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October 18, 2011; 77 (16) Articles

A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS

M.S. Freedman, A. Bar-Or, J. Oger, A. Traboulsee, D. Patry, C. Young, T. Olsson, D. Li, H.-P. Hartung, M. Krantz, L. Ferenczi, T. Verco
First published October 5, 2011, DOI: https://doi.org/10.1212/WNL.0b013e318233b240
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Abstract

Objective: To evaluate the efficacy and safety of MBP8298 in subjects with secondary progressive multiple sclerosis (SPMS) who express human leukocyte antigen (HLA) haplotype DR2 or DR4 (DR2+ or DR4+).

Methods: This multicenter randomized 2-year, double-blind, placebo-controlled study included 612 subjects with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) score of 3.5–6.5, stratified according to baseline EDSS score (3.5–5.0, or 5.5–6.5) and HLA haplotype (DR2+ or DR4+, or DR2−/DR4−). Upon entry of 100 DR2−/DR4− subjects, further study enrollment was limited to DR2+ or DR4+ subjects. Subjects were randomly assigned to either 500 mg MBP8298 or placebo, given by IV injection once every 6 months for 2 years. The primary outcome measure was time to progression by ≥1.0 EDSS point (or 0.5 point if baseline EDSS was 5.5 or higher), confirmed 6 months later. Secondary outcomes included mean change in EDSS, mean change in Multiple Sclerosis Functional Composite, MRI changes, annualized relapse rate, and quality of life.

Results: There were no significant differences between treatment groups in either the primary or secondary endpoints. MBP8298 was well tolerated in all treated subjects with no safety issues identified.

Conclusion: In the population studied, treatment with MBP8298 did not provide a clinical benefit compared to placebo.

Classification of evidence: This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2+ or DR4+.

GLOSSARY

AE=
adverse event;
ANCOVA=
analysis of covariance;
ANOVA=
analysis of variance;
ARR=
annualized relapse rate;
DR2+ or DR4+=
expresses human leukocyte antigen haplotype DR2 or DR4;
DR2−/DR4−=
does not express HLA haplotype DR2 or DR4;
DSMB=
data safety monitoring board;
EAE=
experimental allergic encephalomyelitis;
EDSS=
Expanded Disability Status Scale;
HLA=
human leukocyte antigen;
MBP=
myelin basic protein;
MS=
multiple sclerosis;
MSFC=
Multiple Sclerosis Functional Composite;
MSQoL-54=
Multiple Sclerosis Quality of Life-54;
PPMS=
primary progressive multiple sclerosis;
RRMS=
relapsing-remitting multiple sclerosis;
SPMS=
secondary progressive multiple sclerosis;
QOL=
quality of life;
SAE=
serious adverse event;
SAP=
statistical analysis plan;
SF-36=
Short Form-36;
TTP=
time to progression

Established effective therapy for multiple sclerosis (MS) reduces relapses and MRI activity and slows disease (Expanded Disability Status Scale [EDSS]) progression1 in relapsing patients, including relapsing secondary progressive MS (SPMS),2,–,8 but not in primary progressive MS (PPMS).9 Once relapses cease, EDSS changes probably reflect a different mostly neurodegenerative process10,11 despite pathologic evidence of continued inflammation.12 Antibody targeting of CNS myelin components may be important to this disease progression.13,14 Autoantibodies to amino acids 85–96 of MBP were detected in the CSF of patients with progressive MS,15 similar to the T-cell epitope driving experimental allergic encephalomyelitis (EAE).16 Since the autoantibody specificity was identical to that of HLA-DR2-restricted T-cell clones from patients with MS,17 tolerization to this MBP peptide might reduce the CNS inflammation responsible for disease progression.

MBP8298 (manufacturer: BioMS Medical) is a synthetic peptide with amino acid sequence corresponding to amino acids 82–98 of MBP. Specific antibodies to MBP 82–98 peptides were detected in the CSF of most patients with progressive MS, but only during relapses in RRMS,18 hence Phase I studies of MBP8298 concentrated only on progressive MS, measuring the reduction in CSF titer of anti-MBP antibody19,–,22 as an endpoint. Subsequently a small double-blind, placebo-controlled Phase II study of MBP8298 in progressive MS failed to slow the time to disease progression but post hoc analysis suggested efficacy in a subset of patients with HLA DR2 or DR4.23

The objective of this study was to evaluate the efficacy and safety of MBP8298 in DR2+ or DR4+ subjects with SPMS.

METHODS

Standard protocol approvals, registrations, and patient consents.

The trial was registered under 2 public registries (clinicaltrials.gov; trial identification number NCT00869726 and ISRCTN 98373474). Institutional/ethics review boards at each site approved the study, and all subjects signed written informed consent prior to protocol-required procedures.

Patient selection.

Patients meeting a stringent definition of SPMS (recent confirmed progression in EDSS in the absence of relapse) were eligible for enrollment, overseen by an independent adjudication committee. MS relapses (on-study) were defined as new or recurrent or sudden worsening of neurologic symptoms associated with objective neurologic signs (2-point increase in any 1 Kurtzke functional system subscore, a 1-point increase in 2 functional system subscores, or a 0.5-point increase in the EDSS). Patients were stratified into DR2+ or DR4+ or DR2−/DR4− groups and randomized to treatment or placebo. Eligibility included age 18–65 years, documented history of SPMS, absence of relapse in the 3 months leading up to trial participation, EDSS score of 3.5–6.5, and a Kurtzke pyramidal or cerebellar system subscore ≥3. Exclusion criteria included diagnosis of PPMS, previous treatment with MBP8298, history of malignancy, steroid therapy within 30 days of study entry, treatment with β-interferon, glatiramer acetate within 3 months, or mitoxantrone, cyclophosphamide, methotrexate, azathioprine, or any other immunomodulating or immunosuppressive drugs or plasma exchange within 6 months prior to the first study-specific test, with the exception of corticosteroids or ACTH for relapse treatment, initiation or discontinuation of 4-AP or 3,4-DAP at any time during the study, history of anaphylactic/anaphylactoid reactions to glatiramer acetate or Gd-DTPA, abnormal baseline results deemed clinically significant by the investigator, any condition that could interfere with the performance of study-specific procedures, and any other condition that, in the investigator's opinion, would make the subject unsuitable for participation.

Study design.

Forty-seven centers in 10 countries participated in this 2-year, randomized, double-blind, placebo-controlled trial, comparing the time to confirmed worsening of disability as measured by the EDSS in SPMS. Qualified subjects were randomized to either MBP8298 or placebo with equal probability. Randomization was conducted per a protocol-defined method utilizing central randomization by the unblinded statistician. The randomization code was supplied to the unblinded pharmacist at each site. All other study personnel remained blinded to treatment. Four strata were defined according to 1) whether the subjects belong to the DR2+ or DR4+ or to the DR2−/DR4− subgroup, and 2) whether the subject's EDSS at baseline was in the interval 3.5–5.0 or in the interval 5.5–6.5.

Treatment.

Subjects assigned to 500 mg (10 mL × 50-mg/mL dose) MBP8298 received a total of 4 doses of study drug (at baseline, and months 6, 12, and 18) as a slow IV injection over 3 to 5 minutes. Subjects assigned to placebo (sterile water or saline) received 4 doses at the same intervals. Study drug administration occurred after all other study-related measurements were completed.

Clinical outcome.

Patients were assessed at intervals as shown in figure e-1 on the Neurology® Web site at www.neurology.org. EDSS scores were calculated using the NeuroStatus (version 03/2002, www.neurostatus.net), every 3 months for 24 months, including confirmatory visits at months 27 and 30 as required. Confirmed progression was defined as the date of the first EDSS increase if the EDSS increase was 1) ≥1.0 and sustained for 6 months, and the subject's baseline EDSS score was ≤5.0; or 2) ≥0.5 and sustained for 6 months, and the subject's baseline EDSS score was ≥5.5. The first 100 subjects randomized were treated as a special safety cohort and they received additional EDSS and MSFC examinations after the first and second doses of study medication to correlate with simultaneous MRI scans, and a safety analysis was carried out after they completed 1 year on study.

The primary efficacy outcome was the time to confirmed EDSS progression in the DR2+ or DR4+ subjects. A “treating” neurologist, responsible for daily care, administered the IV study drug and was aware of all side effects whereas all EDSS assessments were performed by a second independent “blinded” neurologist who also was responsible for all relapse assessments. Secondary outcomes included the change in MSFC24 and several MRI metrics (see below). Additional exploratory outcomes included quality of life (QOL) assessed using the Short Form-36 (SF-36) or the Multiple Sclerosis Quality of Life-54 (MSQoL-54) scales.25,26 Post hoc analyses examined subgroups and alternative endpoints, and the data were explored for further leads using a recursive partitioning framework.27 Safety assessments included adverse events (AE), serious AEs (SAEs), laboratory tests, vital signs, ECGs, and physical examinations. An interim blinded futility analysis was carried out after the first 200 subjects had completed the study. There were no changes to the trial outcomes after trial commencement.

A clinical advisory board of participating investigators, all of whom were blinded to subject treatment, supervised the study. Per protocol requirements, an independent data safety monitoring board (DSMB) reviewed safety and efficacy data on semiblinded data at regular intervals.

MRI.

In the first 100 subjects, 2 MRIs (week −4, week 0) were performed prior to the first dose of study medication, followed by further MRIs at weeks 4, 8, and 12. Another MRI was then performed immediately prior to the next dose (week 26), followed by 3 further MRIs at weeks 30, 34, and 38. Annual MRIs were performed at weeks 52 and 104. The next 453 patients (subjects 101–554, group 2) had 2 MRIs performed prior to first dose of medication (weeks −4 and 0) with annual MRIs at weeks 52 and 104. The following MRI variables were evaluated: lesion activity (new T2 or enlarging T2 lesions compared to the previous MRI, T1 gadolinium enhancing activity), lesion burden (T2 burden of disease), and brain volume. MRIs were performed using a standardized protocol and analyzed centrally by blinded radiologists and technologists by the University of British Columbia MS/MRI Research Group.

Statistical considerations.

The study was designed to achieve a 2-sided log-rank test with an overall Type I error not exceeding 0.05. It was assumed that 30% of placebo subjects would progress over 24 months and that MBP8298 would extend the time to progression by 44% compared to placebo (hazard ratio 1.8). Assuming a 10% dropout rate, 408 subjects in the intent-to-treat primary analysis group (DR2+ or DR4+ patients who received at least 1 dose of study drug) were required to complete the study to obtain 98 disease progressions (80% power).

The statistical analysis plan (SAP) was written and approved prior to database lock. All continuous variables except for MRI and laboratory endpoints were summarized by analysis of covariance (ANCOVA) with baseline value included as a covariate or by analysis of variance (ANOVA) if there was no baseline value collected. No imputation was used for missing safety or efficacy data. The model contained main effects for treatment and site, and the difference in least-squares mean of the endpoint was compared between treatment groups. The interaction between treatment group and site was assessed but was not adjusted for in the model.

Fisher exact test and Cochran-Mantel-Haenszel test adjusted for site were used for categorical variables. Cochran-Mantel-Haenszel row mean score test adjusted for site was used for ordinal variables. For continuous variables, descriptive statistics included the number of subjects (n), mean, SD or standard error (as appropriate), minimum, median, and maximum. For categorical data, frequency counts and percentages were presented. Unless otherwise stated, all statistical tests were 2-sided with the probability of a Type I error not to exceed α = 0.05 for the null hypothesis of no difference between the treatment groups.

RESULTS

Subject disposition.

Between December 2004 and April 2009, 612 subjects were randomized and received at least 1 dose of study drug. A total of 539 (88%) subjects received all 4 doses (figure 1). The most common reasons for discontinuation of treatment were patient choice (n = 25), perceived lack of efficacy (n = 22), and SAEs (n = 14). The study was completed according to protocol.

Figure 1
Figure 1 Patient disposition

*Received all doses of study medication. DR2+ or DR4+ = expresses human leukocyte antigen haplotype DR2 or DR4; DR2−/DR4− = does not express HLA haplotype DR2 or DR4; MS = multiple sclerosis.

Demographic and clinical characteristics.

Table 1 shows the baseline characteristics of trial subjects by HLA-DR haplotype and treatment assignment. The subgroups were well matched with respect to treatment assignment.

View this table:
Table 1

Baseline demographic characteristics and disease history of subjects, by HLA-DR haplotype and treatment assignment

Primary endpoint.

In the DR2+ or DR4+ group, more subjects progressed in the MBP8298 group (30.7%) than in the placebo group (27.8%), p = 0.527. In the DR2−/DR4− group, fewer subjects progressed in the MBP8298 group (28.3%) than in the placebo group (35.8%), p = 0.324 (figure 2, A and B).

Figure 2
Figure 2 Kaplan-Meier plot of time to first confirmed progression

*p Value using 2-sided log-rank test of time to progression between dirucotide and placebo. DR2+ or DR4+ = expresses human leukocyte antigen haplotype DR2 or DR4; DR2−/DR4− = does not express HLA haplotype DR2 or DR4.

Secondary endpoints.

There was no significant benefit of MBP8298 in any of the secondary clinical endpoints (table 2). The mean increase in EDSS followed the same pattern as TTP and proportion of subjects progressing; i.e., there was more change in the MBP8298 group for DR2+ or DR4+ subjects and less change in the MBP8298 group for DR2−/DR4− subjects, compared to placebo. The mean changes in MSFC showed a reversal of the pattern seen with the EDSS; namely, there was a trend toward less clinical deterioration in the MBP8298 group for the DR2+ or DR4+ subjects, and a trend toward more deterioration for the DR2−/DR4− subjects. Annualized relapse rates were nearly identical for the DR2+ or DR4+ treatment groups. A total of 81% of subjects were relapse-free. For DR2−/DR4− subjects, there was a trend (p = 0.055) toward benefit of MBP8298 treatment, but the number of subjects having had a relapse in the 24 months prior to treatment was similarly unbalanced (figure 1).

View this table:
Table 2

Secondary outcome results: EDSS changes, MSFC changes, and annualized relapse ratesa

MRI endpoints.

The MRI results are summarized in table 3. There was a significant (p = 0.034) difference in cumulative number of new and enlarging T2 lesions for DR2+ or DR4+ subjects, favoring placebo. No significant differences or trends were seen in T2 burden of disease, number of new gadolinium-enhancing lesions, or change in brain parenchymal fraction.

View this table:
Table 3

MRI resultsa

Quality of life.

No significant differences between treatment groups were seen for summary scores using the SF-36 or MSQoL measures (data not shown).

Post hoc analysis.

There were no significant differences in TTP relative to placebo when results were analyzed according to EDSS stratum at baseline, or with patients who were relapse-free 1 year before and during the study (n = 435, 71%). The frequency of second progressions and the frequency of EDSS improvements were comparable between MBP8298 and placebo. Analysis of selected functional system subscores failed to show treatment-related differences. The MSFC component scores (Timed 25-Foot Walk, 9-Hole Peg Test, PASAT-3; see table 2) did not show significant differences between MBP8298 and placebo treatments. To identify subgroups with a treatment effect substantially larger than that in the overall population, we performed a comprehensive search for all possible subgroups that could be specified by up to 3 covariates using a recursive partitioning framework. The analysis examined 50 covariates with cutoffs at all possible levels using treatment by split interaction as the criterion for evaluating the cutoffs. Input variables included demographic characteristics, vital signs, laboratory values, MRI findings, medical history, HLA haplotype status, and functional capacity, and response variables included EDSS progression, EDSS changes, and occurrence of relapse. Several subgroups based on specific combinations of covariate levels showed treatment differences in favor of MBP8298 treatment, but all were considered coincidental because the identified covariates did not have any clinical rationale, and after adjustment for the multiplicity inherent in the subgroup search process, the effect sizes associated with the top subgroups did not exceed those that would have been expected by chance. The findings were also not confirmed with the test data when the data were randomly divided into training and test sets and the subgroup search was performed on the training set.

Safety.

A total of 88.1% of subjects received all 4 doses of study drug with few differences between MBP8298 and placebo in terms of clinically significant adverse events (table e-1). Almost all subjects experienced at least 1 adverse event during the study (95.4% and 93.8% in the MBP8298 and placebo arms, respectively). There were more injection site reactions and flushing in the treatment arm, consistent with previous studies with MBP8298. There was less back pain, less peripheral coldness, and more musculoskeletal chest pain in the MBP8298 arm. No clinically significant differences were observed between treatment groups in terms of changes to vital signs, ECGs, or laboratory assessments. No pregnancies were reported.

Two adverse events (myelodysplastic syndrome and rectal cancer) lead to death during the study. Both deaths occurred on MBP8298; neither was considered related to study drug. One additional death (acute respiratory distress syndrome) occurred prior to the administration of any study drug. A total of 109 subjects (51 MBP8298; 58 placebo) experienced at least 1 SAE during the study. Nine events occurred prior to first dose of study drug, leaving 49 treatment-emergent SAEs in the MBP8298 arm and 51 in the placebo arms. Most SAEs were considered not related to treatment. The number of SAEs was similar regardless of HLA status.

DISCUSSION

This study was designed to demonstrate a 44% improvement in TTP favoring MBP8298, based on an assumption that 30% of placebo-treated subjects would progress in 2 years. Placebo progressions (28%) occurred near the assumed rate, but no improvement in TTP was seen in the MBP8298-treated subjects. The number of subjects completing the study exceeded the design requirement (440 vs 408), as did the number of observed progressions (150 vs 98). Considering the absence of improvement on MBP8298, the negative outcome cannot be explained by lack of statistical power or other deficiencies in trial design. Secondary outcomes were consistent with the negative result on TTP. In a separate phase II randomized, double-blind, placebo-controlled trial,28 157 DR2+ or DR4+ subjects with RRMS also failed to show efficacy as measured by ARR, EDSS progression, or MRI. Autoantibody levels in CSF were not measured in either this study or the RRMS study because of the intrusive nature of this procedure. No safety concerns were raised.

Post hoc analysis failed to generate a viable hypothesis for an improved trial design that might yield a positive result with MBP8298. Subcomponents of the EDSS and MSFC scores did not show treatment differences, nor did quality of life measures. The homogeneity of this SPMS population was higher than that of previous SPMS studies because of rigorous entry criteria, with 71% of subjects relapse-free on-trial as well as 1 year before entry. The hypothesis-generating recursive partitioning framework analysis failed to identify any subset of the population that might have had a positive response to MBP8298. Extending the trial duration beyond 2 years would have added relatively little data because subjects with low progression rates are enriched in the population that remains progression-free.

Placebo progression in this study (28% in 2 years) was at the low end of the range reported in previous SPMS trials. This may in part be due to the more homogeneous SPMS population that was selected, with 81% of placebo subjects remaining relapse-free for the 2-year duration of the trial. Placebo rates of progression and percentage relapse-free show an inverse relationship in a comparison between the European2,3 and North American6 3-year trials of IFN β-1b; there was 50% progression with 47% relapse-free in the former and only 34% progression with 70% relapse-free in the latter. This relationship is also seen in 3 2-year SPMS trials; 44% progression with 48% relapse-free in the IV immunoglobulin study,29 38% progression with 62% relapse-free in the Nordic study of IFN β-1b (Rebif),8 and 34% progression with 63% relapse-free in the study of IFN β-1a (Avonex).5

Further trials in SPMS should be designed with the expectation that placebo progression rates may be lower when subjects in transition from RRMS to SPMS are excluded.

Statement on classification of level of evidence.

This clinical trial was conducted in order to evaluate the safety and efficacy of MBP8298 (MBP8298) in patients with SPMS in a double-blind, randomized, placebo-controlled, multicenter international trial. The trial was conducted according to the International Conference of Harmonization Good Clinical Practice Guidelines and constitutes a Class 1 trial according to the Neurology® levels of evidence guideline.

AUTHOR CONTRIBUTIONS

Dr. Freedman: lead investigator, design of study, drafting and revision of manuscript. Dr. Bar-Or: design of study, revision of manuscript. J. Oger: design of study, revision of manuscript. Dr. Traboulsee: design of study, analysis of MRI data, revision of manuscript. Dr. Patry: design of study, revision of manuscript. Dr. Young: design of study, revision of manuscript. Dr. Olsson: design of study, revision of manuscript. Dr. Li: design of study, analysis of MRI data, revision of manuscript. Dr. Hartung: design of study, revision of manuscript. Dr. Krantz: design of study, data analysis, drafting and revision of manuscript. L. Ferenczi: design of study, data analysis, revision of manuscript. Dr. Verco: design of study, data analysis, drafting and revision of manuscript.

COINVESTIGATORS

Study participants: Steering Committee: M. Freedman (Ottawa Hospital, Ottawa, Canada); A. Bar Or (McGill University, Montreal, Canada); J. Oger (University of British Columbia, Vancouver, Canada); A. Traboulsee (University of British Columbia, Vancouver, Canada); D. Patry (University of Calgary, Calgary, Canada); C. Young (The Walton Centre, Liverpool, UK); T. Olsson (Karolinska Institutet, Stockholm, Sweden); H.-P. Hartung (Heinrich-Heine University Düsseldorf, Düsseldorf, Germany). Data Safety and Monitoring Board: J. Antel (Chair) (Montreal Neurological Institute, Montreal, Canada); S. Zamvil (Department of Neurology, University of California, San Francisco, CA); D. Arnold (Part) (Montreal Neurological Institute, Montreal, Canada); G. Cutter (University of Alabama, Birmingham, AB); N. DeStefano (Part) (University of Siena, Siena, Italy); F. Lublin (Mount Sinai Medical Center, New York, NY); Z. Chad (Part) (Ottawa, Canada); C. Polman (VU Medical Center, Amsterdam, Netherlands). Principal Investigators—Canada: J.-P. Bouchard (Centre Hopsitalier Affilie, Quebec City); V. Bahn (QEII Centre for Clinical Research, Halifax); P. Duquette (CHUM Hospitalier Notre-Dame, Montreal); M. Freedman (Lead Investigator) (Ottawa General Hospital, Ottawa); L. Lee (University of Toronto, North York); M. Melanson (Part), R.A. Marrie (Part) (Health Sciences Foundation, Winnipeg); P. O'Connor (St. Michael's Hospital, Toronto); J. Oger (University of British Columbia Hospital, Vancouver); D. Patry (Foothill's Medical Center, Calgary); M. Steffanelli (Health Science Centre, St. John's); J. Bakker (Red Deer Regional Hospital, Red Deer); D. Brunet (Kingston Ontario MS Clinic, Kingston); M. Kremenchutzky (London Health Science Center, London). United Kingdom: C. Young (The Walton Centre, Liverpool); B. Sharrack (Royal Hallamshire Hospital, Sheffield); R. Nicholas (Charing Cross Hospital, London); C. O'Leary (Southern General Hospital, Glasgow); C. Constantinescu (Queen's Medical Centre, Nottingham); J. Palace (John Radcliffe Hospital, Oxford). Netherlands: P.J.H. Jongen (Part), C.P. Zwanikken (Part) (Multiple Sclerose Centrum, Nijmegen); E.A.C.M. Sanders (Amphia Ziekenhis, Breda); B. Anten, Maasland Ziekenhuis, Sittard; E.T. van Munster (Poli Neurologie, Hertogenbosch). Sweden: T. Olsson (Universitetssjukhuset–Solna Neurologmottagningen, Stockholm); J. Hillert (Universitetssjukhuset–Huddinge Neurologkliniken, Stockholm); J. Lycke (Universitetssjukhuset–Östra, Göteborg); M. Vrethem (Universitetssjukhuset I Linköping, Linköping); P. Nilsson (Universitetssjukhuset I Lund, Lund); A. Svenningsson (Norrlands Universitetssjukhus, Umeå); C. Martin (Danderyds Sjukhus AB, Stockholm). Denmark: P.S.G. Sörensen (Rigshospitalet, Copenhagen). Finland: J.-P. Erälinna (Turun Päänsärkykeskus, Turku); H. Kuusisto (Tampere University Hospital, Tampere); M. Reunanen (Oulu University Hospital, Oulu); T. Jolma (Porin Lääkäritalo, Pori); A. Färkkilä (Helsinki University Hospital, Helsinki). Germany: H.-P. Hartung (Heinrich-Heine University, Dusseldorf); S. Schimrigk (Part), A. Chan (Part) (Ruhr-Universität, Bochum); T. Ziemssen (TU Dresden, Neurologische Universität Klinik, Dresden); M. Stengel (Medizinische Hochschule, Hannover); C. Heesen (Universitaätsklinikum Hamburg-Eppendorf, Hamburg). Estonia: K. Gross-Paju (West Tallinn Central Hospital, Tallinn); I. Kalbe (Tartu University Hospital, Tartu). Latvia: M. Metra (Vecmilgravis Hospital, Riga). Spain: T. Arbizu (l'Hospitalet de Llobregat, Barcelona); R. Arroyo (Hospital Clìnico San Carlos, Madrid); X. Montalbán (Hospital Vall d'Hebrón, Barcelona). Coinvestigators: Canada—M. Thibault, MD, Clinical Site Sub-Investigator, F. Edmond, MD, S. Verrrault, MD, Clinical Site Sub-Investigator (Centre Hopsitalier Affilie, Quebec City); C.E. Maxner, MD, Clinical Site Sub-Investigator, J.R. McKelvey, MD, Clinical Site Sub-Investigator, A.D. McDougall, MD, Clinical Site Sub-Investigator, R. Vandorpe, MD, Clinical Site Sub-Investigator (QEII Centre for Clinical Research, Halifax); G.P. Bernier, MD, Clinical Site Sub-Investigator, J.M. Girard, MD, Clinical Site Sub-Investigator, A. Prat, MD, Clinical Site Sub-Investigator (CHUM Hospitalier Notre-Dame, Montreal); H. Mclean, MD, Clinical Site Sub-Investigator, H. Rabinovitch, MD, Clinical Site Sub-Investigator, E. Simantirakis, MD, Clinical Site Sub-Investigator, L. Martin, MD, Clinical Site Sub-Investigator, R. Cruce, MD, Clinical Site Sub-Investigator (Ottawa General Hospital, Ottawa); J.E. Ween, MD, Clinical Site Sub-Investigator, S. Symons, MD, Clinical Site Sub-Investigator, B. Murray, MD, Clinical Site Sub-Investigator, M. Masellis, MD, Clinical Site Sub-Investigator (University of Toronto, North York); L. Galimova, MD, Clinical Site Sub-Investigator (Health Sciences Foundation, Winnipeg); J. Burton, MD, Clinical Site Sub-Investigator, T. Gray, MD, Clinical Site Sub-Investigator, D. Selchen, MD, Clinical Site Sub-Investigator, J. Marriott, MD, Clinical Site Sub-Investigator (St. Michael's Hospital, Toronto); V. Devonshire, MD, Clinical Site Sub-Investigator, J. Hooge, MD, Clinical Site Sub-Investigator, P. Smith, MD, Clinical Site Sub-Investigator, S. Hashimoto, MD, Clinical Site Sub-Investigator, L. Kastrukoff, MD, Clinical Site Sub-Investigator, A. Traboulsee, MD, Clinical Site Sub-Investigator, D. Li, MD, Clinical Site Sub-Investigator (University of British Columbia Hospital, Vancouver); M. Yeung, MD, Clinical Site Sub-Investigator, L. Metz, MD, Clinical Site Sub-Investigator, R. Bell, MD, Clinical Site Sub-Investigator, F. Costello, MD, Clinical Site Sub-Investigator, D. McGowan, MD, Clinical Site Sub-Investigator, D. Pearson, MD, Clinical Site Sub-Investigator, J. Davenport, MD, Clinical Site Sub-Investigator, K. Busche, MD, Clinical Site Sub-Investigator (Foothill's Medical Center, Calgary); C. Lim, MD, Clinical Site Sub-Investigator, B. Hope, MD, Clinical Site Sub-Investigator, L. Kelly, MD, Clinical Site Sub-Investigator, A. Goodridge, MD, Clinical Site Sub-Investigator, S. Murntaz, MD, Clinical Site Sub-Investigator (Health Science Centre, St. John's); J. Singh, MD, Clinical Site Sub-Investigator, I. Heinrich, MD, Clinical Site Sub-Investigator (Red Deer Regional Hospital, Red Deer); M. Melanson, MD, Clinical Site Sub-Investigator, S. Reid, MD, Clinical Site Sub-Investigator (Kingston Ontario MS Clinic, Kingston); H.C. Hyson, MD, Clinical Site Sub-Investigator, K. Alikhani, MD, Clinical Site Sub-Investigator (London Health Science Center, London). Unite Kingdom: B. Lecky, MD, Clinical Site Sub-Investigator, R. Mills, MD, Clinical Site Sub-Investigator, J. Ramtahal, MD, Clinical Site Sub-Investigator, S. Rashid, MD, Clinical Site Sub-Investigator, M. Wilson, MD, Clinical Site Sub-Investigator, T.E. Nixon, MD, Clinical Site Sub-Investigator (The Walton Centre, Liverpool); S.J.L. Howell, MD, Clinical Site Sub-Investigator, S. Dhungana, MD, Clinical Site Sub-Investigator, S. Price, MD, Clinical Site Sub-Investigator, S.S. Pujari, MD, Clinical Site Sub-Investigator, O. Suliman, MD, Clinical Site Sub-Investigator (Royal Hallamshire Hospital, Sheffield); J. Chataway, MD, Clinical Site Sub-Investigator, O. Malik, MD, Clinical Site Sub-Investigator, B. Wakerley, MD, Clinical Site Sub-Investigator, J.M. Stevens, MD, Clinical Site Sub-Investigator, B.E. Kendall, MD, Clinical Site Sub-Investigator (Charing Cross Hospital, London); J. Overell, MD, Clinical Site Sub-Investigator, R. Thomas, MD, Clinical Site Sub-Investigator, S. Webb, MD, Clinical Site Sub-Investigator (Southern General Hospital, Glasgow); L. Edwards, MD, Clinical Site Sub-Investigator, B. Gran, MD, Clinical Site Sub-Investigator, D. Auer, MD, Clinical Site Sub-Investigator, L. Sanvito, MD, Clinical Site Sub-Investigator, J. Vilisaar, MD, Clinical Site Sub-Investigator, M. Schubert, MD, Clinical Site Sub-Investigator (Queen's Medical Centre, Nottingham); T. Arun, MD, Clinical Site Sub-Investigator, B. Bernadetti, MD, Clinical Site Sub-Investigator, C.J. Stagg, MD, Clinical Site Sub-Investigator (John Radcliffe Hospital, Oxford). Netherlands: J.A.G. Geelen, MD, Clinical Site Sub-Investigator, S.H.T. Soe, MD, Clinical Site Sub-Investigator, W.J.M. Verhagen, MD, Clinical Site Sub-Investigator (Multiple Sclerose Centrum, Nijmegen); R. van Dijl, MD, Clinical Site Sub-Investigator (Amphia Ziekenhis, Breda); F.A. Rooyer, MD, Clinical Site Sub-Investigator, V. Triebels, MD, Clinical Site Sub-Investigator (Maasland Ziekenhuis, Sittard); R. Bernsen, MD, Clinical Site Sub-Investigator, H.F. Visee, MD, Clinical Site Sub-Investigator, S. Fiets, MD, Clinical Site Sub-Investigator (Poli Neurologie, Hertogenbosch). Sweden: L. Hopia, MD, Clinical Site Sub-Investigator, L. Brundin, MD, Clinical Site Sub-Investigator, M. Marta, MD, Clinical Site Sub-Investigator, F. Pihl, MD, Clinical Site Sub-Investigator, E. Wallstrom, MD, Clinical Site Sub-Investigator, E. Lacobaeus, MD, Clinical Site Sub-Investigator (Universitetssjukhuset–Solna Neurologmottagningen, Stockholm); S. Federiksson, MD, Clinical Site Sub-Investigator, V. Karrenbauer, MD, Clinical Site Sub-Investigator, E. Akesson, MD, Clinical Site Sub-Investigator, K. Weclewiczez, MD, Clinical Site Sub-Investigator, H. Roshani, MD, Clinical Site Sub-Investigator, E. Wallstrom, MD, Clinical Site Sub-Investigator (Universitetssjukhuset–Huddinge Neurologkliniken, Stockholm); M. Axelsson, MD, Clinical Site Sub-Investigator, C. Malmestrom, MD, Clinical Site Sub-Investigator, B. Runmarker, MD, Clinical Site Sub-Investigator (Universitetssjukhuset–Östra, Göteborg); C. Dahle, MD, Clinical Site Sub-Investigator (Universitetssjukhuset I Linköping, Linköping); A. Risedal, MD, Clinical Site Sub-Investigator, M. Sandberg, MD, Clinical Site Sub-Investigator (Universitetssjukhuset I Lund, Lund); A. Sjostrom, MD, Clinical Site Sub-Investigator, P. Sundstrom, MD, Clinical Site Sub-Investigator (Norrlands Universitetssjukhus, Umeå); H. Linda, MD, Clinical Site Sub-Investigator, E. Rydin, MD, Clinical Site Sub-Investigator, L. Sjostrom, MD, Clinical Site Sub-Investigator, A. von Heijne, MD, Clinical Site Sub-Investigator (Danderyds Sjukhus AB, Stockholm). Denmark: M. Blinkenberg, MD, Clinical Site Sub-Investigator, S. Bramow, MD, Clinical Site Sub-Investigator, D. Hesse, MD, Clinical Site Sub-Investigator, F. Selleberg, MD, Clinical Site Sub-Investigator (Rigshospitalet, Copenhagen). Finland: M. Kallela, MD, Clinical Site Sub-Investigator, V. Artto, MD, Clinical Site Sub-Investigator, O. Happola, MD, Clinical Site Sub-Investigator, K.P. Saastamoinen, MD, Clinical Site Sub-Investigator (Turun Päänsärkykeskus, Turku); J. Palmio, MD, Clinical Site Sub-Investigator, A.K. Parkkila, MD, Clinical Site Sub-Investigator, S. Rainesalo, MD, Clinical Site Sub-Investigator, M. Raunio, MD, Clinical Site Sub-Investigator, M. Ukkonen, MD, Clinical Site Sub-Investigator (Tampere University Hospital, Tampere); M. Karppa, MD, Clinical Site Sub-Investigator, I. Keskinarkaus, MD, Clinical Site Sub-Investigator, A. Remes, MD, Clinical Site Sub-Investigator (Oulu University Hospital, Oulu); J.M. Seppa, MD, Clinical Site Sub-Investigator (Porin Lääkäritalo, Pori); O. Happola, MD, Clinical Site Sub-Investigator, K.P. Saastamoinen, MD, Clinical Site Sub-Investigator, V. Arto, MD, Clinical Site Sub-Investigator, M. Kallela, MD, Clinical Site Sub-Investigator (Helsinki University Hospital, Helsinki). Germany: P.M. Albrecht, MD, Clinical Site Sub-Investigator, R. Frohlich, MD, Clinical Site Sub-Investigator, G.V. Geldern, MD, Clinical Site Sub-Investigator, H.-H. Friedemann, MD, Clinical Site Sub-Investigator, D. Toutzaris, MD, Clinical Site Sub-Investigator (Heinrich-Heine University, Dusseldorf); G. Ellrichmann, MD, Clinical Site Sub-Investigator, A. Haghikia, MD, Clinical Site Sub-Investigator, K. Hellwig, MD, Clinical Site Sub-Investigator, S. Salmen, MD, Clinical Site Sub-Investigator (Ruhr-Universität, Bochum); H. Hanso, MD, Clinical Site Sub-Investigator, H. Schneider, MD, Clinical Site Sub-Investigator, W. Schrempf, MD, Clinical Site Sub-Investigator, T. Schultheib, MD, Clinical Site Sub-Investigator (TU Dresden, Neurologische Universität Klinik, Dresden); R. Pul, MD, Clinical Site Sub-Investigator, C. Schroeder, MD, Clinical Site Sub-Investigator, D. Soenmez, MD, Clinical Site Sub-Investigator, C. Trebst, MD, Clinical Site Sub-Investigator, E. Wiesemann, MD, Clinical Site Sub-Investigator (Medizinische Hochschule, Hannover); D. Burkhart, MD, Clinical Site Sub-Investigator, J. Gbadamosi, MD, Clinical Site Sub-Investigator, K.H. Sturner, MD, Clinical Site Sub-Investigator, B. Holst, MD, Clinical Site Sub-Investigator, F. Moller, MD, Clinical Site Sub-Investigator, C. Restemeyer, MD, Clinical Site Sub-Investigator, S. Rosner, MD, Clinical Site Sub-Investigator, S. Schippling, MD, Clinical Site Sub-Investigator (Universitaätsklinikum Hamburg-Eppendorf, Hamburg). Estonia: U. Sorro, MD, Clinical Site Sub-Investigator, A. Nurmiste, MD, Clinical Site Sub-Investigator (West Tallinn Central Hospital, Tallinn); J. Korv, MD, Clinical Site Sub-Investigator, D. Looris, MD, Clinical Site Sub-Investigator (Tartu University Hospital, Tartu). Latvia: J. Kalnina, MD, Clinical Site Sub-Investigator, M. Murzina, MD, Clinical Site Sub-Investigator, A. Paegle, MD, Clinical Site Sub-Investigator, A. Platkajis, MD, Clinical Site Sub-Investigator (Vecmilgravis Hospital, Riga). Spain: L. Gubieras, MD, Clinical Site Sub-Investigator, L. Romero, MD, Clinical Site Sub-Investigator (l'Hospitalet de Llobregat, Barcelona); M. Bartolome, MD, Clinical Site Sub-Investigator, P.D. Gonzales, MD, Clinical Site Sub-Investigator, V. de las Heras, MD, Clinical Site Sub-Investigator (Hospital ClÌnico San Carlos, Madrid); C. Nos, MD Clinical Site Sub-Investigator (Hospital Vall d'Hebrón, Barcelona). Study Coordinators: Canada: F. Gosselin (Centre Hopsitalier Affilie, Quebec City); T. Campbell (QEII Centre for Clinical Research, Halifax); R. Dubois (CHUM Hospitalier Notre-Dame, Montreal); P. Waddell, U. Webb (Ottawa General Hospital, Ottawa); K. Carr (University of Toronto, North York); B. Stanger, L. Wong (Health Sciences Foundation, Winnipeg); J. Beunaflor, M. Lam, R. Subido (St. Michael's Hospital, Toronto); W. Morrison (University of British Columbia Hospital, Vancouver); I. Irvine (Foothill's Medical Center, Calgary); E. Condon, K. Murphy (Health Science Centre, St. John's); B. Blain, D. Cleland (Red Deer Regional Hospital, Red Deer); V. McBride (Kingston Ontario MS Clinic, Kingston); T Bentall (London Health Science Center, London). United Kingdom: L. Owen, D. Watling (The Walton Centre, Liverpool); J. Kemp (Royal Hallamshire Hospital, Sheffield); B. Polito, T. Beeson (Charing Cross Hospital, London); M. Coutts (Southern General Hospital, Glasgow); V. Orpe, M. Harrison (Queen's Medical Centre, Nottingham); A. Cavey (John Radcliffe Hospital, Oxford). Netherlands: C. Slaa (Multiple Sclerose Centrum, Nijmegen); K. Kraus, A. Loon (Amphia Ziekenhis, Breda); S. Liederkerken (Maasland Ziekenhuis, Sittard); E. Mil, Y. Slaats (Poli Neurologie, Hertogenbosch). Sweden: K. Ahlgvist, S. Sundqvist (Universitetssjukhuset–Solna Neurologmottagningen, Stockholm); E. Johnasson, A. Mattisson (Universitetssjukhuset–Huddinge Neurologkliniken, Stockholm); M. Hansson, V. Lindberg, T. Norden (Universitetssjukhuset–Östra, Göteborg); G. Johansson, H. Lundberg (Universitetssjukhuset I Linköping, Linköping); L. Asmoarp, G. Jadback, K. Lennartsson (Universitetssjukhuset I Lund, Lund); A. Jonsseon, Y. Lofstrand (Norrlands Universitetssjukhus, Umeå); A.-M. Parlatore (Danderyds Sjukhus AB, Stockholm). Denmark: V. Jespersen, J. Pietraszek (Rigshospitalet, Copenhagen). Finland: J. Suonketo (Turun Päänsärkykeskus, Turku); A. Airaksinen (Tampere University Hospital, Tampere); T. Ahola, M. Nappa (Oulu University Hospital, Oulu); T. Nyman-Taimi (Porin Lääkäritalo, Pori); A. Nyrthinen (Helsinki University Hospital, Helsinki). Germany: A. Stritzel (Heinrich-Heine University, Dusseldorf); I. Schweppe-Salewski (Ruhr-Universität, Bochum); I. Horenburg, S. Marx (TU Dresden, Neurologische Universität Klinik, Dresden); K. Fricke (Medizinische Hochschule, Hannover); A. Monch, S. Schammler (Universitaätsklinikum Hamburg-Eppendorf, Hamburg). Estonia: L. Vahter, K. Rohulaid (West Tallinn Central Hospital, Tallinn); E. Reiljan (Tartu University Hospital, Tartu). Latvia: L. Elsone (Vecmilgravis Hospital, Riga). Spain: S. Pobla (l'Hospitalet de Llobregat, Barcelona); M.C. Ramirez (Hospital Clìnico San Carlos, Madrid); M. Sallen (Hospital Vall d'Hebrón, Barcelona).

DISCLOSURE

Dr. Freedman serves on scientific advisory boards for sanofi-aventis, Novartis, Merck Serono, Bayer Schering Pharma, BioMS Medical, Celgene, Eli Lilly and Company, Biogen Idec, and Roche; has received funding for travel and speaker honoraria from Merck Serono, Novartis, sanofi-aventis, and Bayer Schering Pharma; serves on the editorial boards of the Journal of the Neurological Sciences, Multiple Sclerosis, Multiple Sclerosis International, and the International Journal of MS Care; and receives research support from Bayer Schering Pharma, Genzyme Corporation, and EMD Serono, Inc. Dr. Bar-Or serves on scientific advisory boards for BioMS Medical, DioGenix, Inc., Ono Pharmaceutical Co. Ltd., GlaxoSmithKline, Roche, Guthy Jackson Greater Good Foundation, and NMO Research and Clinical Care Consortium; serves on the editorial boards of Neurology® and Clinical and Experimental Neuroimmunology; has received speaker honoraria from Biogen Idec, Bayhill Therapeutics, Bayer Schering Pharma (Berlex), Eli Lilly and Company, Genentech, Inc., GlaxoSmithKline, Merck Serono, Novartis, Wyeth, sanofi-aventis, and Teva Pharmaceutical Industries Ltd.; and receives/has received research support from BioMS Medical, Merck Serono, Bayhill Therapeutics, Biogen Idec, Genentech, Inc., and Teva Pharmaceutical Industries Ltd. Dr. Oger serves on scientific advisory boards for Aspreva Pharmaceuticals Inc., Bayer Schering Pharma, Biogen Idec, Novartis, and the Myasthenia Gravis Foundation of America; has received funding for travel from Bayer Schering Pharma/Berlex and Novartis; has received speaker or consulting honoraria from Acorda Therapeutics Inc., sanofi-aventis, BioMS Medical, EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; served as an Associated Editor for Multiple Sclerosis and Immunological Reviews; serves on the speakers' bureau for Bayer Schering Pharma; and receives research support from Bayer Schering Pharma and Christopher Foundation. Dr. Traboulsee serves on a scientific advisory board for BioMS Medical, Roche, EMD Serono, Inc.; serves on the editorial advisory board for Neura; has received speaker/consultant honoraria from Bayer Schering Pharma, EMD Serono, Inc., Biogen Idec, and Teva Pharmaceutical Industries Ltd.; and receives research support from Biogen Idec, Bayer Schering Pharma, the MS Society of Canada, CIHR, the Lotte Hecht Foundation, and Vancouver Hospital Foundation. Dr. Patry has served on a scientific advisory board for BioMS Medical; has received speaker honoraria from EMD Serono, Inc., Novartis, Teva Pharmaceutical Industries Ltd, and Biogen Idec; and receives research support from Bristol-Myers Squibb, sanofi-aventis, Lundbeck Inc., Elan Corporation, and the MS Society of Canada. Dr. Young serves/has served on scientific advisory boards for Bayer Schering Pharma, Merck Serono, Novartis, Teva Pharmaceutical Industries Ltd., and BioMS Medical/Eli Lilly and Company; received funding for travel from Merck Serono and Teva Pharmaceutical Industries Ltd.; and receives research support from Biogen Idec, Novartis, Teva Pharmaceutical Industries Ltd., the Motor Neurone Disease Association, and the British Polio Fellowship. Prof. Olsson serves/has served on scientific advisory boards for Merck Serono, Biogen Idec, sanofi-aventis, and Novartis; has received speaker honoraria from Novartis, Biogen Idec, sanofi-aventis, and Merck Serono; and receives research support from Merck Serono, Biogen Idec, sanofi-aventis, Bayer Schering Pharma, Novartis, the Swedish Research Council, the EU FP6, the Söderbergs Foundation, the Bibbi and Nils Jensens Foundation, the Montel Williams Foundation, and the Swedish Brain foundation. Dr. Li serves on scientific advisory boards for Roche and Nuron Biotherapeutics; serves as a consultant for Genzyme Corporation and Novartis; serves on the speakers' bureau for Consortium of MS Centers; performs MRI (50% effort) in his clinical practice; serves as the Director of the UBC MS/MRI Research Group which has been contracted to perform central analysis of MRI scans for therapeutic trials with Angiotech, Bayer Schering Pharma, BioMS Medical, Centocor Ortho Biotech Inc., Daiichi Sankyo, Roche, Merck Serono, Schering-Plough Corp., Teva Pharmaceutical Industries Ltd., sanofi-aventis, and Transition Therapeutics Inc.; and receives research support from the MS Society of Canada and CIHR. Prof. Hartung serves on scientific advisory boards for and has received funding for travel, speaker honoraria, and research support from Novartis, Merck Serono, Teva Pharmaceutical Industries Ltd., Biogen Idec, and Bayer Schering Pharma. Dr. Krantz was an employee of and owned stock options in BioMS Medical for the duration of the study; and serves as a consultant for Medwell Capital Corp. L. Ferenczi was an employee of and owned stock options in BioMS Medical for the duration of the study. Dr. Verco was an employee of and owned stock options in BioMS Medical for the duration of the study.

ACKNOWLEDGMENT

The authors thank the Contract Research Organizations ICON Plc, Stiris Research Inc, and Sedoc/A+ Science for the project management and monitoring of the study. ICON was additionally responsible for data management and statistics. The authors thank all the patients who participated in the study, Mary Nilsson (Eli Lilly and Company) for contributing to the statistical analysis planning, and ICON Clinical Research for the monitoring of the study, data collection and management, and execution of the statistical analysis plan.

Footnotes

  • Study funding: Sponsored by BioMS Medical Corp.

  • Supplemental data at www.neurology.org

  • Received February 7, 2011.
  • Accepted June 27, 2011.

REFERENCES

  1. 1.↵
    1. Kurtzke JF
    . Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–1452.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    European Study Group on Interferon beta-1b in Secondary Progressive MS. Placebo-controlled multicentre randomized trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352:1491–1497.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Kappos L,
    2. Polman C,
    3. Pozilli C,
    4. et al
    . Final analysis of the European multicenter trial on IFB beta-1b in secondary progressive MS. Neurology 2001;57:1969–1975.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS. Neurology 2001;56:1496–1504.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Cohen JA,
    2. Cutter GR,
    3. Fischer JS,
    4. et al
    . Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002;59:679–687.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    North American Study Group on Interferon beta-1b in Secondary Progressive MS. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004;63:1788–1795.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Kappos L,
    2. Weinshenker B,
    3. Pozzilli C,
    4. et al
    . for the European (EU-SPMS) and North American (NA-SPMS) Interferon beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committees and Independent Advisory Boards. Interferon beta-1b in secondary progressive MS; a combined analysis of the two trials. Neurology 2004;63:1779–1787.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Andersen O,
    2. Elovaara I,
    3. Farkkila M,
    4. et al
    . Multicentre, randomized, double blind, placebo controlled phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2004;75:706–710.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Wolinsky JS,
    2. Narayana PA,
    3. O'Connor P,
    4. et al.
    , the PROMiSe Trial Study Group. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial Ann Neurol 2007;61:14–24.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Confavreux C,
    2. Vukusic S,
    3. Moreau T,
    4. Adeleine P
    . Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430–1438.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Leray E,
    2. Yaouanq J,
    3. Le Page E,
    4. Coustans M,
    5. Laplaud D,
    6. Oger J,
    7. Edan G
    . Evidence for a two-stage disability progression in multiple sclerosis. Brain 2010;133:1900–1913.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Frischer JM,
    2. Bramow S,
    3. Dal-Bianco A,
    4. et al
    . the relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009;132:1175–1189.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Holmoy T
    . Immunopathogenesis of multiple sclerosis: concepts and controversies. Acta Neurol Scand Suppl 2007;187:39–45.
    OpenUrlPubMed
  14. 14.↵
    1. Kasper LH,
    2. Shoemaker J
    . The healthy immune system vs the MS immune system. Neurology 2010;74:S2–S8.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Warren KG,
    2. Catz I,
    3. Steinman L
    . Fine specificity of the antibody response to myelin basic protein in the central nervous system in multiple sclerosis: the minimal B-cell epitope and a model of its features. Proc Natl Acad Sci USA 1995;92:11061–11065.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Sakai K,
    2. Zamvil SS,
    3. Mitchell DJ,
    4. et al
    . Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J Neuroimmunol 1988;19:21–32.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Wucherpfennig KW,
    2. Catz I,
    3. Hausmann S,
    4. et al
    . Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T-cell clones from multiple sclerosis patients: identity of key contact residues in the B-cell and T-cell epitopes. J Clin Invest 1997;100:1114–1122.
    OpenUrlPubMed
  18. 18.↵
    1. Warren KG,
    2. Catz I
    . Diagnostic value of cerebrospinal fluid anti-myelin basic protein in patients with multiple sclerosis. Ann Neurol 1986;20:20–25.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Warren KG,
    2. Catz I
    . Administration of myelin basic protein synthetic peptides to multiple sclerosis patients. J Neurol Sci 1995;133:85–94.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Warren KG,
    2. Catz I
    . The effect of intrathecal MBP synthetic peptides containing epitope P85VVHFFKNIVTP96 on free anti-MBP levels in acute relapsing multiple sclerosis. J Neurol Sci 1997;148:67–78.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Warren KG,
    2. Catz I,
    3. Wucherpfennig KW
    . Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85VVHFFKNIV96 in chronic progressive multiple sclerosis. J Neurol Sci 1997;152:31–38.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Warren KG,
    2. Catz I
    . Kinetic profiles of cerebrospinal fluid anti-MBP in response to intravenous MBP synthetic peptide DENP85VVHFFKNIVTP96RT in multiple sclerosis patients. Mult Scler 2000;6:300–311.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Warren KG,
    2. Catz I,
    3. Ferenczi LZ,
    4. Krantz MJ
    . Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. Eur J Neurol 2006;13:887–895.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Cutter GR,
    2. Baier ML,
    3. Rudick RA,
    4. et al
    . Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999;122:871–882.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Ware JE,
    2. Sherbourne CD
    . The MOS 36-item short-form health survey (SF-36): I: conceptual framework and item selection. Med Care 1992;30:473–483.
    OpenUrlPubMed
  26. 26.↵
    1. Vickrey BG,
    2. Hays RD,
    3. Harooni R,
    4. et al
    . A health-related quality of life measure for multiple sclerosis. Qual Life Res 1995;4:187–206.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Lipkovich I,
    2. Dmitrienko A,
    3. Su E,
    4. Denne J,
    5. Enas G
    . Identification of promising subgroups in the retrospective analysis of clinical trials. Available at: http://bass.georgiasouthern.edu/PDFs/BASS%202008%20Ilya%20Lipkovich.pdf. Accessed January 5, 2011.
  28. 28.↵
    1. Selmaj K,
    2. Verco T,
    3. Ossana M,
    4. et al
    . A double-blind, placebo-controlled multicenter study to evaluate dirucotide in relapsing-remitting multiple sclerosis. Poster presentation, ECTRIMS, Dusseldorf, Germany, September 9–12, 2009, poster number P778.
  29. 29.↵
    1. Hommes OR,
    2. Sorensen PS,
    3. Fazekas F,
    4. et al.
    , for the European Study on Immunoglobulin in Multiple Sclerosis. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomized placebo-controlled trial. Lancet 2004;364:1149–1156.
    OpenUrlCrossRefPubMed

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