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Reduction in magnetic resonance imaging T2 burden of disease in patients with relapsing-remitting multiple… Traboulsee, A; AL-Sabbagh, A; Bennett, R; Chang, P; Li, DKB Apr 21, 2008

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ralssBioMed CentBMC NeurologyOpen AcceResearch articleReduction in magnetic resonance imaging T2 burden of disease in patients with relapsing-remitting multiple sclerosis: analysis of 48-week data from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) studyA Traboulsee*1, A AL-Sabbagh2, R Bennett2, P Chang2, DKB Li3 for the EVIDENCE Study Group and the UBC MS/MRI Research GroupAddress: 1Division of Neurology, Medicine, University of British Columbia, Vancouver, BC, Canada, 2EMD Serono, Inc., Rockland, MA, USA and 3Radiology, University of British Columbia, Vancouver, BC, CanadaEmail: A Traboulsee* - trabouls@interchange.ubc.ca; A AL-Sabbagh - ahmad.al-sabbagh@emdserono.com; R Bennett - randy.bennett@emdserono.com; P Chang - peter.chang@emdserono.com; DKB Li - david.li@ubc.ca* Corresponding author    AbstractBackground: The EVIDENCE (EVidence of Interferon Dose-response: European North American ComparativeEfficacy) study was an international, randomized, open-label, assessor-blinded, parallel-group study assessing theefficacy and tolerability of interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), and IFNbeta-1a, 30 mcg intramuscularly (im) once weekly (qw), in patients with relapsing-remitting multiple sclerosis(RRMS). The aim of this analysis was to assess whether reductions in T2 burden of disease (BOD) were greaterfor patients receiving IFN beta-1a, 44 mcg sc tiw, than for those treated with IFN beta-1a, 30 mcg im qw, and toassess the impact of neutralizing antibodies (NAbs).Methods: A post-hoc analysis was performed on magnetic resonance imaging (MRI) data collected prospectivelyfrom the EVIDENCE study. The analysis included all patients with evaluable T2 MRI scans at the start of dosingand at week 48, and those who received at least one drug dose (n = 553). Lesions were identified by a radiologistblinded to treatment codes and the total volume of T2 lesions (BOD) was reported in mm3.Results: Both median percentage decreases and absolute reduction in BOD were greater in the IFN beta-1a, 44mcg sc tiw, treatment group. The adjusted mean treatment difference in percentage change in BOD from baselineto week 48 showed a significant treatment benefit for patients treated with IFN beta-1a, 44 mcg sc tiw, over thosetreated with IFN beta-1a, 30 mcg im qw (-4.6%; standard error: 2.6%; p = 0.002). The presence of NAbs reducedthe effect of IFN beta-1a 44, mcg sc tiw, on BOD, but BOD changes were still similar to those seen with IFN beta-1a, 30 mcg im qw.Conclusion: Patients with RRMS treated with IFN beta-1a, 44 mcg sc tiw, had greater reduction in T2 BOD after48 weeks than those treated with IFN beta-1a, 30 mcg im qw, which is consistent with other clinical and MRIoutcome measures in the EVIDENCE study. In patients testing positive for NAbs (NAb+) to IFN beta-1a 44 mcgsc tiw, changes in BOD were smaller than in NAb negative (NAb-) patients, but similar to those receiving IFNPublished: 21 April 2008BMC Neurology 2008, 8:11 doi:10.1186/1471-2377-8-11Received: 10 August 2007Accepted: 21 April 2008This article is available from: http://www.biomedcentral.com/1471-2377/8/11© 2008 Traboulsee et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 7(page number not for citation purposes)beta-1a, 30 mcg im qw.BMC Neurology 2008, 8:11 http://www.biomedcentral.com/1471-2377/8/11BackgroundInterferon (IFN) beta-1a, 44 mcg subcutaneously (sc)three times weekly (tiw), and IFN beta-1a, 30 mcg intra-muscularly (im) once weekly (qw), are both licensed forthe treatment of patients with relapsing forms of multiplesclerosis (MS). These two IFN beta-1a formulations werecompared in the EVIDENCE (EVidence of InterferonDose-response: European North American ComparativeEfficacy) study, which was an international, randomized,open-label, assessor-blinded, parallel-group study todetermine if IFN beta-1a, 44 mcg sc tiw, has greater effi-cacy on clinical and magnetic resonance imaging (MRI)outcomes to that of IFN beta-1a, 30 mcg im qw, inpatients with relapsing-remitting MS (RRMS). Patientstreated with IFN beta-1a, 44 mcg sc tiw, had a significantlyhigher odds ratio for remaining relapse free at 24 weeks (p= 0.0005), at 48 weeks (p = 0.009) and over an average of64 weeks (p = 0.023), compared with patients treated withIFN beta-1a, 30 mcg im qw [1-3]. In addition, at the sametime points, new activity on MRI was significantly lowerin patients receiving IFN beta-1a, 44 mcg sc tiw, than inthose receiving IFN beta-1a, 30 mcg im qw: reductionswere seen in gadolinium (Gd)-enhancing lesions, T2active lesions and the proportion of T2 active scans;increases were seen in the proportion of patients with noT2 active lesions [1].Neutralizing antibodies (NAbs) can occur with any IFNtherapy for MS and may impact on efficacy, althoughthere is debate on the degree of this effect [4]. In the EVI-DENCE study, 25% of patients receiving IFN beta-1a, 44mcg sc tiw, and 2% of patients receiving IFN beta-1a, 30mcg im tiw, had NAb titres greater than 20 neutralizingunits/mL at week 48. There was no apparent effect on clin-ical efficacy for relapse outcomes, but fewer T2 activelesions were seen in the IFN beta-1a, 44 mcg sc tiw, NAb-group compared with the NAb+ group (0.6 versus 1.6lesions, p = 0.0004).The aim of this post-hoc analysis of the EVIDENCE datawas to establish whether reductions in T2 burden of dis-ease (BOD) were also greater for patients treated with IFNbeta-1a, 44 mcg sc tiw, than for those treated with IFNbeta-1a, 30 mcg im qw. Whether NAb status affected treat-ment outcomes was also assessed.MethodsDesign and objectivesA post-hoc analysis was performed on MRI data that werecollected prospectively from the EVIDENCE study (proto-col 21125) [3]. This included all randomized patientswho had received at least one dose of the study drug andhad evaluable T2-weighted MRI scans from both beforeperformed the original activity analysis and remainedblinded for the current analysis throughout. An experi-enced MRI radiologist evaluated all MRI scans andremained blinded to treatment. For the T2 BOD analysis,digital data for the proton density/T2 scans for weeks 0and 48 were used and the radiologist electronically taggedall T2 lesions for segmentation. Trained techniciansblinded to study treatment grew each tagged T2 lesionsemi-automatically using proprietary software. The radiol-ogist performed a final quality-control step before sum-marizing the results as a total volume (mm3). Combinedunique lesion activity (CUA) analysis was performed pre-viously up to week 24 and defined as a Gd-enhancinglesion, new T2 lesion and/or enlarging T2 lesion; thistakes into account that a newly active lesion may appearon both the MRI following Gd enhancement and on theT2-weighted MRI, and ensures that it is counted onlyonce. The primary measure of interest was percentagechange in BOD (mm3) from baseline to week 48. Second-ary measures of interest were absolute change in BODfrom baseline (week 0) to week 48; percentage and abso-lute change in BOD from baseline to week 48 when strat-ified by NAb status (patients with NAb titres ≥ 20neutralizing units/mL were considered to be NAb+); andthe correlation between changes in BOD from baseline toweek 48 and changes in CUA from baseline to week 24.NAbs were measured using a cytopathic effect assay [5].Statistical analysesChange in BOD from baseline was compared betweentreatment groups using an analysis of covariance(ANCOVA) model with effect of treatment and baselineBOD as a single covariate. The treatment difference inmeans, adjusted for any baseline parameters that were sig-nificantly different between the groups, and the associatedstandard error (SE), were estimated on the raw data fromthe ANCOVA model. Treatment comparison p valueswere calculated using a similar ANCOVA model onranked data. Histograms were constructed by treatmentgroup to show and evaluate the distribution of percentageand absolute change in BOD from baseline to week 48.Differences in percentage change in BOD betweenpatients receiving IFN beta-1a, 44 mcg sc tiw, and IFNbeta-1a, 30 mcg im qw, were calculated by subtracting cor-responding adjusted mean changes for each group. A neg-ative value of the difference in changes indicated thattreatment with IFN beta-1a, 44 mcg sc tiw, resulted in alarger decrease in BOD than treatment with IFN beta-1a,30 mcg im qw. Absolute change in BOD was calculated bysubtracting the baseline assessment from the post-treat-ment assessment. A negative value in either the absolutechange or percentage change indicated suppression inPage 2 of 7(page number not for citation purposes)the start of dosing (week 0) and at week 48. The centralMRI analysis laboratory (USC MS/MRI Research Group)BOD.BMC Neurology 2008, 8:11 http://www.biomedcentral.com/1471-2377/8/11For each treatment group, the relationship betweenchanges in CUA from baseline to week 24 and changes inBOD from baseline to week 48 was assessed using a Spear-man's rank correlation analysis.ResultsA total of 677 patients were randomized to treatment inthe EVIDENCE study. Of these, 553 patients met theinclusion criteria for this analysis (IFN beta-1a, 44 mcg sctiw group: n = 279; IFN beta-1a, 30 mcg im qw group: n =274). Three of 56 centres that participated in the EVI-DENCE study were only able to provide film (not digital)MRI data that was suitable for the activity analysisreported previously [3], but was not suitable for BOD.This affected both treatment groups equally. The twotreatment groups did not differ significantly in demo-graphics or baseline lesion characteristics (Table 1).Median percentage decreases in BOD were greater in theIFN beta-1a, 44 mcg sc tiw, treatment group (-6.7%; range:-65 to 431%) compared with the IFN beta-1a, 30 mcg imqw, treatment group (-0.6%; range: -61 to 197%). Theadjusted mean treatment difference (AMTD) in percent-age change in BOD from baseline to week 48 showed asignificant treatment benefit for patients treated with IFNbeta-1a, 44 mcg sc tiw, over those treated with IFN beta-1a, 30 mcg im qw (-4.6%; SE: 2.6%; p = 0.002). Corre-spondingly, patients in the IFN beta-1a, 44 mcg sc tiw,treatment group had a greater median absolute change inBOD (-189.55 mm3; range: -23454 to 56869 mm3) com-pared with those in the IFN beta-1a, 30 mcg im qw, treat-ment group (-19.0 mm3; range: -13337 to 10161 mm3;Figure 1). The distribution of absolute and percentagechanges in BOD from baseline to week 48 are presentedin Figures 2 and 3 and indicate that more patients in theIFN beta-1a, 44 mcg sc tiw, treatment group had greaterreductions in BOD compared with the IFN beta-1a, 30mcg im qw, treatment group. In total, 67% of patientsreceiving IFN beta-1a, 44 mcg sc tiw, had a stable orimproved BOD compared with 53% of patients receivingIFN beta-1a, 30 mcg im qw, and 47% of patients in theIFN beta-1a, 30 mcg im qw, treatment group hadincreased BOD between weeks 0 and 48 compared with33% of patients in the IFN beta-1a, 44 mcg sc tiw, treat-ment group.Table 1: Baseline patient demographics and burden of disease.Interferon beta-1a treatment group44 mcg sc tiw (n = 279) 30 mcg im qw (n = 274) p value*Age in years, mean (SD) 38.6 (8.8) 37.7 (8.6) 0.188Sex, n (%) 0.269Men 64 (22.9) 74 (27.0)Women 215 (77.1) 200 (73.0)Race, n (%) 0.935White 258 (92.5) 250 (91.2)Black 12 (4.3) 15 (5.5)Asian 0 1 (0.4)Hispanic 5 (1.8) 4 (1.5)Other 4 (1.4) 4 (1.5)BOD in mm3, median (range) 5438 (85–135276) 6010 (391–103495) 0.541*Treatment comparisons with respect to sex and race distributions were performed using a Chi-squared test or a Fisher's Exact test, where Median absolute change in burden of disease (BOD) in each tr atment groupFigure 1Median absolute change in burden of disease (BOD) in each treatment group. IFN, interferon; im, intramuscu-lar; qw, once weekly; sc, subcutaneous; tiw, three times weekly.0IFN beta-1a,44 mcg sc tiw(n = 279)IFN beta-1a,30 mcg im qw(n = 274)–20–40–60–80–100–120–140–160–180–200Median absolute change in BOD (mm3 )–189.5–19Page 3 of 7(page number not for citation purposes)appropriate. With respect to age and baseline BOD, an analysis of covariance model using ranked data was performed with effects for treatment.Numbers do not add to 100% due to rounding.BOD, burden of disease; im, intramuscular; qw, once weekly; sc, subcutaneous; SD, standard deviation; tiw, three times weekly.BMC Neurology 2008, 8:11 http://www.biomedcentral.com/1471-2377/8/11Meaningful between-group comparisons by NAb statuswere not possible, as only seven (2.5%) patients devel-oped NAbs in the IFN beta-1a, 30 mcg im qw, treatmentgroup. Patients receiving IFN beta-1a, 30 mcg im qw,were, therefore, treated as a single group. Median percent-age changes in BOD in the IFN beta-1a, 44 mcg sc tiw,NAb+ patients, IFN beta-1a, 44 mcg sc tiw, NAb- patientsand IFN beta-1a, 30 mcg im qw, patients were -0.8, -8.0and -0.6, respectively. Absolute BOD changes were -46.2,-254.6 and -19.0, respectively. There was no evidence of asignificant difference in percentage change in BOD frombaseline to week 48 between NAb+ patients receiving IFNbeta-1a, 44 mcg sc tiw, and those receiving IFN beta-1a, 30mcg im qw (AMTD: 0.5%; SE: 3.9%; p = 0.583; Figure 4).The AMTD in percentage change in BOD from baseline toweek 48 significantly favoured NAb- patients in the IFNbeta-1a, 44 mcg sc tiw, group over the IFN beta-1a, 30 mcgim qw, group (-6.6%; SE: 2.8%; p < 0.0001).week 24 within the IFN beta-1a, 44 mcg sc tiw, treatmentgroup (r = 0.385; p < 0.0001 for absolute and percentagechanges) and the IFN beta-1a, 30 mcg im qw, treatmentgroup (r = 0.179; p < 0.01 for absolute and percentagechanges), respectively.Discussion and conclusionIn the current post-hoc analysis, patients with RRMS whowere treated with IFN beta-1a, 44 mcg sc tiw, had a greaterreduction in T2 BOD after 48 weeks than those given IFNbeta-1a, 30 mcg im qw. This finding is consistent withother clinical and MRI outcome measures in the prospec-tive EVIDENCE study. Previous prospectively definedanalyses showed that patients receiving IFN beta-1a, 44mcg sc tiw, also had a reduced likelihood of relapse andhad significant reductions in CUA and T2 active lesionscompared with those randomized to IFN beta-1a, 30 mcgim qw [1-3].Distribution of absolute change in burden of disease (BOD) from baseline to week 48 in the two treatment groupsFigure 2Distribution of absolute change in burden of disease (BOD) from baseline to week 48 in the two treatment groups. For presentation purposes, two patients receiving interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), were removed from this plot; one patient had an extreme increase from baseline value of 56868.5 mm3 and another had an extreme reduction from baseline of 23453.6 mm3 percent changes in BOD. im, intramuscular; qw, once weekly.4540353025IFN beta-1a, 44 mcg sc tiw (n = 277)IFN beta-1a, 30 mcg im qw (n = 274)20151050–16000–14000–12000–10000–8000–6000–4000–2000Absolute change in BOD from baseline to week 48 (mm3)0200040006000800010000Stable or improved BODIFN beta-1a, 44 mcg sc tiw: 67% of patientsIFN beta-1a, 30 mcg im qw: 53% of patientsBOD increasedIFN beta-1a, 44 mcg sc tiw: 33% of patientsIFN beta-1a, 30 mcg im qw: 47% of patientsPatients (%)Page 4 of 7(page number not for citation purposes)A correlation was seen between the change in BOD frombaseline to week 48 and change in CUA from baseline toIn general, the impact of both IFNs on suppressing Gd-enhancing lesions on MRI is seen quite early, within theBMC Neurology 2008, 8:11 http://www.biomedcentral.com/1471-2377/8/11first 1–2 months of initiating therapy [6]. Thus, it was con-sidered reasonable to compare the overall change in T2BOD for a relatively short duration of observation. Fur-thermore, from previous experience, looking at BOD dif-ferences over 12 months maximizes the group changeover the 'noise' created by individual variability. For com-pleteness, the data are presented as a histogram to showthe spread of the response for both therapies. In this wayit can be seen that both therapies can be associated with astable MRI outcome or a worsening MRI outcome.The distribution of absolute and percentage changes inBOD (Figures 2 and 3) in the current analysis indicatesthat patients in both treatment groups benefited fromtreatment with IFN beta-1a, but 14% more patients in theIFN beta-1a, 44 mcg sc tiw, treatment group had a stableor improved BOD compared with those treated with IFNbeta-1a, 30 mcg im qw. In this 48-week analysis, there wasan insufficient number of patients who had a clinical pro-gression in EDSS to explore this relationship further.A new formulation of IFN beta-1a, 44 mcg sc tiw, has beendeveloped and is currently being studied in a large-scale,genic potential, which should reduce the likelihood ofNAb development [7].It is unclear how much NAbs affect clinical efficacy. NAbstake time to develop and patients with NAbs at 48 weeksmay not have had NAbs during most of the precedingtime. Likewise, some patients who had developed NAbsearlier may have lost them by week 48. Although somestudies suggest that treatment success rates may be cur-tailed by the development of high titres of persistent NAbsin a minority of patients following long-term treatmentwith IFN beta [8-10], other studies have shown that theclinical efficacy of IFN beta is the same in patients who areNAb+ as in those who are NAb- [1,2,11]. However, thestudies that did not show an effect of NAbs were less than2 years in duration, and thus may not have been of suffi-cient duration to show an effect of NAbs on clinical out-comes. In the current analysis, sample sizes were not largeenough to allow a direct comparison between NAb+patients in each treatment group. Still, a comparison ofpatients receiving IFN beta-1a, 44 mcg sc tiw, who devel-oped NAbs, with all patients receiving IFN beta-1a, 30mcg im qw (irrespective of NAb status), suggested thatDistribution of percentage change in burden of disease (BOD) from baseline to week 48 in the two treatment groupsFigure 3Distribution of percentage change in burden of disease (BOD) from baseline to week 48 in the two treatment groups. For presentation purposes, two patients were removed from this plot because they had extreme percentage changes in BOD from baseline to week 48; one patient receiving interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), had an increase of 431% from baseline and the other patient receiving IFN beta-1a, 30 mcg intramuscularly (im) once weekly (qw), had an increase of 197%.353025IFN beta-1a, 44 mcg sc tiw (n = 277)IFN beta-1a, 30 mcg im qw (n = 274)20151050–70 –60 –50 –40 –30 –20 –10 0 10 20 30 40 50 60 70 80 90 100 110 120 130Change in BOD from baseline (%)Patients (%)Page 5 of 7(page number not for citation purposes)Phase III, clinical trial (protocol 25632). Initial data indi-cate that this new formulation has a reduced immuno-NAb+ patients in the IFN beta-1a, 44 mcg sc tiw, treatmentgroup had a similar reduction in T2 BOD to the overallBMC Neurology 2008, 8:11 http://www.biomedcentral.com/1471-2377/8/11IFN beta-1a, 30 mcg im qw, treatment group. In otherwords, patients with NAbs who receive high-dose, high-frequency IFN beta still gain similar treatment benefits asthose, regardless of NAb status, who receive low-dose,low-frequency IFN beta. This means that, although effi-cacy may be attenuated with NAbs, therapeutic effect isstill provided by IFN beta-1a, 44 mcg sc tiw, on BOD sup-pression. At week 48, a similar number of T2 active lesionswas seen in NAb+ patients in the IFN beta-1a, 44 mcg sctiw, treatment group (mean 1.6 lesions/patient/scan) asoverall (NAb+ and NAb-) in the IFN beta-1a, 30 mcg imqw, treatment group (mean 1.4 lesions/patient/scan).However, the reduction in BOD was smaller in the IFNbeta-1a, 44 mcg sc tiw, NAb+ group than in the IFN beta-1a, 44 mcg sc tiw, NAb- group at 48 weeks. This may sug-gest that MRI is more sensitive than clinical outcomes inshowing an early effect of NAbs on efficacy.This study is probably too short to address adequately adelayed impact of NAbs on MRI outcomes. To somedegree, this has been assessed in the PRISMS (Preventionof Relapses and disability by Interferon beta-1a Subcuta-neously in Multiple Sclerosis) study, in which results at 48months showed an increase in BOD in the NAb+ group of17.6% and a decrease of 8.5% in the NAb- group (p <0.001) [12].Interestingly, in the present study there was no apparentimpact of NAbs on relapse outcomes at week 48. Thus,these MRI data indicate only a partial impact of NAbs onefficacy outcomes at this time.Competing interestsDrs A AL-Sabbagh, R Bennett and P Chang are employedby EMD Serono, Inc. The study was supported by MerckMean treatment difference for percentage change in T2 burden of disease (BOD) between interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times we kly (tiw), eutralizing antibody neg tive (NAb-), or IFN beta-1a, 44 mcg sc tiw, NAb+, ver-s IFN beta-1a, 30 mcg intramuscularly ( m  once weekly (qw)Figure 4Mean treatment difference for percentage change in T2 burden of disease (BOD) between interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), neutralizing antibody negative (NAb-), or IFN beta-1a, 44 mcg sc tiw, NAb+, versus IFN beta-1a, 30 mcg intramuscularly (im) once weekly (qw).7–6.6%p < 0.001 in favourof IFN beta-1a,44 mcg sc tiwIn favour of IFN beta-1a, 30 mcg im qwIn favour of IFN beta-1a, 44 mcg sc tiw0.5%,No significantdifferenceNAb+ patients receivingIFN beta-1a, 44 mcg sc tiw,versus all patients receivingIFN beta-1a, 30 mcg im qwNAb– patients receivingIFN beta-1a, 44 mcg sc tiw,versus all patients receivingIFN beta-1a, 30 mcg im qw531–1–3–5–7Mean treatment differencefor percent change in T2 BODPage 6 of 7(page number not for citation purposes)Serono International S.A., Geneva, Switzerland.Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central BMC Neurology 2008, 8:11 http://www.biomedcentral.com/1471-2377/8/11Authors' contributionsAT and DL carried out the MRI design and analysis andinterpretation of results. All authors have read andapproved the manuscript.AcknowledgementsThe authors thank Claire Inness (supported by Merck Serono International S.A., an affiliate of Merck KGaA, Darmstadt, Germany) and Robert Glanz-man, who at the time of the analysis was employed by Pfizer Global Phar-maceuticals and is now employed by Novartis Pharmaceuticals Corporation (US affiliate of Novartis AG), for their assistance in the prep-aration of this manuscript.Dr Guojun Zhao, UBC MS/MRI Research Group, identified all lesions for segmentation. Analysis technicians were Aileen To, Yu Wang, Jin Xiu Han, Leila Lagroix and Melinda Medina. Radiologists were Yan Cheng and Guo Jun Zhao.References1. Panitch H: Differences between IFN beta-1a 44 mcg tiw and30 mcg qw sustained to 16 months: final EVIDENCE results.Intl J MS Care 2003, 5:80.2. Panitch H, Goodin D, Francis G, Chang P, Coyle P, O'Connor P, Li D,Weinshenker B: for the EVIDENCE study group and the Uni-versity of British Columbia MS/MRI Research Group. Bene-fits of high-dose, high-frequency interferon beta-1a inrelapsing-remitting multiple sclerosis are sustained to 16months: final comparative results of the EVIDENCE trial.  JNeurol Sci 2005, 239:67–74.3. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O'Connor P,Monaghan E, Li D, Weinshenker B: Randomized, comparativestudy of interferon beta-1a treatment regimens in MS: theEVIDENCE trial.  Neurology 2002, 59(10):1496–1506.4. Goodin DS, Frohman EM, Hurwitz B, O'Connor PW, Oger JJ, RederAT, Stevens JC: Neutralizing antibodies to interferon beta:assessment of their clinical and radiographic impact: an evi-dence report: report of the Therapeutics and TechnologyAssessment Subcommittee of the American Academy ofNeurology.  Neurology 2007, 68(13):977–984.5. Abdul-Ahad AK, Galazka AR, Revel M, Biffoni M, Borden EC: Inci-dence of antibodies to interferon-beta in patients treatedwith recombinant human interferon-beta 1a from mamma-lian cells.  Cytokines Cell Mol Ther 1997, 3(1):27–32.6. Li DK, Paty DW: Magnetic resonance imaging results of thePRISMS trial: a randomized, double-blind, placebo-control-led study of interferon-beta1a in relapsing-remitting multi-ple sclerosis. Prevention of Relapses and Disability byInterferon-beta1a Subcutaneously in Multiple Sclerosis.  AnnNeurol 1999, 46(2):197–206.7. Traboulsee A, AL-Sabbagh A, Bennett R, Chang P, Glanzman R, Rus-sell H, Li DKB: Greater reduction of MRI T2 burden of diseasewith interferon beta-1a 44 mcg administered subcutane-ously three times weekly than 30 mcg administered intra-muscularly once weekly: analysis of 48-week data from theEVIDENCE study: (27-30 September), Madrid, Spain.   Vol-ume P678. ; 2006. 8. Francis GS, Rice GP, Alsop JC: Interferon beta-1a in MS: resultsfollowing development of neutralizing antibodies in PRISMS.Neurology 2005, 65(1):48–55.9. Kappos L, Clanet M, Sandberg-Wollheim M, Radue EW, Hartung HP,Hohlfeld R, Xu J, Bennett D, Sandrock A, Goelz S: Neutralizingantibodies and efficacy of interferon beta-1a: a 4-year con-trolled study.  Neurology 2005, 65(1):40-47.10. Perini P, Calabrese M, Biasi G, Gallo P: The clinical impact ofinterferon beta antibodies in relapsing-remitting MS.  J Neurol2004, 251(3):305-309.11. Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, Mon-tanari E, Zaffaroni M: Every-other-day interferon beta-1b ver-12. PRISMS Study Group and the University of British Columbia MS/MRIAnalysis Group: PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS.  Neurology 2001, 56(12):1628–1636.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2377/8/11/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 7 of 7(page number not for citation purposes)sus once-weekly interferon beta-1a for multiple sclerosis:results of a 2-year prospective randomised multicentrestudy (INCOMIN).  Lancet 2002, 359(9316):1453–1460.

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