


Prior 3 y 13 21 15 21

Prior 1 y 05 09 06 11


Prior 3 y 97 (44) 80 (37)

Prior 1 y 135 (62) 129 (59)


40 52 34 50




1004 2745 1659 6965


0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11)





















MSFC

Mean SD 0495 158 0362 141


T25FW

Mean SD 1191 313 0979 262


9HPT

Mean SD 0290 0494 0202 0476


PASAT3

Mean SD 0004 0473 0094 0498












T25FW s

Baseline

Mean SD 146 154 144 174


91 (65ndash161) 91 (64ndash146)

Month 24

Mean SD 320 530 290 470


119 (73ndash271) 104 (71ndash221)

9HPT s

Baseline

Mean SD 332 300 311 161


275 (232ndash348) 264 (230ndash328)

Month 24

Mean SD 531 903 447 828


296 (238ndash398) 275 (237ndash370)

PASAT3 no correct

Baseline

Mean SD 468 123 471 123


510 (390ndash570) 520 (390ndash570)

Month 24

Mean SD 467 137 483 129


520 (380ndash580) 540 (430ndash580)




Month 12 195 (100) 190 (100)

0 113 (58) 147 (77)

1 31 (16) 22 (12)

2 14 (7) 9 (5)

3 13 (7) 4 (2)

4 24 (12) 8 (4) 0001

Month 24 180 (100) 176 (100)

0 75 (42) 111 (63)

1 19 (11) 18 (10)

2 22 (12) 20 (11)

3 11 (6) 10 (6)

4 53 (29) 17 (10) 0001
















Baseline 207 (100) 210 (100)

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11) 0350

Month 12 192 (100) 189 (100)

0 131 (68) 165 (87)

1 26 (14) 14 (7)

2 13 (7) 5 (3)

3 3 (2) 2 (1)

4 19 (10) 3 (2) 0001

Month 24 186 (100) 180 (100)

0 133 (72) 156 (87)

1 20 (11) 17 (9)

2 6 (3) 2 (1)

3 12 (6) 2 (1)

4 15 (8) 3 (2) 0001















































































Reprints



















MSFC

Mean SD 0495 158 0362 141


T25FW

Mean SD 1191 313 0979 262


9HPT

Mean SD 0290 0494 0202 0476


PASAT3

Mean SD 0004 0473 0094 0498












T25FW s

Baseline

Mean SD 146 154 144 174


91 (65ndash161) 91 (64ndash146)

Month 24

Mean SD 320 530 290 470


119 (73ndash271) 104 (71ndash221)

9HPT s

Baseline

Mean SD 332 300 311 161


275 (232ndash348) 264 (230ndash328)

Month 24

Mean SD 531 903 447 828


296 (238ndash398) 275 (237ndash370)

PASAT3 no correct

Baseline

Mean SD 468 123 471 123


510 (390ndash570) 520 (390ndash570)

Month 24

Mean SD 467 137 483 129


520 (380ndash580) 540 (430ndash580)




Month 12 195 (100) 190 (100)

0 113 (58) 147 (77)

1 31 (16) 22 (12)

2 14 (7) 9 (5)

3 13 (7) 4 (2)

4 24 (12) 8 (4) 0001

Month 24 180 (100) 176 (100)

0 75 (42) 111 (63)

1 19 (11) 18 (10)

2 22 (12) 20 (11)

3 11 (6) 10 (6)

4 53 (29) 17 (10) 0001
















Baseline 207 (100) 210 (100)

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11) 0350

Month 12 192 (100) 189 (100)

0 131 (68) 165 (87)

1 26 (14) 14 (7)

2 13 (7) 5 (3)

3 3 (2) 2 (1)

4 19 (10) 3 (2) 0001

Month 24 186 (100) 180 (100)

0 133 (72) 156 (87)

1 20 (11) 17 (9)

2 6 (3) 2 (1)

3 12 (6) 2 (1)

4 15 (8) 3 (2) 0001















































































Reprints











MSFC

Mean SD 0495 158 0362 141


T25FW

Mean SD 1191 313 0979 262


9HPT

Mean SD 0290 0494 0202 0476


PASAT3

Mean SD 0004 0473 0094 0498












T25FW s

Baseline

Mean SD 146 154 144 174


91 (65ndash161) 91 (64ndash146)

Month 24

Mean SD 320 530 290 470


119 (73ndash271) 104 (71ndash221)

9HPT s

Baseline

Mean SD 332 300 311 161


275 (232ndash348) 264 (230ndash328)

Month 24

Mean SD 531 903 447 828


296 (238ndash398) 275 (237ndash370)

PASAT3 no correct

Baseline

Mean SD 468 123 471 123


510 (390ndash570) 520 (390ndash570)

Month 24

Mean SD 467 137 483 129


520 (380ndash580) 540 (430ndash580)




Month 12 195 (100) 190 (100)

0 113 (58) 147 (77)

1 31 (16) 22 (12)

2 14 (7) 9 (5)

3 13 (7) 4 (2)

4 24 (12) 8 (4) 0001

Month 24 180 (100) 176 (100)

0 75 (42) 111 (63)

1 19 (11) 18 (10)

2 22 (12) 20 (11)

3 11 (6) 10 (6)

4 53 (29) 17 (10) 0001
















Baseline 207 (100) 210 (100)

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11) 0350

Month 12 192 (100) 189 (100)

0 131 (68) 165 (87)

1 26 (14) 14 (7)

2 13 (7) 5 (3)

3 3 (2) 2 (1)

4 19 (10) 3 (2) 0001

Month 24 186 (100) 180 (100)

0 133 (72) 156 (87)

1 20 (11) 17 (9)

2 6 (3) 2 (1)

3 12 (6) 2 (1)

4 15 (8) 3 (2) 0001















































































Reprints









T25FW s

Baseline

Mean SD 146 154 144 174


91 (65ndash161) 91 (64ndash146)

Month 24

Mean SD 320 530 290 470


119 (73ndash271) 104 (71ndash221)

9HPT s

Baseline

Mean SD 332 300 311 161


275 (232ndash348) 264 (230ndash328)

Month 24

Mean SD 531 903 447 828


296 (238ndash398) 275 (237ndash370)

PASAT3 no correct

Baseline

Mean SD 468 123 471 123


510 (390ndash570) 520 (390ndash570)

Month 24

Mean SD 467 137 483 129


520 (380ndash580) 540 (430ndash580)




Month 12 195 (100) 190 (100)

0 113 (58) 147 (77)

1 31 (16) 22 (12)

2 14 (7) 9 (5)

3 13 (7) 4 (2)

4 24 (12) 8 (4) 0001

Month 24 180 (100) 176 (100)

0 75 (42) 111 (63)

1 19 (11) 18 (10)

2 22 (12) 20 (11)

3 11 (6) 10 (6)

4 53 (29) 17 (10) 0001
















Baseline 207 (100) 210 (100)

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11) 0350

Month 12 192 (100) 189 (100)

0 131 (68) 165 (87)

1 26 (14) 14 (7)

2 13 (7) 5 (3)

3 3 (2) 2 (1)

4 19 (10) 3 (2) 0001

Month 24 186 (100) 180 (100)

0 133 (72) 156 (87)

1 20 (11) 17 (9)

2 6 (3) 2 (1)

3 12 (6) 2 (1)

4 15 (8) 3 (2) 0001















































































Reprints













Baseline 207 (100) 210 (100)

0 136 (66) 130 (62)

1 35 (17) 34 (16)

2 11 (5) 13 (6)

3 5 (2) 10 (5)

4 20 (10) 23 (11) 0350

Month 12 192 (100) 189 (100)

0 131 (68) 165 (87)

1 26 (14) 14 (7)

2 13 (7) 5 (3)

3 3 (2) 2 (1)

4 19 (10) 3 (2) 0001

Month 24 186 (100) 180 (100)

0 133 (72) 156 (87)

1 20 (11) 17 (9)

2 6 (3) 2 (1)

3 12 (6) 2 (1)

4 15 (8) 3 (2) 0001















































































Reprints












































































Reprints


































































Reprints









































Reprints



















Reprints


Documents

Benefit of interferon -1a on MSFC progression in secondary progressive MS