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1. MRI-based prediction of conversion from clinically isolated syndrome to clinically definite multiple sclerosis using SVM and lesion geometry.

Author

Bendfeldt K, Taschler B, Gaetano L, Madoerin P, Kuster P, Mueller-Lenke N, Amann M, Vrenken H, Wottschel V, Barkhof F, Borgwardt S, Klöppel S, Wicklein EM, Kappos L, Edan G, Freedman MS, Montalbán X, Hartung HP, Pohl C, Sandbrink R, Sprenger T, Radue EW, Wuerfel J, and Nichols TE

Subjects
Adult, Female, Humans, Magnetic Resonance Imaging, Male, Randomized Controlled Trials as Topic, Disease Progression, Gray Matter pathology, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology, Support Vector Machine
Abstract

Neuroanatomical pattern classification using support vector machines (SVMs) has shown promising results in classifying Multiple Sclerosis (MS) patients based on individual structural magnetic resonance images (MRI). To determine whether pattern classification using SVMs facilitates predicting conversion to clinically definite multiple sclerosis (CDMS) from clinically isolated syndrome (CIS). We used baseline MRI data from 364 patients with CIS, randomised to interferon beta-1b or placebo. Non-linear SVMs and 10-fold cross-validation were applied to predict converters/non-converters (175/189) at two years follow-up based on clinical and demographic data, lesion-specific quantitative geometric features and grey-matter-to-whole-brain volume ratios. We applied linear SVM analysis and leave-one-out cross-validation to subgroups of converters (n = 25) and non-converters (n = 44) based on cortical grey matter segmentations. Highest prediction accuracies of 70.4% (p = 8e-5) were reached with a combination of lesion-specific geometric (image-based) and demographic/clinical features. Cortical grey matter was informative for the placebo group (acc.: 64.6%, p = 0.002) but not for the interferon group. Classification based on demographic/clinical covariates only resulted in an accuracy of 56% (p = 0.05). Overall, lesion geometry was more informative in the interferon group, EDSS and sex were more important for the placebo cohort. Alongside standard demographic and clinical measures, both lesion geometry and grey matter based information can aid prediction of conversion to CDMS.

Published
2019
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2. gMS-Classifier1 does not predict disability progression in multiple sclerosis.

Author

van Rossum JA, Killestein J, Villar LM, Riskind PN, Freedman MS, and Teunissen C

Subjects
Adolescent, Adult, Biomarkers blood, Female, Follow-Up Studies, Humans, Immunoglobulin M blood, Male, Middle Aged, Multiple Sclerosis blood, Predictive Value of Tests, Prognosis, Young Adult, Antibodies blood, Disease Progression, Multiple Sclerosis diagnosis
Published
2019
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3. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension.

Author

Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, Goldman MD, Hartung HP, Havrdová EK, Jeffery D, Miller A, Sellebjerg F, Cadavid D, Mikol D, and Steiner D

Subjects
Adolescent, Adult, Double-Blind Method, Female, Humans, Immunologic Factors administration & dosage, Immunologic Factors adverse effects, Male, Middle Aged, Natalizumab administration & dosage, Natalizumab adverse effects, Research Design, Young Adult, Disease Progression, Hand physiopathology, Immunologic Factors pharmacology, Multiple Sclerosis, Chronic Progressive drug therapy, Multiple Sclerosis, Chronic Progressive physiopathology, Natalizumab pharmacology, Outcome Assessment, Health Care, Severity of Illness Index
Abstract

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses., Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181., Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred., Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components., Funding: Biogen., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
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5. No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT.

Author

Munger KL, Fitzgerald KC, Freedman MS, Hartung HP, Miller DH, Montalbán X, Edan G, Barkhof F, Suarez G, Radue EW, Sandbrink R, Kappos L, Pohl C, and Ascherio A

Subjects
Adult, Biomarkers blood, Cotinine blood, Female, Follow-Up Studies, Humans, Immunoglobulin G blood, Longitudinal Studies, Male, Multiple Sclerosis epidemiology, Prospective Studies, Tobacco Use epidemiology, Young Adult, Disease Progression, Herpesvirus 4, Human metabolism, Multiple Sclerosis blood, Multiple Sclerosis diagnosis, Tobacco Use blood
Abstract

Objective: To evaluate whether Epstein-Barr virus (EBV) immunoglobulin G (IgG) antibody levels or tobacco use were associated with conversion to multiple sclerosis (MS) or MS progression/activity in patients presenting with clinically isolated syndrome (CIS)., Methods: In this prospective, longitudinal study, we measured EBV IgG antibody and cotinine (biomarker of tobacco use) levels at up to 4 time points (baseline, months 6, 12, and 24) among 468 participants with CIS enrolled in the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) clinical trial. Outcomes included time to conversion to clinically definite or McDonald MS, number of relapses, Expanded Disability Status Scale (EDSS) changes, brain and T2 lesion volume changes, and number of new active lesions over 5 years. Analyses were adjusted for age, sex, treatment allocation, baseline serum 25-hydroxyvitamin D level, number of T2 lesions, body mass index, EDSS, steroid treatment, and CIS onset type., Results: We found no associations between any EBV IgG antibody or cotinine levels with conversion from CIS to MS or MS progression as measured by EDSS or activity clinically or on MRI. The relative risk of conversion from CIS to clinically definite MS was 1.14 (95% confidence interval 0.76-1.72) for the highest vs the lowest quintile of EBNA-1 IgG levels, and 0.96 (95% confidence interval 0.71-1.31) for cotinine levels >25 ng/mL vs <10., Conclusions: Neither increased levels of EBV IgG antibodies, including against EBNA-1, nor elevated cotinine levels indicative of tobacco use, were associated with an increased risk of CIS conversion to MS, or MS activity or progression over a 5-year follow-up., (© 2015 American Academy of Neurology.)

Published
2015
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6. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial.

Author

Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung HP, Vermersch P, Casset-Semanaz F, and Scaramozza M

Subjects
Administration, Oral, Adolescent, Adult, Demyelinating Diseases diagnosis, Demyelinating Diseases drug therapy, Demyelinating Diseases epidemiology, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Multiple Sclerosis epidemiology, Time Factors, Treatment Outcome, Young Adult, Cladribine administration & dosage, Disease Progression, Immunosuppressive Agents administration & dosage, Multiple Sclerosis diagnosis, Multiple Sclerosis drug therapy
Abstract

Background: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS., Methods: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985., Findings: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group., Interpretation: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS., Funding: Merck Serono SA Geneva, a subsidiary of Merck KGaA, Darmstadt, Germany., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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7. Long-term clinical outcomes in patients with CIS treated with interferon beta-1b: results from the 15-year follow up of the BENEFIT trial.

Author

Kappos, Ludwig, Edan, Gilles, Freedman, Mark S., Hartung, Hans-Peter, Montalbán, Xavier, Barkhof, Frederik, Koelbach, Ralf, MacManus, David G., and Wicklein, Eva-Maria

Subjects
INTERFERON beta 1b, TREATMENT effectiveness, TREATMENT delay (Medicine), MULTIPLE sclerosis, DISEASE progression
Abstract

Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group (– 30.5%; hazard ratio 0.695 [95% CI, 0.547–0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b. [ABSTRACT FROM AUTHOR]

Published
2024
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8. From progression to progress: The future of multiple sclerosis.

Author

Oh, Jiwon, Giacomini, Paul S., Yong, V. Wee, Costello, Fiona, Blanchette, François, and Freedman, Mark S.

Abstract

Significant advances have been made in the diagnosis and treatment of multiple sclerosis in recent years yet challenges remain. The current classification of MS phenotypes according to disease activity and progression, for example, does not adequately reflect the underlying pathophysiological mechanisms that may be acting in an individual with MS at different time points. Thus, there is a need for clinicians to transition to a management approach based on the underlying pathophysiological mechanisms that drive disability in MS. A Canadian expert panel convened in January 2023 to discuss priorities for clinical discovery and scientific exploration that would help advance the field. Five key areas of focus included: identifying a mechanism-based disease classification system; developing biomarkers (imaging, fluid, digital) to identify pathologic processes; implementing a data-driven approach to integrate genetic/environmental risk factors, clinical findings, imaging and biomarker data, and patient-reported outcomes to better characterize the many factors associated with disability progression; utilizing precision-based treatment strategies to target different disease processes; and potentially preventing disease through Epstein-Barr virus (EBV) vaccination, counselling about environmental risk factors (e.g. obesity, exercise, vitamin D/sun exposure, smoking) and other measures. Many of the tools needed to meet these needs are currently available. Further work is required to validate emerging biomarkers and tailor treatment strategies to the needs of individual patients. The hope is that a more complete view of the individual's pathobiology will enable clinicians to usher in an era of truly personalized medicine, in which more informed treatment decisions throughout the disease course achieve better long-term outcomes. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Cerebrospinal fluid camk2a levels at baseline predict long-term progression in multiple sclerosis.

Author

Sohaei, Dorsa, Thebault, Simon, Avery, Lisa M., Batruch, Ihor, Lam, Brian, Xu, Wei, Saadeh, Rubah S., Scarisbrick, Isobel A., Diamandis, Eleftherios P., Prassas, Ioannis, and Freedman, Mark S.

Subjects
MULTIPLE sclerosis, TANDEM mass spectrometry, CEREBROSPINAL fluid, NATALIZUMAB, DISEASE progression
Abstract

Background: Multiple sclerosis (MS) remains a highly unpredictable disease. Many hope that fluid biomarkers may contribute to better stratification of disease, aiding the personalisation of treatment decisions, ultimately improving patient outcomes. Objective: The objective of this study was to evaluate the predictive value of CSF brain-specific proteins from early in the disease course of MS on long term clinical outcomes. Methods: In this study, 34 MS patients had their CSF collected and stored within 5 years of disease onset and were then followed clinically for at least 15 years. CSF concentrations of 64 brain-specific proteins were analyzed in the 34 patient CSF, as well as 19 age and sex-matched controls, using a targeted liquid-chromatography tandem mass spectrometry approach. Results: We identified six CSF brain-specific proteins that significantly differentiated MS from controls (p < 0.05) and nine proteins that could predict disease course over the next decade. CAMK2A emerged as a biomarker candidate that could discriminate between MS and controls and could predict long-term disease progression. Conclusion: Targeted approaches to identify and quantify biomarkers associated with MS in the CSF may inform on long term MS outcomes. CAMK2A may be one of several candidates, warranting further exploration. [ABSTRACT FROM AUTHOR]

Published
2023
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10. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial

Author

Kappos, Ludwig, Fox, Robert J., Burcklen, Michel, Freedman, Mark S., Kubala Havrdova, Eva, Hennessy, Brian, Hohlfeld, Reinhard, Lublin, Fred, Montalban, Xavier, Pozzilli, Carlo, Scherz, Tatiana, D'Ambrosio, Daniele, Linscheid, Philippe, Vaclavkova, Andrea, Pirozek-Lawniczek, Magdalena, Kracker, Hilke, Sprenger, Till, and Universitat Autònoma de Barcelona

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Toluidines, Hydroxybutyrates, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, law, Internal medicine, Teriflunomide, Nitriles, medicine, Clinical endpoint, Humans, Immunologic Factors, 030212 general & internal medicine, Original Investigation, Expanded Disability Status Scale, business.industry, Multiple sclerosis, McDonald criteria, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Thiazoles, chemistry, Ponesimod, Tolerability, Crotonates, Disease Progression, Female, Neurology (clinical), Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

IMPORTANCE: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). OBJECTIVE: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P(1)) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity. INTERVENTIONS: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P(1) modulators and a follow-up period of 30 days. MAIN OUTCOMES AND MEASURES: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ–RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status. RESULTS: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P

Published
2021

11. Ocrelizumab treatment for relapsing-remitting multiple sclerosis after a suboptimal response to previous disease-modifying therapy: A nonrandomized controlled trial.

Author

Weinstock-Guttman, Bianca, Bermel, Robert, Cutter, Gary, Freedman, Mark S, Leist, Thomas P, Ma, Xiaoye, Kile, Deidre, Musch, Bruno, Reder, Anthony T, and Wolinsky, Jerry S

Subjects
MAGNETIC resonance imaging, MULTIPLE sclerosis, DISEASE relapse
Abstract

Background: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). Objective: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. Methods: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions. Results: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population (n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials. Conclusion: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed. [ABSTRACT FROM AUTHOR]

Published
2022
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12. Sodium intake and multiple sclerosis activity and progression in BENEFIT

Author

Fitzgerald, Kathryn C., Munger, Kassandra L., Hartung, Hans peter, Freedman, Mark S., Montalbã¡n, Xavier, Edan, Gilles, Wicklein, Eva maria, Radue, Ernst wilhelm, Kappos, Ludwig, Pohl, Christoph, Ascherio, Alberto, Strasser fuchs, S., Berger, T., Vass, K., Sindic, C., Dubois, B., Dive, D., Debruyne, J., Metz, L., Rice, G., Duquette, P., Lapierre, Y., Freedman, M., Traboulsee, A., O'Connor, P., Å touraä, P., Talab, R., Zapletalova, O., Kovaå™ova, I., Medova, E., Fiedler, J., Frederiksen, J., Brochet, B., Moreau, T., Vermersch, P., Pelletier, J., Edan, G., Clanet, M., Clavelou, P., Lebrun frenay, C., Gout, O., Kallela, M., Pirttila, T., Ruutiainen, J., Koivisto, K., Reunanen, M., Elovaara, I., Villringer, A., Altenkirch, H., Wessel, K., Hartung, H. . P., Steinke, W., Kã¶lmel, H., Oschmann, P., Diem, R., Dressel, A., Hoffmann, F., Baum, K., Jung, S., Petereit, H., Reske, D., Sailer, M., Kohler, J., Sommer, N., Hohlfeld, R., Henn, K. . H., Tumani, H., Gold, R., Rieckmann, P., Komoly, R., Gacs, G., Jakab, G., Csiba, L., Vecsei, L., Miller, A., Karussis, D., Chapman, J., Ghezzi, A., Gallo, P., Cosi, V., Durelli, L., Anten, B., Visser, L., Myhr, K. . M., Szczudlik, A., Selmaj, K., Stelmasiak, Z., Podemski, R., Maciejek, Z., Cunha, L., Sega jazbec, S., Montalban, X., Arbizu, T., Saiz, A., Barcena, J., Arroyo, R., Fernandez, O., Izquierdo, G., Casanova, B., Lycke, J., Kappos, L., Mattle, H., Beer, K., Coleman, R., Chataway, J., Riordan, J. O., Howell, S., COMI, GIANCARLO, Fitzgerald, Kathryn C., Munger, Kassandra L., Hartung, Hans peter, Freedman, Mark S., Montalbã¡n, Xavier, Edan, Gille, Wicklein, Eva maria, Radue, Ernst wilhelm, Kappos, Ludwig, Pohl, Christoph, Ascherio, Alberto, Strasser fuchs, S., Berger, T., Vass, K., Sindic, C., Dubois, B., Dive, D., Debruyne, J., Metz, L., Rice, G., Duquette, P., Lapierre, Y., Freedman, M., Traboulsee, A., O'Connor, P., Å touraä , P., Talab, R., Zapletalova, O., Kovaå ova, I., Medova, E., Fiedler, J., Frederiksen, J., Brochet, B., Moreau, T., Vermersch, P., Pelletier, J., Edan, G., Clanet, M., Clavelou, P., Lebrun frenay, C., Gout, O., Kallela, M., Pirttila, T., Ruutiainen, J., Koivisto, K., Reunanen, M., Elovaara, I., Villringer, A., Altenkirch, H., Wessel, K., Hartung, H. . P., Steinke, W., Kã¶lmel, H., Oschmann, P., Diem, R., Dressel, A., Hoffmann, F., Baum, K., Jung, S., Petereit, H., Reske, D., Sailer, M., Kohler, J., Sommer, N., Hohlfeld, R., Henn, K. . H., Tumani, H., Gold, R., Rieckmann, P., Komoly, R., Gacs, G., Jakab, G., Csiba, L., Vecsei, L., Miller, A., Karussis, D., Chapman, J., Ghezzi, A., Comi, Giancarlo, Gallo, P., Cosi, V., Durelli, L., Anten, B., Visser, L., Myhr, K. . M., Szczudlik, A., Selmaj, K., Stelmasiak, Z., Podemski, R., Maciejek, Z., Cunha, L., Sega jazbec, S., Montalban, X., Arbizu, T., Saiz, A., Barcena, J., Arroyo, R., Fernandez, O., Izquierdo, G., Casanova, B., Lycke, J., Kappos, L., Mattle, H., Beer, K., Coleman, R., Chataway, J., Riordan, J. O., and Howell, S.

Subjects
Adult, Male, Brain, Demyelinating Disease, Neuroimaging, Sodium, Dietary, Magnetic Resonance Imaging, Disability Evaluation, Young Adult, Neurology, Multiple Sclerosi, Disease Progression, Female, Neurology (clinical), Human, Interferon beta-1b
Abstract

Objective: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. Methods: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13–16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. Results: Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67–1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97–1.13; relative change in T2 lesion volume: −0.11, 95% CI = −0.25 to 0.04; change in EDSS: −0.01, 95% CI = −0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56–1.07). Results were similar in categorical analyses using quintiles. Interpretation: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20–29.

Published
2017
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13. Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years.

Author

Horáková, Dana, Boster, Aaron, Bertolotto, Antonio, Freedman, Mark S, Firmino*, Isabel, Cavalier, Steven J, Jacobs*, Alan K, Thangavelu*, Karthinathan, Daizadeh, Nadia, Poole*, Elizabeth M, Baker, Darren P, Margolin*, David H, and Ziemssen, Tjalf

Subjects
MULTIPLE sclerosis, ALEMTUZUMAB, BRAIN damage, DEFINITIONS, INTERFERONS, JOHN Cunningham virus
Abstract

Background: Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective: Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods: Patients (N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. Results: Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%–4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. Conclusions: The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression. ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553. [ABSTRACT FROM AUTHOR]

Published
2020
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14. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

Author

Hauser, Stephen L., Bar-Or, Amit, Comi, Giancarlo, Giovannoni, Gavin, Hartung, Hans-Peter, Hemmer, Bernhard, Lublin, Fred, Montalban, Xavier, Rammohan, Kottil W., Selmaj, Krzysztof, Traboulsee, Anthony, Wolinsky, Jerry S., Arnold, Douglas L., Klingelschmitt, Gaelle, Masterman, Donna, Fontoura, Paulo, Belachew, Shibeshih, Chin, Peter, Mairon, Nicole, Garren, Hideki, Kappos, Ludwig, And Opera Ii Clinical Investigators, Opera I., Reingold, Stephen C., Sandberg-Wollheim, Magnhild, Barkhof, Frederik, Dörmer, Thomas, Evans, Scott, Mcfarland, Henry F., Steiner, Israel, Yaldizli, Özgür, D Souza, Marcus, Andelova, Michaela, Rust, Heiko, Ballario, Carlos, Giannaula, Rolando, Reich, Edgardo Gabriel, Parratt, John, Eggers, Christian, Buyle, Maarten, Pesch, Vincent, Vanopdenbosch, Ludo, Carneiro, Denise, Friedrich, Mauricio, Longo, Alexandre Luiz, Genov, Krasimir, Ivanova, Sonya, Maslarov, Dimitar, Lilovski, Hristo, Staikov, Ivan, Cueto, German, Dufek, Michal, Havrdova, Eva, Novotna, Alena, Skoda, Ondrej, Talabova, Marika, Vachova, Marta, Gross-Paju, Katrin, Haldre, Sulev, Elovaara, Irina, Brochet, Bruno, Castelnovo, Giovanni, Clavelou, Pierre, Seze, Jerome, Debouverie, Marc, Braune, Stefan, Haas, Judith, Heidenreich, Fedor, Schwarz, Wolfgang, Siever, Arno, Urban, Peter Paul, Zettl, Uwe, Ziemann, Ulf, Ziemssen, Tjalf, Zipp, Frauke, Debreczeni, Robert, Rozsa, Csilla, Satori, Maria, Chapman, Joab, Ghezzi, Angelo, Perini, Paola, Pozzilli, Carlo, Kalnina, Jolanta, Millers, Andrejs, Budrys, Valmantas, Kizlaitiene, Rasa, Malciene, Lina, Vaitkus, Antanas, Castro Farfan, Guillermo, Gongora Rivera, Juan Fernando, Frequin, S. T. F. M., Gavidia Chucan, Jorge Martin, Perez Villegas, Julio, Pretell, Edwin Javier, Rodriguez Kadota, Liliana Elizabe, Fryze, Waldemar, Hertmanowska, Hanka, Maciejowski, Maciej, Opala, Grzegorz, Cerqueira, João, Arefieva, Elena, Maslova, Natalia, Odinak, Miroslav, Pankratov, Evgeny, Perfiliev, Semen, Poverennova, Irina, Sazonov, Denis, Shirshova, Elena, Sivertseva, Stella, Volkova, Larisa, Vorobyova, Olga, Knezevic, Zorica, Raicevic, Ranko, Vojinovic, Slobodan, Hancinova, Viera, Saffova, Patricia, Turcani, Peter, Vyletelka, Juraj, Coetzee, Christo C., Garcia-Merino, Antonio, Hernandez, Miguel A., Izquierdo Ayuso, Guillermo, Rodriguez Antigüedad, Alfredo, Gobbi, Claudio, Belal, Samir, Frih-Ayed, Mahbouba, Gouider, Riadh, Mrissa, Ridha, Sergii Moskovko, Sanotskyy, Yanosh, Sokolova, Larysa, Statinova, Olena, Voloshyna, Nataliya, Turner, Benjamin, Wilson, Martin, Applebee, Angela, Bandari, Daniel, Belkin, Martin, Birnbaum, Gary, Borresen, Thor, Boyd, James, Cascione, Mark, Cohan, Stanley, Cohen, Bruce, Conway, Jill, Cree, Bruce, Dihenia, Bhupesh, Dissin, Jonathan, Flitman, Stephen, Ford, Corey, Giancarlo, Thomas, Gold, Scott, Green, Barbara, Gwynn, Matthews, Honeycutt, David, Huddlestone, John, Klawiter, Eric, Kohrman, Bruce, Langer-Gould, Annette, Lava, Neil, Lindsey, William, Mitchell, Galen, Naismith, Robert, Nicolas, Joseph, Pardo, Gabriel, Patel, Malti, Porter, John A. H., Racke, Michael, Robertson, Derrick, Rossman, Howard, Schafer, John, Shubin, Richard, Singer, Barry, Smith, Charles, Suski, Valerie, Thrower, Ben, Wilson, Christopher, Wynn, Daniel, Zabad, Rana, Estol, Conrado J., Scarlatti, Annita, Alekseenko, Yuri, Fedulau, Aliaksandr, Kulesh, Sergey, Navumava, Halina, Willekens, Barbara, Alajbegovic, Azra, Sinanovic, Osman, Christo, Paulo, Papais Alvarenga, Regina Maria, Pereira Damasceno, Benito, Baldaranov, Dimo, Grigorova, Olga, Haralanov, Lyubomir, Milanova, Milena, Ayotte, Charles, Blevins, Gregg, Freedman, Mark, Grand Maison, François, Jacques, François, Yeung, Michael, Basic, Silvio, Hajnsek, Sanja, Janko-Labinac, Dolores, Kidjemet Piskac, Spomenka, Benesova, Yvonne, Hradilek, Pavel, Brassat, David, Edan, Gilles, Hautecoeur, Patrick, Moreau, Thibault, Papeix, Caroline, Tourbah, Ayman, Vukusic, Sandra, Aktas, Orhan, Berthele, Achim, Bodenschatz, Ralf, Foerch, Christian, Hohlfeld, Reinhard, Landefeld, Harald, Lang, Michael, Platten, Michael, Puzich, Reinhard, Schmidt, Stephan, Tubridy, Niall, Ardito, Bonaventura, Capra, Ruggero, Centonze, Diego, Crociani, Paola, Danni, Maura, Grimaldi, Luigi, Gusmaroli, Graziano, Mantegazza, Renato, Mirabella, Massimiliano, Uccelli, Antonio, Carbajal Ramirez, Angelica, Lopez Meza, Elmer Guillermo, Lopez Prieto, Juan Jose, Oropeza Alba, Jose Luis, Reyes-Morales, Sarug, San Juan Orta, Daniel, Myhr, Kjell Morten, Binek, Maciej, Czarnecki, Maciej, Klodowska-Duda, Gabriela, Stelmasiak, Zbigniew, Szczudlik, Andrzej, Tutaj, Andrzej, Belova, Anna, Dorogov, Nikolay, Fedyanin, Alexander, Khasanova, Dina, Makarov, Nikolay, Mishin, Gennadiy, Sherman, Mikhail, Skoromets, Alexander, Trushnikova, Tatiana, Donath, Vladimir, Dupejova, Beata, Gurcik, Ladislav, Arroyo, Rafael, Andres, Clara, Fernandez Fernandez, Oscar, Lainez Andrep, Jose Miguel, Martinez Gines, Maria Luisa, Martinez Rodriguez, Jose Enrique, Martinez Yelamos, Sergio, Oreja Guevara, Celia, Perez Sempere, Angel, Ramio, Luis, Ramo Tello, Cristina, Lycke, Jan, Olsson, Tomas, Roshanisefat, Homayoun, Sundström, Peter, Svenningsson, Anders, Akman Demir, Gulsen, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Karabudak, Rana, Siva, Aksel, Terzi, Murat, Yuceyar, Ayse Nur, Chmyr, Galyna, Goncharova, Yana, Kareta, Serhiy, Lutskiy, Igor, Harrower, Timothy, Hawkins, Clive, Pearson, Owen, Silber, Eli, Absher, John, Arnold, Thomas, Bass, Ann, Bernitsas, Evanthia, Braley, Tiffany, Calkwood, Jonathan, Carnes, Kenneth, Coyle, Patricia, Dunn, Jeffrey, Edwards, Keith, English, Jeffrey, Ferencz, Gerald, Fox, Edward, Frohman, Elliott, Gazda, Suzanne, Gitt, Jeffrey, Goodman, Andrew, Gross, Jeffrey, Hendin, Barry, Herrman, Craig, Hillen, Machteld, Huang, Deren, Hunter, Samuel, Hutton, George, Jacobs, Daniel, Keller, Bridget, Khan, Omar, Kister, Ilya, Krupp, Lauren, Lathi, Ellen, Lynch, Sharon, Miller, Tamara, Miravalle, Augusto, Omidvar, Omid, Perumal, Jai, Picone, Maryann, Rao, T. Hemanth, Repovic, Pavle, Riskind, Peter, Rowe, Vernon, Sheremata, William, Steingo, Brian, Twyman, Cary, Weisman, David, Wendt, Jeanette, Wray, Sibyl, Yapundich, Robert, Zarif, Myassar, Lääketieteen ja biotieteiden tiedekunta - Faculty of Medicine and Life Sciences, Tampere University, Hauser, S. L., Bar or, A., Comi, Giancarlo, Giovannoni, G., Hartung, H. . P., Hemmer, B., Lublin, F., Montalban, X., Rammohan, K. W., Selmaj, K., Traboulsee, A., Wolinsky, J. S., Arnold, D. L., Klingelschmitt, G., Masterman, D., Fontoura, P., Belachew, S., Chin, P., Mairon, N., Garren, H., Kappos, L., Universidade do Minho, Willekens, Barbara, and OPERA I and OPERA II Clinical Investigators

Subjects
0301 basic medicine, Male, Esclerosi múltiple, Adult, Antibodies, Monoclonal, Humanized, Antigens, CD20, B-Lymphocytes, Brain, Disease Progression, Female, Humans, Immunologic Factors, Infusions, Intravenous, Interferon-beta, Magnetic Resonance Imaging, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Recurrence, Medicine (all), Relapsing-Remitting, Gastroenterology, Medicina Clínica [Ciências Médicas], law.invention, 0302 clinical medicine, Immunologic Factor, Randomized controlled trial, law, Monoclonal, Clinical endpoint, Infusions, Intravenou, Immunologia, Humanized, Hazard ratio, B-Lymphocyte, General Medicine, Settore MED/26 - Neurologia, Intravenous, Neurotieteet - Neurosciences, medicine.drug, Human, medicine.medical_specialty, Infusions, Multiple Sclerosis, Immunology, Antibodies, Multiple sclerosis, 03 medical and health sciences, Internal medicine, medicine, CD20, Antigens, Ciências Médicas::Medicina Clínica, business.industry, Interferon beta-1a, medicine.disease, Confidence interval, Ocrelizumab, Interferon Beta-1a, Relapsing Multiple Sclerosis, 030104 developmental biology, Monoclonal antibodies, Human medicine, business, Anticossos monoclonals, 030217 neurology & neurosurgery
Abstract

BACKGROUND B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 mu g three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P, info:eu-repo/semantics/publishedVersion

Published
2017

15. Machine learning in secondary progressive multiple sclerosis: an improved predictive model for short-term disability progression.

Author

Law, Marco T. K., Traboulsee, Anthony L., Li, David K. B., Carruthers, Robert L., Freedman, Mark S., Kolind, Shanon H., and Tam, Roger

Abstract

Background Enhanced prediction of progression in secondary progressive multiple sclerosis (SPMS) could improve clinical trial design. Machine learning (ML) algorithms are methods for training predictive models with minimal human intervention. Objective To evaluate individual and ensemble model performance built using decision tree (DT)-based algorithms compared to logistic regression (LR) and support vector machines (SVMs) for predicting SPMS disability progression. Methods SPMS participants (n = 485) enrolled in a 2-year placebo-controlled (negative) trial assessing the efficacy of MBP8298 were classified as progressors if a 6-month sustained increase in Expanded Disability Status Scale (EDSS) (≥1.0 or ≥0.5 for a baseline of ≤5.5 or ≥6.0 respectively) was observed. Variables included EDSS, Multiple Sclerosis Functional Composite component scores, T2 lesion volume, brain parenchymal fraction, disease duration, age, and sex. Area under the receiver operating characteristic curve (AUC) was the primary outcome for model evaluation. Results Three DT-based models had greater AUCs (61.8%, 60.7%, and 60.2%) than independent and ensemble SVM (52.4% and 51.0%) and LR (49.5% and 51.1%). Conclusion SPMS disability progression was best predicted by non-parametric ML. If confirmed, ML could select those with highest progression risk for inclusion in SPMS trial cohorts and reduce the number of low-risk individuals exposed to experimental therapies. [ABSTRACT FROM AUTHOR]

Published
2019
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16. The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis.

Author

Cadavid, Diego, Kinch, Deborah, Lee, Sophia, Shang, Shulian, Mikol, Daniel, Sellebjerg, Finn, Cohen, Jeffrey A., Freedman, Mark S., Goldman, Myla D., Hartung, Hans-Peter, Havrdova, Eva, Jeffery, Douglas, Kapoor, Raj, and Miller, Aaron

Subjects
MULTIPLE sclerosis diagnosis, DISABILITY identification, DISEASE progression, MEASUREMENT of the anatomical extremities, COGNITIVE analysis, MULTIPLE sclerosis, PATIENTS
Abstract

Background: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. Objective: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. Methods: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm (n = 215) data, we analyzed disability progression using a novel progression endpoint, “EDSS-Plus,” defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. Results: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors’ times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. Conclusion: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression. [ABSTRACT FROM AUTHOR]

Published
2017
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17. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis.

Author

Kappos, Ludwig, De Stefano, Nicola, Freedman, Mark S., Cree, Bruce A. C., Radue, Ernst-Wilhelm, Sprenger, Till, Sormani, Maria Pia, Smith, Terence, Häring, Dieter A., Piani Meier, Daniela, and Tomic, Davorka

Subjects
MULTIPLE sclerosis treatment, DISEASE relapse, DISEASE remission, DISEASE progression, NEURODEGENERATION, FINGOLIMOD
Abstract

Background: ‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression. Objective: To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’) Methods: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%–1.2%). Results: At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01–4.41; p < 0.0001). Conclusion: NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies. [ABSTRACT FROM AUTHOR]

Published
2016
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18. Evaluating response to disease-modifying therapy in relapsing multiple sclerosis.

Author

Freedman, Mark S and Abdoli, Mohammad

Abstract

Despite the broadening range of available treatments, the response of multiple sclerosis patients to disease-modifying therapies remains quite heterogeneous, thus a scheme is required in order to flag individuals achieving a suboptimal treatment response, so that they may switch to a different, possibly more effective disease-modifying therapy. There are several treatment outcomes that can be defined as surrogate markers for continued treatment efficacy and can be used for optimizing disease-modifying therapy. As no single marker is validated, we must make use of all available potential surrogates to help predict the future course of the disease. Only by putting all of the outcome measures together can a true picture be derived that will indicate an optimal response to treatment. [ABSTRACT FROM AUTHOR]

Published
2015
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19. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

Author

Kappos, Ludwig, Freedman, Mark S, Polman, Chris H, Edan, Gilles, Hartung, Hans-Peter, Miller, David H, Montalbán, Xavier, Barkhof, Frederik, Radü, Ernst-Wilhelm, Metzig, Carola, Bauer, Lars, Lanius, Vivian, Sandbrink, Rupert, and Pohl, Christoph

Subjects
*INTERFERONS, *MULTIPLE sclerosis treatment, *CLINICAL trials, *DISEASE progression, *DEMYELINATION, *ANTINEOPLASTIC agents, *PATIENTS
Abstract

Summary: Background: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. Methods: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 μg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. Findings: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0·63, 95% CI 0·48–0·83; p=0·003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0·76, 0·52–1·11; p=0·177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. Interpretation: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. Funding: Bayer Schering Pharma. [Copyright &y& Elsevier]

Published
2009
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20. Recognizing and treating suboptimally controlled multiple sclerosis: steps toward regaining command.

Author

Freedman, Mark S., Cohen, Bruce, Dhib-Jalbut, Suhayl, Jeffery, Douglas, Reder, Anthony T., Sandberg-Wollheim, Magnhild, and Weinstock-Guttman, Bianca

Subjects
*MULTIPLE sclerosis, *NATALIZUMAB, *COMBINATION drug therapy, *TREATMENT failure
Abstract

The therapies available today for multiple sclerosis (MS) reduce but do not fully control disease activity. The objective of this article is to review the definitions of and treatments for suboptimally controlled MS and highlight the challenges faced by clinicians to increase awareness of recognizing and managing patients with suboptimally controlled MS. Published literature describing treatment failure, treatment optimization paradigms or algorithms, clinical studies of therapies in patients with suboptimally controlled MS, or case reports of management of patients with suboptimally controlled MS were identified from searches of EMBASE and MEDLINE. This was supplemented with case reports and discussions from an expert panel meeting of MS specialists focused on the diagnosis and treatment of suboptimally controlled MS. Several groups have created recommendations for evaluating suboptimal response to disease-modifying drugs (DMDs) in MS. Currently no robust evidence-based data exist to guide treatment decisions in patients who have suboptimal response to a particular therapy. In the absence of data, several treatment paradigms for suboptimally controlled MS have been proposed using a step therapy or platform therapy approach. Therapy modifications require consideration of disease- and patient-specific factors while accounting for the risk-benefit profile of the agent(s). Unapproved drugs and combination therapies should be reserved as agents of last resort because of the experimental nature of these treatments. In the absence of evidence-based data, identifying and treating MS patients with suboptimal response to the available platform therapies remains challenging. Developing algorithms able to quantify breakthrough disease activity and suboptimal response to DMDs in individual MS patients remains an important target for the MS community. Consideration should be given for all reasons why a particular DMD may not be working for a given patient and for the use of an individualized step therapy. [ABSTRACT FROM AUTHOR]

Published
2009
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21. A Physician-Completed Digital Tool for Evaluating Disease Progression (Multiple Sclerosis Progression Discussion Tool): Validation Study.

Author

Ziemssen, Tjalf, Piani-Meier, Daniela, Bennett, Bryan, Johnson, Chloe, Tinsley, Katie, Trigg, Andrew, Hach, Thomas, Dahlke, Frank, Tomic, Davorka, Tolley, Chloe, and Freedman, Mark S

Subjects
MULTIPLE sclerosis, DISEASE progression, RECEIVER operating characteristic curves, INTRACLASS correlation, INTER-observer reliability
Abstract

Background: Defining the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) can be challenging and delayed. A digital tool (MSProDiscuss) was developed to facilitate physician-patient discussion in evaluating early, subtle signs of multiple sclerosis (MS) disease progression representing this transition.Objective: This study aimed to determine cut-off values and corresponding sensitivity and specificity for predefined scoring algorithms, with or without including Expanded Disability Status Scale (EDSS) scores, to differentiate between RRMS and SPMS patients and to evaluate psychometric properties.Methods: Experienced neurologists completed the tool for patients with confirmed RRMS or SPMS and those suspected to be transitioning to SPMS. In addition to age and EDSS score, each patient's current disease status (disease activity, symptoms, and its impacts on daily life) was collected while completing the draft tool. Receiver operating characteristic (ROC) curves determined optimal cut-off values (sensitivity and specificity) for the classification of RRMS and SPMS.Results: Twenty neurologists completed the draft tool for 198 patients. Mean scores for patients with RRMS (n=89), transitioning to SPMS (n=47), and SPMS (n=62) were 38.1 (SD 12.5), 55.2 (SD 11.1), and 69.6 (SD 12.0), respectively (P<.001, each between-groups comparison). Area under the ROC curve (AUC) including and excluding EDSS were for RRMS (including) AUC 0.91, 95% CI 0.87-0.95, RRMS (excluding) AUC 0.88, 95% CI 0.84-0.93, SPMS (including) AUC 0.91, 95% CI 0.86-0.95, and SPMS (excluding) AUC 0.86, 95% CI 0.81-0.91. In the algorithm with EDSS, the optimal cut-off values were ≤51.6 for RRMS patients (sensitivity=0.83; specificity=0.82) and ≥58.9 for SPMS patients (sensitivity=0.82; specificity=0.84). The optimal cut-offs without EDSS were ≤46.3 and ≥57.8 and resulted in similar high sensitivity and specificity (0.76-0.86). The draft tool showed excellent interrater reliability (intraclass correlation coefficient=.95).Conclusions: The MSProDiscuss tool differentiated RRMS patients from SPMS patients with high sensitivity and specificity. In clinical practice, it may be a useful tool to evaluate early, subtle signs of MS disease progression indicating the evolution of RRMS to SPMS. MSProDiscuss will help assess the current level of progression in an individual patient and facilitate a more informed physician-patient discussion. [ABSTRACT FROM AUTHOR]

Published
2020
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22. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

Author

Lublin, Fred, Miller, David H., Freedman, Mark S., Cree, Bruce A. C., Wolinsky, Jerry S., Weiner, Howard, Lubetzki, Catherine, Hartung, Hans-Peter, Montalban, Xavier, Uitdehaag, Bernard M. J., Merschhemke, Martin, Bingbing Li, Putzki, Norman, Liu, Fonda C., Häring, Dieter A., Kappos, Ludwig, Li, Bingbing, and INFORMS study investigators

Subjects
*FINGOLIMOD, *MULTIPLE sclerosis, *MYELIN sheath diseases, *SPHINGOSINE, *GADOLINIUM, *COMPARATIVE studies, *DOSE-effect relationship in pharmacology, *IMMUNOSUPPRESSIVE agents, *RESEARCH methodology, *MEDICAL cooperation, *ORAL drug administration, *RESEARCH, *EVALUATION research, *RANDOMIZED controlled trials, *TREATMENT effectiveness, *BLIND experiment, *DISEASE progression
Abstract

Background: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis.Methods: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed.Findings: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%).Interpretation: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis.Funding: Novartis Pharma AG. [ABSTRACT FROM AUTHOR]

Published
2016
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23. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

Author

Cree, Bruce A C, Cutter, Gary, Wolinsky, Jerry S, Freedman, Mark S, Comi, Giancarlo, Giovannoni, Gavin, Hartung, Hans-Peter, Arnold, Douglas, Kuhle, Jens, Block, Valerie, Munschauer, Frederick E, Sedel, Frédéric, Lublin, Fred D, and SPI2 investigative teams

Subjects
*MULTIPLE sclerosis, *BIOTIN, *WALKING speed, *PLACEBOS, *CELL physiology, *DISEASE progression, *RESEARCH, *RESEARCH methodology, *EVALUATION research, *MEDICAL cooperation, *VITAMIN B complex, *SEVERITY of illness index, *COMPARATIVE studies, *BLIND experiment
Abstract

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort.Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29).Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies.Interpretation: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis.Funding: MedDay Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Published
2020
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24. Uncertain BENEFIT of early interferon beta-1b treatment

Author

Pittock, Sean J, Kappos, Ludwig, Freedman, Mark S, Polman, Chris H, Edan, Gilles, Hartung, Hans-Peter, Miller, David H, Montalbán, Xavier, Barkhof, Frederik, Radü, Ernst-Wilhelm, Metzig, Carola, Bauer, Lars, Lanius, Vivian, Sandbrink, Rupert, Pohl, Christoph, and BENEFIT Study Group

Subjects
*THERAPEUTIC use of interferons, *CLINICAL trials, *COMPARATIVE studies, *FUNCTIONAL assessment, *MAGNETIC resonance imaging, *RESEARCH methodology, *MEDICAL cooperation, *MULTIPLE sclerosis, *RESEARCH, *RISK assessment, *STATISTICS, *DATA analysis, *EVALUATION research, *RANDOMIZED controlled trials, *PROPORTIONAL hazards models, *BLIND experiment, *DISEASE progression, *KAPLAN-Meier estimator
Abstract

Background: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression.Methods: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211.Findings: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0.63, 95% CI 0.48-0.83; p=0.003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, 0.52-1.11; p=0.177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b.Interpretation: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes.Funding: Bayer Schering Pharma. [ABSTRACT FROM AUTHOR]

Published
2009
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25. Management of relapsing–remitting multiple sclerosis in Latin America: Practical recommendations for treatment optimization.

Author

Correale, Jorge, Abad, Patricio, Alvarenga, Regina, Alves-Leon, Soniza, Armas, Elizabeth, Barahona, Jorge, Buzó, Ricardo, Corona, Teresa, Cristiano, Edgardo, Gracia, Fernando, Bonitto, Juan García, Macías, Miguel Angel, Soto, Arnoldo, Vizcarra, Darwin, and Freedman, Mark S.

Subjects
*MULTIPLE sclerosis treatment, *LATIN Americans, *EPIDEMIOLOGY, *DISEASE progression, *FOLLOW-up studies (Medicine), *MAGNETIC resonance imaging, *DISEASES
Abstract

Abstract: The Latin American MS Experts' Forum has developed practical recommendations on the initiation and optimization of disease-modifying therapies in patients with relapsing–remitting multiple sclerosis (RRMS). The recommendations reflect the unique epidemiology of MS and the clinical practice environment in Latin American countries. Treatment response may be evaluated according to changes in relapses; progression, as assessed by the Expanded Disability Status Scale and the Timed 25-foot Walk; and lesion number on magnetic resonance imaging. Follow-up assessments are recommended every six months, or annually for stable patients. Cognitive function should be evaluated in all RRMS patients at baseline and annually thereafter. These recommendations are intended to assist clinicians in Latin America in developing a rational approach to treatment selection and sequencing for their RRMS patients. [Copyright &y& Elsevier]

Published
2014
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26. Ofatumumab versus Teriflunomide in Multiple Sclerosis

Author

Hauser S. L., Bar-Or A., Cohen J. A., Comi G., Correale J., Coyle P. K., Cross A. H., de Seze J., Leppert D., Montalban X., Selmaj K., Wiendl H., Kerloeguen C., Willi R., Li B., Kakarieka A., Tomic D., Goodyear A., Pingili R., Haring D. A., Ramanathan K., Merschhemke M., Kappos L., Stephen L Hauser, Ludwig Kappos, Amit Bar-Or, Jeffrey A Cohen, Giancarlo Comi, Jorge Correale, Patricia K Coyle, Anne Cross, Jerome de Seze, Xavier Montalban, Krzysztof Selmaj, Heinz Wiendl, Stephen C Reingold, Garry R Cutter, Thomas Doerner, Hans-Peter Hartung, Per Soelberg Sørensen, Israel Steiner, Jerry S Wolinsky, Carlos Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana Liwacki, Jeannette Lechner-Scott, John Parratt, Suzanne Hodgkinson, Eva-Maria Maida, Fritz Leutmezer, Barbara Willekens, Bart Van Wijmeersch, Guy Laureys, Jo Caekebeke, Karine Geens, Ludo Vanopdenbosch, Olivier Deryck, Valerie Delvaux, Vincent Van Pesch, Ivan Milanov, Ivaylo Tarnev, Lyubomir Haralanov, Maria Manova Slavova, Penko Shotekov, Francois Emond, Francois Grandmaison, Francois Jacques, Liesly Lee, Marie Sarah Gagne Brosseau, Mark Freedman, Martin Cloutier, Robert Carruthers, Sarah Morrow, Yves Lapierre, Anton Vladic, Hana Bokun, Igor Antoncic, Marija Bosnjak Pasic, Mario Habek, Silva Butkovic Soldo, Vladimira Vuletic, Alena Martinkova, Eva Meluzinova, Ivana Stetkarova, Jan Mares, Jolana Markova, Marta Vachova, Martin Valis, Michaela Tyblova, Michal Dufek, Ondrej Skoda, Pavel Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina Svendsen, Mads Ravnborg, Peter Vestergaard Rasmussen, Katrin Gross-Paju, Sulev Haldre, Juha Pekka Eralinna, Marja-Liisa Sumelahti, Bruno Brochet, Celine Louapre, Christine Lebrun-Frenay, David Axel Laplaud, Gilles Edan, Giovanni Castelnovo, Marc Debouverie, Patrick Vermersch, Pierre Clavelou, Pierre Labauge, Achim Berthele, Aiden Haghikia, Anselm Kornhuber, Arnfin Bergmann, Benedikt Frank, Birte Elias-Hamp, Bjoern Tackenberg, Brigitte Wildemann, Erik Strauss, Eugen Schlegel, Florian Then Bergh, Gereon Nelles, Hayrettin Tumani, Karl-Otto Sigel, Martin Stangel, Matthias Boehringer, Olaf Martin Hoffmann, Patrick Oschmann, Reinhard Hohlfeld, Silke Walter, Sylvia Menck, Till Sprenger, Tjalf Ziemssen, Veit Ulrich Becker, Vera Straeten, Konstantinos Kilidireas, Konstantinos Voumvourakis, Nikolaos Fakas, Nikolaos Grigoriadis, Agnes Koves, Csilla Rozsa, Krisztina Kovacs, Laszlo Vecsei, Satori Maria, Zita Biro, Anshu Rohatgi, Dheeraj Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha Pandit, Meena Angamuthu Kanikannan, Pahari Ghosh, Rahul Chakor, Rahul Kulkarni, Roopkumar Gursahani, Sangeeta Ravat, Srinivasa Rangasetty, Suresh Kumar, Alla Shifrin, Arnon Karni, Radi Shahien, Ron Milo, Antonio Uccelli, Carlo Pozzilli, Francesco Sacca, Giacomo Lus, Girolama Alessandra Marfia, Laura Brambilla, Marco Salvetti, Massimo Filippi, Mauro Zaffaroni, Paolo Gallo, Silvia Rossi, Simona Bonavita, Valeria Studer, Andrejs Millers, Guntis Karelis, Jolanta Kalnina, Dalia Mickeviciene, Rasa Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs Wokke, Bob W Van Oosten, Peter Van Domburg, Raymond Hupperts, Rogier Q Hintzen, Astrid Edland, Cesar Castaneda, Julio Perez, Martin Gavidia, Andrzej Wiak, Bartosz Karaszewski, Elzbieta Jasinska, Halina Bartosik Psujek, Iwona Jastrzebska, Jaroslaw Slawek, Maciej Maciejowski, Miroslaw Dziki, Monika Adamczyk Sowa, Robert Bonek, Waldemar Fryze, Ana Martins Da Silva, Angela Timoteo, Antonio Vasco Salgado, Carlos Capela, Carlos Veira, Filipe Correia, Joao Cerqueira, Joao De Sa, Livia De Sousa, Raquel Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon Kurca, Georgi Krastev, Miroslav Brozman, Peter Koleda, Peter Turcani, Peter Valkovic, Viera Hancinova, Vladimir Donath, Chris Retief, Michael Isaacs, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik Piehl, Jan Lycke, Chiara Zecca, Tobias Derfuss, Thy-Sheng Lin, Somsak Tiamkao, Ayse Nur Yuceyar, Aysun Soysal, Belgin Petek Balci, Cavit Boz, Husnu Efendi, Murat Terzi, Serhan Sevim, Serkan Ozakbas, Andrew Gale, Ben Turner, David Barnes, David Paling, Eli Silber, James Overell, Matthew Craner, Aaron Carlson, Adam Wolff, Adaeze Onuoha, Adnan Subei, Ahmad Ata, Aimee Borazanci, Akram Dastagir, Alberto Vasquez, Alison Brooke Allen, Andrew P Keegan, Angel Carrasco, Angel R Chinea Martinez, Ann Bass, Annette Okai, April Erwin, Ariel Antezana-Antezana, Barbara Green, Bharathy E Sundaram, Bhupendra Khatri, Bhupesh Dihenia, Bogdan Gheorghiu, Brian Costell, Brian Steingo, Bruce L Hughes, Carrie M Hersh, Christopher Laganke, Christopher Luzzio, Corey Ford, Craig Edward Herrman, Craig Senzon, Cynthia Huffman, Daniel R Wynn, David D O Bear, David Lesch, David H Mattson, David Weisman, Deborah A Burke, Dennis W Dietrich, Deren Huang, Derrick Robertson, Djamchid Lotfi, Don Joseph Alfonso, Dusan Stefoski, Edward J Fox, Emily Pharr, Enrique Alvarez, Evanthia Bernitsas, Faria Amjad, Gabriel Pardo, Geoffrey Eubank, Gerald Mcintosh, Giles F Crowell, Hemanth Rao, J Michael Hemphill, Jack H Florin, Jacqueline Nicholas, James Napier, James Scott, Jason M Silversteen, Javier Vasallo, Jean-Raphael Schneider, Jeanette Wendt, Jeffrey Cohen, Jeffrey Gross, Jeffrey Groves, Jeffrey Kaplan, Jessica Stulc, Joanna A Cooper, John Foley, John Scagnelli, Jonathan C Calkwood, Jose Pizarro Otero, Jose Rafecas, Joshua Katz, Juliette S Saad, Katherine Standley, Keith Edwards, Kenneth Sharlin, Khurram Bashir, Kimberly Wagner, Kore Liow, Larry Lee Blankenship Jr, Laszlo Mate, Liliana Montoya, Lon D Lynn, Mark Agius, Mark Cascione, Mark Allan Goldstein, Mark Janicki, Martin R Bialow, Mary Denise Hughes, Matthew J Baker, Michelle Apperson, Michelle B Kuczma, M Mateo Paz Soldan, Mirela Cerghet, Nathaniel Robb Whaley, Paul K Winner, Pavle Repovic, Praful Kelkar, Romero Rekha Pillai, Ricardo Ayala, Richard Sater, Randall Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert Naismith, Ronald S Murray, Samuel Hunter, Sara Qureshi, Sharon Lynch, Sibyl Wray, Silvia R Delgado, Stacy Donlon, Stanley Cohan, Stanya Smith, Stuart James Shafer, Susan Azalone, Susan Hibbs, Tamara A Miller, Thomas Giancarlo, Troy Desai, Varun K Saxena, Virginia Simnad, William David Honeycutt, William Logan, William E McElveen, William Wagner, University of California [San Francisco] (UCSF), University of California, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Cleveland Clinic, IRCCS Ospedale San Raffaele [Milan, Italy], Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Vall d'Hebron University Hospital [Barcelona], University of Warmia and Mazury [Olsztyn], University of Münster, Novartis Pharma S.A.S., Novartis Pharmaceuticals, University of Basel (Unibas), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Willekens, Barbara, ASCLEPIOS I and ASCLEPIOS II Trial Groups, Hauser, S. L., Bar-Or, A., Cohen, J. A., Comi, G., Correale, J., Coyle, P. K., Cross, A. H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Haring, D. A., Ramanathan, K., Merschhemke, M., Kappos, L., Asclepios, I and ASCLEPIOS II Trial Group, Filippi, M, L Hauser, Stephen, Kappos, Ludwig, Bar-Or, Amit, A Cohen, Jeffrey, Comi, Giancarlo, Correale, Jorge, K Coyle, Patricia, Cross, Anne, de Seze, Jerome, Montalban, Xavier, Selmaj, Krzysztof, Wiendl, Heinz, C Reingold, Stephen, R Cutter, Garry, Doerner, Thoma, Hartung, Hans-Peter, Soelberg Sørensen, Per, Steiner, Israel, S Wolinsky, Jerry, Ballario, Carlo, Calvo Vildoso, Christian, Gustavo Jose, Jorge, Haydee Deri, Norma, Liwacki, Susana, Lechner-Scott, Jeannette, Parratt, John, Hodgkinson, Suzanne, Maida, Eva-Maria, Leutmezer, Fritz, Van Wijmeersch, Bart, Laureys, Guy, Caekebeke, Jo, Geens, Karine, Vanopdenbosch, Ludo, Deryck, Olivier, Delvaux, Valerie, Van Pesch, Vincent, Milanov, Ivan, Tarnev, Ivaylo, Haralanov, Lyubomir, Manova Slavova, Maria, Shotekov, Penko, Emond, Francoi, Grandmaison, Francoi, Jacques, Francoi, Lee, Liesly, Sarah Gagne Brosseau, Marie, Freedman, Mark, Cloutier, Martin, Carruthers, Robert, Morrow, Sarah, Lapierre, Yve, Vladic, Anton, Bokun, Hana, Antoncic, Igor, Bosnjak Pasic, Marija, Habek, Mario, Butkovic Soldo, Silva, Vuletic, Vladimira, Martinkova, Alena, Meluzinova, Eva, Stetkarova, Ivana, Mares, Jan, Markova, Jolana, Vachova, Marta, Valis, Martin, Tyblova, Michaela, Dufek, Michal, Skoda, Ondrej, Hradilek, Pavel, Voldsgaard Jensen, Ana, Hvilsted Nielsen, Helle, Svendsen, Kristina, Ravnborg, Mad, Vestergaard Rasmussen, Peter, Gross-Paju, Katrin, Haldre, Sulev, Pekka Eralinna, Juha, Sumelahti, Marja-Liisa, Brochet, Bruno, Louapre, Celine, Lebrun-Frenay, Christine, Axel Laplaud, David, Edan, Gille, Castelnovo, Giovanni, Debouverie, Marc, Vermersch, Patrick, Clavelou, Pierre, Labauge, Pierre, Berthele, Achim, Haghikia, Aiden, Kornhuber, Anselm, Bergmann, Arnfin, Frank, Benedikt, Elias-Hamp, Birte, Tackenberg, Bjoern, Wildemann, Brigitte, Strauss, Erik, Schlegel, Eugen, Then Bergh, Florian, Nelles, Gereon, Tumani, Hayrettin, Sigel, Karl-Otto, Stangel, Martin, Boehringer, Matthia, Martin Hoffmann, Olaf, Oschmann, Patrick, Hohlfeld, Reinhard, Walter, Silke, Menck, Sylvia, Sprenger, Till, Ziemssen, Tjalf, Ulrich Becker, Veit, Straeten, Vera, Kilidireas, Konstantino, Voumvourakis, Konstantino, Fakas, Nikolao, Grigoriadis, Nikolao, Koves, Agne, Rozsa, Csilla, Kovacs, Krisztina, Vecsei, Laszlo, Maria, Satori, Biro, Zita, Rohatgi, Anshu, Khurana, Dheeraj, Durai Pandian, Jeyaraj, Dev Mukherji, Joy, Pandit, Lekha, Angamuthu Kanikannan, Meena, Ghosh, Pahari, Chakor, Rahul, Kulkarni, Rahul, Gursahani, Roopkumar, Ravat, Sangeeta, Rangasetty, Srinivasa, Kumar, Suresh, Shifrin, Alla, Karni, Arnon, Shahien, Radi, Milo, Ron, Uccelli, Antonio, Pozzilli, Carlo, Sacca, Francesco, Lus, Giacomo, Alessandra Marfia, Girolama, Brambilla, Laura, Salvetti, Marco, Filippi, Massimo, Zaffaroni, Mauro, Gallo, Paolo, Rossi, Silvia, Bonavita, Simona, Studer, Valeria, Millers, Andrej, Karelis, Gunti, Kalnina, Jolanta, Mickeviciene, Dalia, Kizlaitiene, Rasa, Carbajal Ramirez, Angelica, Jose Lopez Prieto, Juan, Wokke, Beatrij, W Van Oosten, Bob, Van Domburg, Peter, Hupperts, Raymond, Q Hintzen, Rogier, Edland, Astrid, Castaneda, Cesar, Perez, Julio, Gavidia, Martin, Wiak, Andrzej, Karaszewski, Bartosz, Jasinska, Elzbieta, Bartosik Psujek, Halina, Jastrzebska, Iwona, Slawek, Jaroslaw, Maciejowski, Maciej, Dziki, Miroslaw, Adamczyk Sowa, Monika, Bonek, Robert, Fryze, Waldemar, Martins Da Silva, Ana, Timoteo, Angela, Vasco Salgado, Antonio, Capela, Carlo, Veira, Carlo, Correia, Filipe, Cerqueira, Joao, De Sa, Joao, De Sousa, Livia, Gouveia, Raquel, Sergeevna Agafina, Alina, Naumovna Belova, Anna, Viktorovich Sazonov, Deni, Pokhabov, Dmitry, Igorevna Kairbekova, Ekaterina, Gennadievna Arefieva, Elena, Axatovich Khabirov, Farit, Vyacheslavovich Litvinenko, Igor, Stolyarov, Igor, Aleksandrovna Sokolova, Irina, Ivanovna Volkova, Larisa, Vafaevna Davydovskaya, Maria, Nikolaevna Zaharova, Maria, Alekseevna Malkova, Nadezhda, Agafonovna Totolyan, Natalia, Vasilievich Dorogov, Nikolay, Anatolievna Sivertseva, Stella, Kurca, Egon, Krastev, Georgi, Brozman, Miroslav, Koleda, Peter, Turcani, Peter, Valkovic, Peter, Hancinova, Viera, Donath, Vladimir, Retief, Chri, Isaacs, Michael, Saiz Hinarejos, Albert, Rodriguez Antigüedad, Alfredo, Casanova Estruch, Bonaventura, Oreja-Guevara, Celia, Reig Rosello, Gemma, Carlos Alvarez Cermeño, Jose, Martinez Rodriguez, Jose, Meca Lallana, Jose, Antonio Garcia Merino, Juan, Forero Diaz, Lucia, Costa Frossard Franca, Lucienne, Querol Gutierrez, Lui, Ramio Torrenta, Llui, Serrano Castro, Pedro, Arroyo Gonzalez, Rafael, Eichau Madueño, Sara, Martinez Yelamos, Sergio, Castillo Trivino, Tamara, Meca Lallana, Virgina, Montalban Gairin, Xaviere, Piehl, Fredrik, Lycke, Jan, Zecca, Chiara, Derfuss, Tobia, Lin, Thy-Sheng, Tiamkao, Somsak, Nur Yuceyar, Ayse, Soysal, Aysun, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Terzi, Murat, Sevim, Serhan, Ozakbas, Serkan, Gale, Andrew, Turner, Ben, Barnes, David, Paling, David, Silber, Eli, Overell, Jame, Craner, Matthew, Carlson, Aaron, Wolff, Adam, Onuoha, Adaeze, Subei, Adnan, Ata, Ahmad, Borazanci, Aimee, Dastagir, Akram, Vasquez, Alberto, Brooke Allen, Alison, P Keegan, Andrew, Carrasco, Angel, R Chinea Martinez, Angel, Bass, Ann, Okai, Annette, Erwin, April, Antezana-Antezana, Ariel, Green, Barbara, E Sundaram, Bharathy, Khatri, Bhupendra, Dihenia, Bhupesh, Gheorghiu, Bogdan, Costell, Brian, Steingo, Brian, L Hughes, Bruce, M Hersh, Carrie, Laganke, Christopher, Luzzio, Christopher, Ford, Corey, Edward Herrman, Craig, Senzon, Craig, Huffman, Cynthia, R Wynn, Daniel, O Bear, David D, Lesch, David, H Mattson, David, Weisman, David, A Burke, Deborah, W Dietrich, Denni, Huang, Deren, Robertson, Derrick, Lotfi, Djamchid, Joseph Alfonso, Don, Stefoski, Dusan, J Fox, Edward, Pharr, Emily, Alvarez, Enrique, Bernitsas, Evanthia, Amjad, Faria, Pardo, Gabriel, Eubank, Geoffrey, Mcintosh, Gerald, F Crowell, Gile, Rao, Hemanth, Michael Hemphill, J, H Florin, Jack, Nicholas, Jacqueline, Napier, Jame, Scott, Jame, M Silversteen, Jason, Vasallo, Javier, Schneider, Jean-Raphael, Wendt, Jeanette, Cohen, Jeffrey, Gross, Jeffrey, Groves, Jeffrey, Kaplan, Jeffrey, Stulc, Jessica, A Cooper, Joanna, Foley, John, Scagnelli, John, C Calkwood, Jonathan, Pizarro Otero, Jose, Rafecas, Jose, Katz, Joshua, S Saad, Juliette, Standley, Katherine, Edwards, Keith, Sharlin, Kenneth, Bashir, Khurram, Wagner, Kimberly, Liow, Kore, Lee Blankenship Jr, Larry, Mate, Laszlo, Montoya, Liliana, D Lynn, Lon, Agius, Mark, Cascione, Mark, Allan Goldstein, Mark, Janicki, Mark, R Bialow, Martin, Denise Hughes, Mary, J Baker, Matthew, Apperson, Michelle, B Kuczma, Michelle, Mateo Paz Soldan, M, Cerghet, Mirela, Robb Whaley, Nathaniel, K Winner, Paul, Repovic, Pavle, Kelkar, Praful, Rekha Pillai, Romero, Ayala, Ricardo, Sater, Richard, Trudell, Randall, Fairborn Armstrong, Robert, Thomas Nahouraii, Robert, Naismith, Robert, S Murray, Ronald, Hunter, Samuel, Qureshi, Sara, Lynch, Sharon, Wray, Sibyl, R Delgado, Silvia, Donlon, Stacy, Cohan, Stanley, Smith, Stanya, James Shafer, Stuart, Azalone, Susan, Hibbs, Susan, A Miller, Tamara, Giancarlo, Thoma, Desai, Troy, K Saxena, Varun, Simnad, Virginia, David Honeycutt, William, Logan, William, E McElveen, William, Wagner, William, Stephen, L Hauser, Ludwig, Kappo, Amit, Bar-Or, Jeffrey, A Cohen, Giancarlo, Comi, Jorge, Correale, Patricia, K Coyle, Anne, Cro, Jerome de Seze, Xavier, Montalban, Krzysztof, Selmaj, Heinz, Wiendl, Stephen, C Reingold, Garry, R Cutter, Thomas, Doerner, Hans-Peter, Hartung, Per Soelberg Sørensen, Israel, Steiner, Jerry, S Wolinsky, Carlos, Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana, Liwacki, Jeannette, Lechner-Scott, John, Parratt, Suzanne, Hodgkinson, Eva-Maria, Maida, Fritz, Leutmezer, Barbara, Willeken, Bart Van Wijmeersch, Guy, Laurey, Karine, Geen, Ludo, Vanopdenbosch, Olivier, Deryck, Valerie, Delvaux, Vincent Van Pesch, Ivan, Milanov, Ivaylo, Tarnev, Lyubomir, Haralanov, Maria Manova Slavova, Penko, Shotekov, Francois, Emond, Francois, Grandmaison, Francois, Jacque, Liesly, Lee, Marie Sarah Gagne Brosseau, Mark, Freedman, Martin, Cloutier, Robert, Carruther, Sarah, Morrow, Yves, Lapierre, Anton, Vladic, Hana, Bokun, Igor, Antoncic, Marija Bosnjak Pasic, Mario, Habek, Silva Butkovic Soldo, Vladimira, Vuletic, Alena, Martinkova, Eva, Meluzinova, Ivana, Stetkarova, Jan, Mare, Jolana, Markova, Marta, Vachova, Martin, Vali, Michaela, Tyblova, Michal, Dufek, Ondrej, Skoda, Pavel, Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina, Svendsen, Mads, Ravnborg, Peter Vestergaard Rasmussen, Katrin, Gross-Paju, Sulev, Haldre, Juha Pekka Eralinna, Marja-Liisa, Sumelahti, Bruno, Brochet, Celine, Louapre, Christine, Lebrun-Frenay, David Axel Laplaud, Gilles, Edan, Giovanni, Castelnovo, Marc, Debouverie, Patrick, Vermersch, Pierre, Clavelou, Pierre, Labauge, Achim, Berthele, Aiden, Haghikia, Anselm, Kornhuber, Arnfin, Bergmann, Benedikt, Frank, Birte, Elias-Hamp, Bjoern, Tackenberg, Brigitte, Wildemann, Erik, Strau, Eugen, Schlegel, Florian Then Bergh, Gereon, Nelle, Hayrettin, Tumani, Karl-Otto, Sigel, Martin, Stangel, Matthias, Boehringer, Olaf Martin Hoffmann, Patrick, Oschmann, Reinhard, Hohlfeld, Silke, Walter, Sylvia, Menck, Till, Sprenger, Tjalf, Ziemssen, Veit Ulrich Becker, Vera, Straeten, Konstantinos, Kilidirea, Konstantinos, Voumvouraki, Nikolaos, Faka, Nikolaos, Grigoriadi, Agnes, Kove, Csilla, Rozsa, Krisztina, Kovac, Laszlo, Vecsei, Satori, Maria, Zita, Biro, Anshu, Rohatgi, Dheeraj, Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha, Pandit, Meena Angamuthu Kanikannan, Pahari, Ghosh, Rahul, Chakor, Rahul, Kulkarni, Roopkumar, Gursahani, Sangeeta, Ravat, Srinivasa, Rangasetty, Suresh, Kumar, Alla, Shifrin, Arnon, Karni, Radi, Shahien, Ron, Milo, Antonio, Uccelli, Carlo, Pozzilli, Sacca', Francesco, Giacomo, Lu, Girolama Alessandra Marfia, Laura, Brambilla, Marco, Salvetti, Massimo, Filippi, Mauro, Zaffaroni, Paolo, Gallo, Silvia, Rossi, Simona, Bonavita, Valeria, Studer, Andrejs, Miller, Guntis, Kareli, Jolanta, Kalnina, Dalia, Mickeviciene, Rasa, Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs, Wokke, Bob, W Van Oosten, Peter Van Domburg, Raymond, Huppert, Rogier, Q Hintzen, Astrid, Edland, Cesar, Castaneda, Julio, Perez, Martin, Gavidia, Andrzej, Wiak, Bartosz, Karaszewski, Elzbieta, Jasinska, Halina Bartosik Psujek, Iwona, Jastrzebska, Jaroslaw, Slawek, Maciej, Maciejowski, Miroslaw, Dziki, Monika Adamczyk Sowa, Robert, Bonek, Waldemar, Fryze, Ana Martins Da Silva, Angela, Timoteo, Antonio Vasco Salgado, Carlos, Capela, Carlos, Veira, Filipe, Correia, Joao, Cerqueira, Joao De Sa, Livia De Sousa, Raquel, Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry, Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor, Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon, Kurca, Georgi, Krastev, Miroslav, Brozman, Peter, Koleda, Peter, Turcani, Peter, Valkovic, Viera, Hancinova, Vladimir, Donath, Chris, Retief, Michael, Isaac, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia, Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik, Piehl, Jan, Lycke, Chiara, Zecca, Tobias, Derfu, Thy-Sheng, Lin, Somsak, Tiamkao, Ayse Nur Yuceyar, Aysun, Soysal, Belgin Petek Balci, Cavit, Boz, Husnu, Efendi, Murat, Terzi, Serhan, Sevim, Serkan, Ozakba, Andrew, Gale, Ben, Turner, David, Barne, David, Paling, Eli, Silber, James, Overell, Matthew, Craner, Aaron, Carlson, Adam, Wolff, Adaeze, Onuoha, Adnan, Subei, Ahmad, Ata, Aimee, Borazanci, Akram, Dastagir, Alberto, Vasquez, Alison Brooke Allen, Andrew, P Keegan, Angel, Carrasco, Angel, R Chinea Martinez, Ann, Ba, Annette, Okai, April, Erwin, Ariel, Antezana-Antezana, Barbara, Green, Bharathy, E Sundaram, Bhupendra, Khatri, Bhupesh, Dihenia, Bogdan, Gheorghiu, Brian, Costell, Brian, Steingo, Bruce, L Hughe, Carrie, M Hersh, Christopher, Laganke, Christopher, Luzzio, Corey, Ford, Craig Edward Herrman, Craig, Senzon, Cynthia, Huffman, Daniel, R Wynn, David D, O Bear, David, Lesch, David, H Mattson, David, Weisman, Deborah, A Burke, Dennis, W Dietrich, Deren, Huang, Derrick, Robertson, Djamchid, Lotfi, Don Joseph Alfonso, Dusan, Stefoski, Edward, J Fox, Emily, Pharr, Enrique, Alvarez, Evanthia, Bernitsa, Faria, Amjad, Gabriel, Pardo, Geoffrey, Eubank, Gerald, Mcintosh, Giles, F Crowell, Hemanth, Rao, J Michael Hemphill, Jack, H Florin, Jacqueline, Nichola, James, Napier, James, Scott, Jason, M Silversteen, Javier, Vasallo, Jean-Raphael, Schneider, Jeanette, Wendt, Jeffrey, Cohen, Jeffrey, Gro, Jeffrey, Grove, Jeffrey, Kaplan, Jessica, Stulc, Joanna, A Cooper, John, Foley, John, Scagnelli, Jonathan, C Calkwood, Jose Pizarro Otero, Jose, Rafeca, Joshua, Katz, Juliette, S Saad, Katherine, Standley, Keith, Edward, Kenneth, Sharlin, Khurram, Bashir, Kimberly, Wagner, Kore, Liow, Larry Lee Blankenship Jr, Laszlo, Mate, Liliana, Montoya, Lon, D Lynn, Mark, Agiu, Mark, Cascione, Mark Allan Goldstein, Mark, Janicki, Martin, R Bialow, Mary Denise Hughes, Matthew, J Baker, Michelle, Apperson, Michelle, B Kuczma, M Mateo Paz Soldan, Mirela, Cerghet, Nathaniel Robb Whaley, Paul, K Winner, Pavle, Repovic, Praful, Kelkar, Romero Rekha Pillai, Ricardo, Ayala, Richard, Sater, Randall, Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert, Naismith, Ronald, S Murray, Samuel, Hunter, Sara, Qureshi, Sharon, Lynch, Sibyl, Wray, Silvia, R Delgado, Stacy, Donlon, Stanley, Cohan, Stanya, Smith, Stuart James Shafer, Susan, Azalone, Susan, Hibb, Tamara, A Miller, Thomas, Giancarlo, Troy, Desai, Varun, K Saxena, Virginia, Simnad, William David Honeycutt, William, Logan, William, E McElveen, William, Wagner, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Herrada, Anthony, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Male, MESH: Multiple Sclerosis, Relapsing-Remitting, T-Lymphocytes, Hydroxybutyrates, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Pharmacology, Relapsing-Remitting, MESH: Magnetic Resonance Imaging, chemistry.chemical_compound, 0302 clinical medicine, Teriflunomide, Monoclonal, MESH: Double-Blind Method, 030212 general & internal medicine, Humanized, MESH: Toluidines, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Subcutaneous, B-Lymphocyte, Brain, General Medicine, Magnetic Resonance Imaging, MESH: Crotonates, Crotonates, Pyrimidine metabolism, Disease Progression, Female, MESH: Disease Progression, Antibody, Human, Adult, Multiple Sclerosis, Toluidines, medicine.drug_class, Injections, Subcutaneous, Injections, Subcutaneou, Monoclonal antibody, Ofatumumab, Settore MED/26, Antibodies, Monoclonal, Humanized, Crotonate, Antibodies, Injections, 03 medical and health sciences, MESH: Brain, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, MESH: B-Lymphocytes, Nitriles, medicine, Humans, MESH: Kaplan-Meier Estimate, MESH: Humans, business.industry, Multiple sclerosis, MESH: Injections, Subcutaneous, MESH: Adult, medicine.disease, MESH: Male, MESH: T-Lymphocytes, T-Lymphocyte, Multicenter study, chemistry, MESH: Antibodies, Monoclonal, Humanized, biology.protein, Human medicine, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Published
2020
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27. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Author

Ludwig Kappos, Amit Bar-Or, Bruce A C Cree, Robert J Fox, Gavin Giovannoni, Ralf Gold, Patrick Vermersch, Douglas L Arnold, Sophie Arnould, Tatiana Scherz, Christian Wolf, Erik Wallström, Frank Dahlke, Anat Achiron, Lutz Achtnichts, Kadriye Agan, Gulsen Akman-Demir, Alison B Allen, Jack P Antel, Alfredo Rodriguez Antiguedad, Michelle Apperson, Angela M Applebee, Guillermo Izquierdo Ayuso, Masayuki Baba, Ovidiu Bajenaru, Rodica Balasa, Belgin Petek Balci, Michael Barnett, Ann Bass, Veit U Becker, Mihaela Bejinariu, Florian Then Bergh, Arnfin Bergmann, Evanthia Bernitsas, Achim Berthele, Virender Bhan, Felix Bischof, Randall John Bjork, Gregg Blevins, Matthias Boehringer, Thomas Boerner, Robert Bonek, James D Bowen, Allen Bowling, Alexey N Boyko, Cavit Boz, Vera Bracknies, Stefan Braune, Vincenzo Brescia Morra, Bruno Brochet, Waldemar Brola, Paul Kenneth Brownstone, Miroslav Brozman, Donald Brunet, Ioan Buraga, Margaret Burnett, Mathias Buttmann, Helmut Butzkueven, Jonathan Cahill, Jonathan C Calkwood, William Camu, Mark Cascione, Giovani Castelnovo, Diego Centonze, Joao Cerqueira, Andrew Chan, Andrea Cimprichova, Stanley Cohan, Giancarlo Comi, Jill Conway, Joanna A Cooper, John Corboy, Jorge Correale, Brian Costell, David A Cottrell, Patricia K Coyle, Matthew Craner, Liying Cui, Luis Cunha, Anna Czlonkowska, Ana Martins da Silva, Joao de Sa, Jérôme de Seze, Marc Debouverie, Jan Debruyne, Danny Decoo, Gilles Defer, Tobias Derfuss, Norma H Deri, Bhupesh Dihenia, Peter Dioszeghy, Vladimir Donath, Benedicte Dubois, Martin Duddy, Pierre Duquette, Gilles Edan, Husnu Efendi, Stanton Elias, Peter J Emrich, Bonaventura Casanova Estruch, Evgeniy P Evdoshenko, Juergen Faiss, Alexander S Fedyanin, Wolfgang Feneberg, Jiske Fermont, Oscar Fernandez Fernandez, Francisco Coret Ferrer, Katharina Fink, Helen Ford, Corey Ford, Ada Francia, Mark Freedman, Benjamin Frishberg, Simonetta Galgani, George P Garmany, Klaus Gehring, Jeffrey Gitt, Claudio Gobbi, Lawrence P Goldstick, Rafael Arroyo Gonzalez, Francois Grandmaison, Nikolaos Grigoriadis, Olga Grigorova, Luigi Maria Edoardo Grimaldi, Jeffrey Gross, Katrin Gross-Paju, Mark Gudesblatt, Daniel Guillaume, Judith Haas, Viera Hancinova, Anca Hancu, Orla Hardiman, Arndt Harmjanz, Fedor R Heidenreich, G J D Hengstman, Joseph Herbert, Mark Herring, Suzanne Hodgkinson, Olaf M Hoffmann, Werner E Hofmann, William D Honeycutt, Le Hanh Hua, Dehui Huang, Yining Huang, DeRen Huang, Raymond Hupperts, Piroska Imre, Alan Keith Jacobs, Gabor Jakab, Elzbieta Jasinska, Kenichi Kaida, Jolanta Kalnina, Ara Kaprelyan, Guntis Karelis, Dimitrios Karussis, Amos Katz, Farit A Khabirov, Bhupendra Khatri, Takashi Kimura, Ilya Kister, Rasa Kizlaitiene, Eleonora Klimova, Juergen Koehler, Aparna Komatineni, Anselm Kornhuber, Krisztina Kovacs, Agnes Koves, Wojciech Kozubski, Georgi Krastev, Lauren B Krupp, Egon Kurca, Christoph Lassek, Guy Laureys, Liesly Lee, Eckart Lensch, Fritz Leutmezer, Hongzeng Li, Ralf A Linker, Michael Linnebank, Petra Liskova, Cristina Llanera, Jiahong Lu, Andreas Lutterotti, Jan Lycke, Richard Macdonell, Maciej Maciejowski, Mathias Maeurer, Rim V Magzhanov, Eva-Maria Maida, Lina Malciene, Yang Mao-Draayer, Girolama Alessandra Marfia, Clyde Markowitz, Vasileios Mastorodimos, Klotild Matyas, Jose Meca-Lallana, Juan Antonio Garcia Merino, Ioan Gheorghe Mihetiu, Ivan Milanov, Aaron E Miller, Andrejs Millers, Massimiliano Mirabella, Masanori Mizuno, Xavier Montalban, Lilina Montoya, Masahiro Mori, Stefanie Mueller, Jin Nakahara, Yuji Nakatsuji, Scott Newsome, Richard Nicholas, A Scott Nielsen, Esmaeil Nikfekr, Ugo Nocentini, Chiyoko Nohara, Kyoichi Nomura, Miroslav M Odinak, Tomas Olsson, B W van Oosten, Celia Oreja-Guevara, Patrick Oschmann, James Overell, Andrew Pachner, Gyula Panczel, Massimo Pandolfo, Caroline Papeix, Liliana Patrucco, Jean Pelletier, Raul Piedrabuena, Misha Pless, Udo Polzer, Krisztian Pozsegovits, Daiva Rastenyte, Sebastian Rauer, Gerd Reifschneider, Roberto Rey, Syed A Rizvi, Derrick Robertson, Jose Martinez Rodriguez, David Rog, Homayoun Roshanisefat, Vernon Rowe, Csilla Rozsa, Susan Rubin, Stanislaw Rusek, Francesco Saccà, Takahiko Saida, Antonio Vasco Salgado, Victoria Eugenia Fernandez Sanchez, Kalina Sanders, Maria Satori, Denis V Sazonov, Elio Angelo Scarpini, Eugen Schlegel, Myriam Schluep, Stephan Schmidt, Erich Scholz, H M Schrijver, Matthias Schwab, Raymond Schwartz, James Scott, Krzysztof Selmaj, Stuart Shafer, Basil Sharrack, Ivan A Shchukin, Yuko Shimizu, Penko Shotekov, Arno Siever, Karl-Otto Sigel, Scott Silliman, Magdolna Simo, Mihaela Simu, Vladimiro Sinay, Antonio Escartin Siquier, Aksel Siva, Ondrej Skoda, Andrew Solomon, Martin Stangel, Dusan Stefoski, Brian Steingo, Igor D Stolyarov, Pavel Stourac, Katrin Strassburger-Krogias, Erik Strauss, Olaf Stuve, Ivaylo Tarnev, Antonios Tavernarakis, Cristina Ramo Tello, Murat Terzi, Veronika Ticha, Marina Ticmeanu, Klaus Tiel-Wilck, Toomas Toomsoo, Niall Tubridy, Mark J Tullman, Hayrettin Tumani, Peter Turcani, Ben Turner, Antonio Uccelli, Francisco Javier Olascoaga Urtaza, Marta Vachova, Attila Valikovics, Silke Walter, Bart Van Wijmeersch, Ludo Vanopdenbosch, Joerg R Weber, Sara Weiss, Robert Weissert, Timothy West, Heinz Wiendl, Sandrine Wiertlewski, Brigitte Wildemann, Barbara Willekens, L H Visser, Galina Vorobeychik, Xianhao Xu, Takashi Yamamura, Yi N Yang, Sergio Martinez Yelamos, Michael Yeung, Alan Zacharias, Marvin Zelkowitz, Uwe Zettl, Meini Zhang, Hongyu Zhou, Ulf Zieman, Tjalf Ziemssen, Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital, University of Basel, Basel, Center for Neuroinflammation and Neurotherapeutics, and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, Mellen Centre for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, Department of Neurology St. Josef-Hospital, Ruhr University Bochum, Germany, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Montreal Neurological Institute, McGill University, Montreal, QC, Canada, NeuroRx Research, Montreal, QC, Novartis Pharma AG, Lycalis, Brussels, AP-HM, CHU Timone, Pole de Neurosciences Cliniques, Department of Neurology, Marseille, France., Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Kappos, Ludwig, Bar-Or, Amit, Cree, Bruce A C, Fox, Robert J, Giovannoni, Gavin, Gold, Ralf, Vermersch, Patrick, Arnold, Douglas L, Arnould, Sophie, Scherz, Tatiana, Wolf, Christian, Wallström, Erik, Dahlke, Frank, Achiron, Anat, Achtnichts, Lutz, Agan, Kadriye, Akman-Demir, Gulsen, Allen, Alison B, Antel, Jack P, Antiguedad, Alfredo Rodriguez, Apperson, Michelle, Applebee, Angela M, Ayuso, Guillermo Izquierdo, Baba, Masayuki, Bajenaru, Ovidiu, Balasa, Rodica, Balci, Belgin Petek, Barnett, Michael, Bass, Ann, Becker, Veit U, Bejinariu, Mihaela, Bergh, Florian Then, Bergmann, Arnfin, Bernitsas, Evanthia, Berthele, Achim, Bhan, Virender, Bischof, Felix, Bjork, Randall John, Blevins, Gregg, Boehringer, Matthia, Boerner, Thoma, Bonek, Robert, Bowen, James D, Bowling, Allen, Boyko, Alexey N, Boz, Cavit, Bracknies, Vera, Braune, Stefan, Brescia Morra, Vincenzo, Brochet, Bruno, Brola, Waldemar, Brownstone, Paul Kenneth, Brozman, Miroslav, Brunet, Donald, Buraga, Ioan, Burnett, Margaret, Buttmann, Mathia, Butzkueven, Helmut, Cahill, Jonathan, Calkwood, Jonathan C, Camu, William, Cascione, Mark, Castelnovo, Giovani, Centonze, Diego, Cerqueira, Joao, Chan, Andrew, Cimprichova, Andrea, Cohan, Stanley, Comi, Giancarlo, Conway, Jill, Cooper, Joanna A, Corboy, John, Correale, Jorge, Costell, Brian, Cottrell, David A, Coyle, Patricia K, Craner, Matthew, Cui, Liying, Cunha, Lui, Czlonkowska, Anna, da Silva, Ana Martin, de Sa, Joao, de Seze, Jérôme, Debouverie, Marc, Debruyne, Jan, Decoo, Danny, Defer, Gille, Derfuss, Tobia, Deri, Norma H, Dihenia, Bhupesh, Dioszeghy, Peter, Donath, Vladimir, Dubois, Benedicte, Duddy, Martin, Duquette, Pierre, Edan, Gille, Efendi, Husnu, Elias, Stanton, Emrich, Peter J, Estruch, Bonaventura Casanova, Evdoshenko, Evgeniy P, Faiss, Juergen, Fedyanin, Alexander S, Feneberg, Wolfgang, Fermont, Jiske, Fernandez, Oscar Fernandez, Ferrer, Francisco Coret, Fink, Katharina, Ford, Helen, Ford, Corey, Francia, Ada, Freedman, Mark, Frishberg, Benjamin, Galgani, Simonetta, Garmany, George P, Gehring, Klau, Gitt, Jeffrey, Gobbi, Claudio, Goldstick, Lawrence P, Gonzalez, Rafael Arroyo, Grandmaison, Francoi, Grigoriadis, Nikolao, Grigorova, Olga, Grimaldi, Luigi Maria Edoardo, Gross, Jeffrey, Gross-Paju, Katrin, Gudesblatt, Mark, Guillaume, Daniel, Haas, Judith, Hancinova, Viera, Hancu, Anca, Hardiman, Orla, Harmjanz, Arndt, Heidenreich, Fedor R, Hengstman, G J D, Herbert, Joseph, Herring, Mark, Hodgkinson, Suzanne, Hoffmann, Olaf M, Hofmann, Werner E, Honeycutt, William D, Hua, Le Hanh, Huang, Dehui, Huang, Yining, Huang, Deren, Hupperts, Raymond, Imre, Piroska, Jacobs, Alan Keith, Jakab, Gabor, Jasinska, Elzbieta, Kaida, Kenichi, Kalnina, Jolanta, Kaprelyan, Ara, Karelis, Gunti, Karussis, Dimitrio, Katz, Amo, Khabirov, Farit A, Khatri, Bhupendra, Kimura, Takashi, Kister, Ilya, Kizlaitiene, Rasa, Klimova, Eleonora, Koehler, Juergen, Komatineni, Aparna, Kornhuber, Anselm, Kovacs, Krisztina, Koves, Agne, Kozubski, Wojciech, Krastev, Georgi, Krupp, Lauren B, Kurca, Egon, Lassek, Christoph, Laureys, Guy, Lee, Liesly, Lensch, Eckart, Leutmezer, Fritz, Li, Hongzeng, Linker, Ralf A, Linnebank, Michael, Liskova, Petra, Llanera, Cristina, Lu, Jiahong, Lutterotti, Andrea, Lycke, Jan, Macdonell, Richard, Maciejowski, Maciej, Maeurer, Mathia, Magzhanov, Rim V, Maida, Eva-Maria, Malciene, Lina, Mao-Draayer, Yang, Marfia, Girolama Alessandra, Markowitz, Clyde, Mastorodimos, Vasileio, Matyas, Klotild, Meca-Lallana, Jose, Merino, Juan Antonio Garcia, Mihetiu, Ioan Gheorghe, Milanov, Ivan, Miller, Aaron E, Millers, Andrej, Mirabella, Massimiliano, Mizuno, Masanori, Montalban, Xavier, Montoya, Lilina, Mori, Masahiro, Mueller, Stefanie, Nakahara, Jin, Nakatsuji, Yuji, Newsome, Scott, Nicholas, Richard, Nielsen, A Scott, Nikfekr, Esmaeil, Nocentini, Ugo, Nohara, Chiyoko, Nomura, Kyoichi, Odinak, Miroslav M, Olsson, Toma, van Oosten, B W, Oreja-Guevara, Celia, Oschmann, Patrick, Overell, Jame, Pachner, Andrew, Panczel, Gyula, Pandolfo, Massimo, Papeix, Caroline, Patrucco, Liliana, Pelletier, Jean, Piedrabuena, Raul, Pless, Misha, Polzer, Udo, Pozsegovits, Krisztian, Rastenyte, Daiva, Rauer, Sebastian, Reifschneider, Gerd, Rey, Roberto, Rizvi, Syed A, Robertson, Derrick, Rodriguez, Jose Martinez, Rog, David, Roshanisefat, Homayoun, Rowe, Vernon, Rozsa, Csilla, Rubin, Susan, Rusek, Stanislaw, Saccà, Francesco, Saida, Takahiko, Salgado, Antonio Vasco, Sanchez, Victoria Eugenia Fernandez, Sanders, Kalina, Satori, Maria, Sazonov, Denis V, Scarpini, Elio Angelo, Schlegel, Eugen, Schluep, Myriam, Schmidt, Stephan, Scholz, Erich, Schrijver, H M, Schwab, Matthia, Schwartz, Raymond, Scott, Jame, Selmaj, Krzysztof, Shafer, Stuart, Sharrack, Basil, Shchukin, Ivan A, Shimizu, Yuko, Shotekov, Penko, Siever, Arno, Sigel, Karl-Otto, Silliman, Scott, Simo, Magdolna, Simu, Mihaela, Sinay, Vladimiro, Siquier, Antonio Escartin, Siva, Aksel, Skoda, Ondrej, Solomon, Andrew, Stangel, Martin, Stefoski, Dusan, Steingo, Brian, Stolyarov, Igor D, Stourac, Pavel, Strassburger-Krogias, Katrin, Strauss, Erik, Stuve, Olaf, Tarnev, Ivaylo, Tavernarakis, Antonio, Tello, Cristina Ramo, Terzi, Murat, Ticha, Veronika, Ticmeanu, Marina, Tiel-Wilck, Klau, Toomsoo, Tooma, Tubridy, Niall, Tullman, Mark J, Tumani, Hayrettin, Turcani, Peter, Turner, Ben, Uccelli, Antonio, Urtaza, Francisco Javier Olascoaga, Vachova, Marta, Valikovics, Attila, Walter, Silke, Van Wijmeersch, Bart, Vanopdenbosch, Ludo, Weber, Joerg R, Weiss, Sara, Weissert, Robert, West, Timothy, Wiendl, Heinz, Wiertlewski, Sandrine, Wildemann, Brigitte, Willekens, Barbara, Visser, L H, Vorobeychik, Galina, Xu, Xianhao, Yamamura, Takashi, Yang, Yi N, Yelamos, Sergio Martinez, Yeung, Michael, Zacharias, Alan, Zelkowitz, Marvin, Zettl, Uwe, Zhang, Meini, Zhou, Hongyu, Zieman, Ulf, Ziemssen, Tjalf, and EXPAND Clinical Investigators

Subjects
Adult, Male, 0301 basic medicine, Relative risk reduction, medicine.medical_specialty, Adolescent, Placebo, law.invention, Cohort Studies, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Multiple Sclerosis, Chronic Progressive / drug therapy, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, Benzyl Compounds, Clinical endpoint, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Hazard ratio, General Medicine, Middle Aged, Multiple Sclerosis, Chronic Progressive, Fingolimod, Treatment Outcome, Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITÀ MOTORIE, 030104 developmental biology, Siponimod, chemistry, Disease Progression, Azetidines, Female, Settore MED/26 - Neurologia, Human medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, medicine.drug
Abstract

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

Published
2018
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