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101. Survey of diagnostic and treatment practices for multiple sclerosis (MS) in Europe. Part 2:Progressive MS, paediatric MS, pregnancy and general management

Author: Fernández, O., Delvecchio, M., Edan, G., Fredrikson, S., Giovannoni, G., Hartung, H. P., Havrdova, E., Kappos, L., Pozzilli, C., Soerensen, P. S., Tackenberg, B., Vermersch, P., Comi, G., Fernández, O., Delvecchio, M., Edan, G., Fredrikson, S., Giovannoni, G., Hartung, H. P., Havrdova, E., Kappos, L., Pozzilli, C., Soerensen, P. S., Tackenberg, B., Vermersch, P., and Comi, G.
Abstract: Background and purpose: The European Charcot Foundation supported the development of a set of surveys to understand current practice patterns for the diagnosis and management of multiple sclerosis (MS) in Europe. Part 2 of the report summarizes survey results related to secondary progressive MS (SPMS), primary progressive MS (PPMS), pregnancy, paediatric MS and overall patient management. Methods: A steering committee of MS neurologists developed case- and practice-based questions for two sequential surveys distributed to MS neurologists throughout Europe. Results: Respondents generally favoured changing rather than stopping disease-modifying treatment (DMT) in patients transitioning from relapsing−remitting MS to SPMS, particularly with active disease. Respondents would not initiate DMT in patients with typical PPMS symptoms, although the presence of ≥1 spinal cord or brain gadolinium-enhancing lesion might affect that decision. For patients considering pregnancy, respondents were equally divided on whether to stop treatment before or after conception. Respondents strongly favoured starting DMT in paediatric MS with active disease; recommended treatments included interferon, glatiramer acetate and, in John Cunningham virus negative patients, natalizumab. Additional results regarding practice-based questions and management are summarized. Conclusions: Results of part 2 of the survey of diagnostic and treatment practices for MS in Europe largely mirror results for part 1, with neurologists in general agreement about the treatment and management of SPMS, PPMS, pregnancy and paediatric MS as well as the general management of MS. However, there are also many areas of disagreement, indicating the need for evidence-based recommendations and/or guidelines.
Published: 2018

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

Author: Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), Terzi M., Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), and Terzi M.
Abstract: 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) receptor1,5 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
Published: 2018

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

Author: Lublin, F, Miller, D, Freedman, M, Cree, B, Wolinsky, J, Weiner, H, Lubetzki, C, Hartung, H, Montalban, X, Uitdehaag, B, Kappos, L, Easton, J, Kesselring, J, Weinshenker, B, Laupacis, A, Zarbin, M, Calandra, T, Temkin, N, Dimarco, J, Polman, C, Yousry, T, Hodgkinson, S, Barnett, M, King, J, Butzkueven, H, Macdonell, R, Taylor, B, D'Hooghe, M, Dubois, B, Seeldrayers, P, Mulleners, E, Willekens, B, Delvaux, V, Antel, J, Bhan, V, Devonshire, V, Grandmaison, F, O'Connor, P, Vorobeychik, G, Patry, D, Veloso, F, Duquette, P, Blevins, G, Jacques, F, Lee, L, Berger, J, Havrdova, E, Ticha, V, Kanovsky, P, Rektor, I, Minks, E, Pazdera, L, Vachova, M, Hradilek, P, Frederiksen, J, Petersen, T, Stenager, E, Kallela, M, Eralinna, J, Elovaara, I, Brochet, B, Pelletier, J, Camu, W, Wierstlewski, S, Edan, G, Vermersch, P, de Seze, J, Buttmann, M, Haas, J, Linker, R, Hohlfeld, R, Kieseier, B, Rauer, S, Baum, K, Faiss, J, Tiel Wilck, K, Ziemssen, T, Berthele, A, Maschke, M, Meuth, S, Sailer, M, Kastrup, O, Kleiter, I, Stangel, M, Jakab, G, Csiba, L, Csanyi, A, Imre, P, Rozsa, A, Sándor, P, Valikovics, A, Comi, G, Trojano, M, Lugaresi, A, Colle, A, Ghezzi, A, Mancardi, G, Capra, R, Perini, P, Scarpini, E, Centonze, D, Pozzilli, C, Patti, F, Grimaldi, L, Bertolotto, A, van Oosten, B, de Jong, B, Hupperts, R, van Dijl, R, Frequin, S, Hengstman, G, Selmaj, K, Czlonkowska, A, Kaminska, A, Stelmasiak, Z, Ramo, C, Ramio, L, Izquierdo, G, Arroyo, R, Casanova, B, Garcia Merino, J, Rodriguez Antigüedad, A, Brieva, L, Martinez Yelamos, S, Diaz Tejedor, E, Saiz Hinarejos, A, Olsson, T, Lycke, J, Linnebank, M, Schluep, M, Kamm, C, Gobbi, C, Bebek, N, Dokuz, E, Zorlu, Y, Karabudak, R, Terzi, M, Duddy, M, Lee, M, Nicholas, R, Silber, E, Sharrack, B, Chataway, J, Cottrell, D, Rog, D, Schmierer, K, Mitchell, G, Nelson, F, Saidha, S, Houtchens, M, Graves, D, Miller, A, Agius, M, Bowen, J, Rae Grant, A, Lynch, S, Reder, A, Cascione, M, Cohen, B, Coyle, P, Brook, S, Luzzio, C, Goldman, M, Conway, J, Khan, O, Parks, B, Steingo, B, Weinstock Guttman, B, Lathi, E, Bandari, D, Corboy, J, English, J, Picone, M, Goodman, A, Applebee, A, Gazda, S, Kisanuki, Y, Skeen, M, Wray, S, Moses, H, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Willekens, Barbara, and INFORMS study investigators
Subjects: 0301 basic medicine, Male, Clinical Trial, Phase III, administration & dosage, Placebo-controlled study, Aucun, Administration, Oral, chemistry.chemical_compound, 0302 clinical medicine, 10. No inequality, Medicine(all), education.field_of_study, Research Support, Non-U.S. Gov't, Orvostudományok, General Medicine, Middle Aged, Multiple Sclerosis, Chronic Progressive, Fingolimod, 3. Good health, drug therapy, Multicenter Study, Treatment Outcome, Randomized Controlled Trial, Disease Progression, Female, Settore MED/26 - Neurologia, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Population, Klinikai orvostudományok, Placebo, 03 medical and health sciences, Young Adult, Double-Blind Method, Internal medicine, Fingolimod Hydrochloride, Journal Article, medicine, Humans, education, Aged, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Multiple sclerosis, medicine.disease, Surgery, 030104 developmental biology, Siponimod, chemistry, Human medicine, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
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 (
Published: 2016
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104. Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis

Author: Paul, O'Connor, Wolinsky, Jerry S., Christian, Confavreux, Giancarlo, Comi, Ludwig, Kappos, Olsson, Tomas P., Hadj, Benzerdjeb, Philippe, Truffinet, Lin, Wang, Aaron, Miller, Temso Trial Group Reingold, Freedman Ms S., Cutter, G., Antel, J., Barkhof, F., Maddrey, W., Ravnborg, M., Schenker, S., O'Connor, P., Wolinsky, J. S., Confavreux, C., Comi, G., Kappos, L., Olsson, T. P., Miller, A., Freedman, Mark S., Narayana, P. A., Nelson, F., Vainrub, I., Datta, S., He, R., Gates, B., Ton, K., Wamil, B., Truffinet, P., Igau, B., Nicolas, V., Notelet, L., Payrard, S., Wijnand, P., Devore, S., H. H., Li, Osho, T., Wang, L., Wei, L., Dukovic, D., Ling, Y., Benzerdjeb, H., Mednikova, Z., Trabelsi, N., Musset, M., Merrill, D., Turpault, S., Williams, B., Nortmeyer, H., Kirst, E., Witthaus, E., Chen, S., Maida, E., Auff, E., Fazekas, F., Berger, T., Bhan, V., Bouchard, J. P., Duquette, P., Freedman, M., Grand'Maison, F., Kremenchutzky, M., Bourque, C., Marrie, R. A., Melanson, M., Patry, D., Oger, J., Stefanelli, M., Jacques, F., Venegas, P., Miranda, M., Barrientos, N., Tenhamm, E., Gloger, S., Rohde, G., Mares, J., Frederiksen, J., Stenager, E., Haldre, S., Gross Paju, K., Elovaara, I., Sumelahti, M. L., Erälinna, J. P., Farkkila, M., Harno, H., Reunanen, M., Jolma, T., Camu, W., Clavelou, P., Magy, L., Debouverie, M., Edan, G., Lebrun Frenay, C., Moreau, T., Pelletier, J., Roullet, E., Alamowitch, S., Clanet, M., Hautecoeur, P., Damier, P., Rumbach, L., Chan, A., Schimrigk, S., Haas, J., Lensch, E., Diener, H., Limmroth, V., Anders, D., Berghoff, M., Oschmann, P., Stangel, M., Frese, A., Kiefer, R., Marziniak, M., Zettl, U., Stark, E., Jendroska, K., Reifschneider, G., Amato, M. P., Cosi, V., Gallo, P., Gasperini, Claudio, Ghezzi, A., Trojano, M., Pozzilli, Carlo, Montanari, E., Zwanikken, C. P., Jongen, P. J., Van Munster, E. T., Hupperts, R. M., Anten, B., Sanders, E. A., Celius, E., Hovdal, H., Krogseth, S. B., Kozubski, W., Kwiecinski, H., Czlonkowska, A., Stelmasiak, Z., Selmaj, K., Hasiec, T., Fryze, W., Drozdowski, W., Kochanowicz, J., Cunha, L., De Sa, J., Sena, A. H., Odinak, M., Skoromets, A., Gusev, E., Boiko, A., Lashch, N., Stolyarov, I., Belova, A., Malkova, N., Doronin, B., Yakupov, E., Brundin, L., Hillert, J., Karabudak, R., Irkec, C., Idiman, E., Turan, O., Efendi, H., Gedizlioglu, M., Buchakchyyska, N., Goloborodko, A., Ipatov, A., Kobets, S., Lebedynets, V., Moskovko, S., Sanotskyy, Y., Smolanka, V., Yavorskaya, V., Bates, D., Evangelou, N., Hawkins, C., Mclean, B., O'Riordan, J., Price, S., Turner, B., Barnes, D., Zajicek, J., Honeycutt, W., Khan, O., Spikol, L., Stevens, J., Klinische Neurowetenschappen, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: medicine.medical_specialty, biology, Nausea, business.industry, Incidence (epidemiology), Placebo-controlled study, General Medicine, Placebo, Gastroenterology, Surgery, chemistry.chemical_compound, Alanine transaminase, chemistry, Internal medicine, Relative risk, Teriflunomide, medicine, biology.protein, medicine.symptom, business, Leflunomide, medicine.drug
Abstract: Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teri flunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P
Published: 2011
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105. A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis

Author: Giovannoni, G, Comi, G, Cook, S, Rammohan, K, Rieckmann, P, Soelberg Sørensen, P, Vermersch, P, Sandberg Wollheim, M, Cuzick, J, Juliusson, G, Reingold, S, King, J, Pollard, J, Sedal, L, Aichner, F, Eggers, C, Dive, D, Medaer, R, Ferreira, M, Manchev, I, Milanov, I, Haralanov, L, Deleva, N, Petrova, N, Bozhinov, P, Zahariev, Z, Stamenov, B, Shotekov, P, Petrov, I, Moskov, R, Emond, F, Freedman, M, Grand'Maison, F, Jacques, F, Vorobeychik, G, Demarin, V, Kovacicek, M, Lusic, I, Perhat Bucevic, T, Havrdova, E, Talab, R, Kanovsky, P, Petersen, T, Gross Paju, K, Kalbe, I, Toomsoo, T, Elovaara, I, Eralinna, Jp, Reunanen, M, Clavelou, P, Damier, P, Debouverie, M, Edan, G, Gout, O, Labauge, P, Laplaud, D, Wiertlewski, S, Heidenreich, F, Mäurer, M, Kieseier, B, Limmroth, V, Oschmann, P, Schimrigk, S, Steinbrecher, A, Zettl, U, Ziemann, U, Karageorgiou, K, Kyritsis, A, Papadimitriou, A, Amato, Mp, Bernardi, G, Morra, Vb, Galgani, S, Gallo, Paolo, Patti, F, Marrosu, M, Pozzilli, C, Trojano, M, Mancardi, Gl, Gebeily, S, Koussa, S, Wehbe, M, Yamout, B, Vaitkus, A, Metra, M, Messouak, O, Mossaddaq, R, Slassi, I, Yahyaoui, M, Hupperts, Rm, Czlonkowska, A, Kozubski, W, Nyka, W, Selmaj, K, Szczudlik, A, Figueiredo, J, Pedrosa, R, Alifirova, V, Balyazin, V, Barbarash, O, Belova, A, Boyko, A, Gusev, E, Elchaninov, A, Jacoupov, E, Julev, N, Kotov, S, Kudryavtsev, A, Laskov, V, Lesnyak, O, Odinak, M, Pasechnik, E, Poverennonva, I, Skoromets, A, Spirin, N, Stolyarov, I, Vorobieva, O, Voskresenskaya, O, Zaslavskiy, L, Zonova, E, Bohlega, S, El Jumah, M, Drulovic, J, Nadj, C, Goebels, N, Schluep, M, Ayed Frih, M, Hentati, F, Mhiri, C, Mrabet, A, Mrissa, R, Idiman, E, Karabudak, R, Turan, Of, Ahmed, F, Constantinescu, C, Hawkins, C, Palace, J, Sharrack, B, Loganovsky, K, Moskovko, S, Nehrych, T, Voloshyna, Np, Carlini, W, English, J, Garmany, G, Glyman, S, Huddlestone, J, Hurwitz, B, Kresa Reahl, K, Mikol, D, Pardo, G, Rao, H, Reif, M, Thrower, B, Royal, W, Webb, R, Wynn, D, Naga, C, Allen, N, Lin, K, Stefoski, D, Balabanov, R., Klinische Neurowetenschappen, RS: MHeNs School for Mental Health and Neuroscience, G., Giovannoni, G., Comi, S., Cook, K., Rammohan, P., Rieckmann, P. S., Sorensen, P., Vermersch, P., Chang, A., Hamlett, B., Musch, S. J., Greenberg, Altri, and BRESCIA MORRA, Vincenzo
Subjects: Male, Medizin, Placebo-controlled study, Administration, Oral, Relapsing-Remitting, drug therapy/pathology, Gastroenterology, Disability Evaluation, Cladribine, Hazard ratio, Brain, General Medicine, Middle Aged, Administration, Oral, Adolescent, Adult, Aged, Analysis of Variance, Brain, pathology, Cladribine, adverse effects/therapeutic use, Disability Evaluation, Disease Progression, Double-Blind Method, Female, Herpes Zoster, etiology, Humans, Immunosuppressive Agents, adverse effects/therapeutic use, Intention to Treat Analysis, Lymphopenia, chemically induced, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, drug therapy/pathology, Young Adult, Magnetic Resonance Imaging, Intention to Treat Analysis, adverse effects/therapeutic use, Disease Progression, chemically induced, Female, Immunosuppressive Agents, medicine.drug, Oral, Adult, medicine.medical_specialty, Multiple Sclerosis, Adolescent, etiology, cladribine, immunomodulation, multiple sclerosis, trial, Lower risk, Placebo, DIAGNOSIS, Herpes Zoster, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, Lymphopenia, Internal medicine, medicine, Humans, Adverse effect, Aged, Analysis of Variance, business.industry, MS, medicine.disease, Confidence interval, Surgery, CELLS, pathology, Lymphocytopenia, business
Abstract: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing–remitting multiple sclerosis. We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33 ; P
Published: 2010
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106. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial

Author: Mikol, Dd1, Barkhof, F, Chang, P, Coyle, Pk, Jeffery, Dr, Schwid, Sr, Stubinski, B, Uitdehaag, B, Ballario, Ch, Caceres, Fj, Correale, J, Cristiano, E, Garcea, Do, Leutic, Gg, Aicher, F, Barreira, Aa, Freedman, M, Grand'Maison, F, Jacques, F, Lee, L, Stefanelli, M, Edan, G, Pelletier, J, Berghoff, M, Keifer, R, Koehler, J, Hardiman, O, Comi, G, Mancardi, GIOVANNI LUIGI, Pozzilli, C, Trojano, Mp, Jongen, P, Uitdehaag, Bm, Belova, An, Boyko, An, Elchaninov, Ap, Kozlov, Va, Odinak, Mm, Shvarkov, Sb, Skoromets, Aa, Spirin, Nn, Stolyarov, Id, Vorobieva, Ov, Zavalishin, I, Arbizu, T, Fernandez, O, Izquierdo, G, Montalban, X, Goebels, N, Bates, D, Constantinescu, C, Turner, B, Bashir, K, Bever, Ct, Birnbaum, G, Brod, Sa, Carlini, W, Dunne, P, Elias, S, Estronza, N, Fox, E, Glyman, S, Gross, J, Guarnaccia, Jb, Gupta, A, Kaufman, M, Khan, O, Khatri, B, Kresa reahl, K, Lava, N, Leist, T, Markowitz, C, Mihai, C, Mikol, Dd, Miller, T, Panitch, H, Parry, G, Rammohan, Kw, Reder, A, Sheppard, C, Simsarian, Jp, Smiroldo, J, Spier, L, Thrower, B, Vollmer, T, Wendt, J, Wray, S, Wynn, D., Radiology and nuclear medicine, Epidemiology and Data Science, Neurology, and Neuroscience Campus Amsterdam 2008
Subjects: Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Injections, Subcutaneous, Population, Placebo-controlled study, Relapsing-Remitting, drug therapy/pathology, Drug Administration Schedule, Injections, methods, law.invention, Disability Evaluation, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, law, Internal medicine, Adolescent, Adult, Confidence Intervals, Disability Evaluation, Disease Progression, Drug Administration Schedule, Female, Humans, Immunologic Factors, administration /&/ dosage, Injections, Subcutaneous, methods, Interferon-beta, administration /&/ dosage, Magnetic Resonance Imaging, methods, Male, Middle Aged, Multiple Sclerosis, drug therapy/pathology, Peptides, administration /&/ dosage, Retrospective Studies, Treatment Outcome, Confidence Intervals, medicine, Humans, Immunologic Factors, Glatiramer acetate, administration /&/ dosage, education, Retrospective Studies, education.field_of_study, Intention-to-treat analysis, business.industry, Interferon beta-1a, McDonald criteria, Glatiramer Acetate, Interferon-beta, Middle Aged, Magnetic Resonance Imaging, Treatment Outcome, Tolerability, Immunology, Disease Progression, Female, Neurology (clinical), Peptides, business, medicine.drug
Abstract: Summary Background Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS. Methods In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 μg subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338. Findings Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0·94, 95% CI 0·74 to 1·21; p=0·64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0·24 vs 0·41 lesions per patient per scan, 95% CI −0·4 to 0·1; p=0·0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks. Interpretation There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS. Funding EMD Serono; Pfizer.
Published: 2008
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107. Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study

Author: Barbin, L. (Laetitia), Rousseau, C. (Chloe), Jousset, N. (Natacha), Casey, R. (Romain), Debouverie, M. (Marc), Vukusic, S. (Sandra), De Seze, J. (Jerome), Brassat, D. (David), Wiertlewski, S. (Sandrine), Brochet, B. (Bruno), Pelletier, J. (Jean), Vermersch, P. (Patrick), Edan, G. (Gilles), Lebrun-Frenay, C. (Christine), Clavelou, P. (Pierre), Thouvenot, E. (Eric), Camdessanché, J. (Jean-Philippe), Tourbah, A. (Ayman), Stankoff, B. (Bruno), Al Khedr, A. (Abdullatif), Cabre, P. (Philippe), Papeix, C. (Caroline), Berger, E. (Eric), Heinzlef, O. (Olivier), Debroucker, T. (Thomas), Moreau, T. (Thibault), Gout, O. (Olivier), Bourre, B. (Bertrand), Créange, A. (Alain), Labauge, P. (Pierre), Magy, L. (Laurent), Defer, G. (Gilles), Foucher, Y. (Yohann), Laplaud, D. (David A), CFSEP and OFSEP groups, Jonchère, Laurent, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, PRES Université Nantes Angers Le Mans (UNAM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), ReLSEP, Lorraine Register of MS, EA 4360, Department of Neurology, CHU Nancy, Department of Neurology, CHU Lyon, Service de Neurologie [Lyon], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Bordeaux (UB), Pôle de Neurosciences Cliniques, Department of Neurology, Hôpital de la Timone [CHU - APHM] (TIMONE), Inflammation: mécanismes et régulation et interactions avec la nutrition et les candidoses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Service de neurologie D, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Clermont-Ferrand, CHU Saint-Etienne, Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU de la Martinique [Fort de France], CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Neurologie [CHRU Besançon], Service de Neurologie [CHU de Poissy], CHU De Poissy, Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Fondation Ophtalmologique Rothschild, Excitabilité nerveuse et thérapeutique (ENT), Hôpital Henri Mondor-EA 4391, Service de Physiologie Explorations Fonctionnelles-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), CHU Limoges, Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biostatistique, Recherche Clinique et Mesures Subjectives en Santé, Université de Nantes (UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-EA 4391, Service de Physiologie Explorations Fonctionnelles-Hôpital Henri Mondor, Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), and Service de Neurologie [CHU Besançon]
Subjects: Male, [SDV]Life Sciences [q-bio], Aucun, diagnosis, drug therapy, epidemiology, Cohort Studies, 0302 clinical medicine, Natalizumab, Medicine, 030212 general & internal medicine, 10. No inequality, Fingolimod, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Cohort, Female, France, Immunosuppressive Agents, medicine.drug, Cohort study, Adult, medicine.medical_specialty, Multiple Sclerosis, Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], Article, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, Fingolimod Hydrochloride, Internal medicine, Humans, Immunologic Factors, Expanded Disability Status Scale, business.industry, Multiple sclerosis, medicine.disease, Surgery, Propylene Glycols, therapeutic use, Propensity score matching, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: OBJECTIVE: To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis. METHODS: Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0-5.5 and an available brain MRI performed within the year before treatment initiation. The data were collected for 326 patients treated with natalizumab and 303 with fingolimod. The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting). RESULTS: The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775). Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p < 0.0001; new T2 lesions: 10.6% vs 29.6%, p < 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation. CONCLUSION: Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod. comparative study journal article multicenter study observational study research support, non-u.s. gov't 2016 Feb 23 2016 01 29 imported
Published: 2016
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108. Foreword

Author: Timsit, S., primary and Edan, G., additional
Published: 2017
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109. Journée Société française de neurologie au JNLF 2017 : « Excellence in Neurology 2016 »

Author: Edan, G., primary
Published: 2017
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110. Predicting conversion to clinically definite multiple sclerosis using machine learning on the basis of cerebral grey matter segmentations

Author: Bendfeldt, K., Taschler, B., Gaetano, L., Madoerin, P., Kuster, P., Mueller-Lenke, N., Amann, M., Vrenken, H., Barkhof, F., Stefan Borgwardt, Kloeppel, S., Nichols, T. E., Suarez, G., Kappos, L., Edan, G., Freedman, M. S., Montalban, X., Hartung, H. -P, Pohl, C., Sandbrink, R., Wuerfel, J., Radue, E. -W, Sprenger, T., University Hospital Basel [Basel], Vrije Universiteit Amsterdam [Amsterdam] (VU), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience; no abstract
Published: 2015

111. Survey of diagnostic and treatment practices for multiple sclerosis in Europe

Author: Fernández, O, Delvecchio, M, Edan, G, Fredrikson, S, Gionvannoni, G, Hartung, H-P, Havrdova, E, Kappos, L, Pozzilli, C, Soerensen, P S, Tackenberg, B, Vermersch, P, Comi, G, Fernández, O, Delvecchio, M, Edan, G, Fredrikson, S, Gionvannoni, G, Hartung, H-P, Havrdova, E, Kappos, L, Pozzilli, C, Soerensen, P S, Tackenberg, B, Vermersch, P, and Comi, G
Abstract: BACKGROUND AND PURPOSE: Up-to-date information is needed on the extent to which neurologists treating multiple sclerosis (MS) in Europe are integrating rapidly evolving diagnostic criteria, disease-modifying therapies and recommendations for monitoring disease activity into their clinical practice.METHODS: A steering committee of MS neurologists used a modified Delphi process to develop case- and practice-based questions for two sequential surveys distributed to MS neurologists throughout Europe. Case-based questions were developed for radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS) and RRMS with breakthrough disease.RESULTS: Multiple sclerosis neurologists from 11 European countries responded to survey 1 (n = 233) and survey 2 (n = 171). Respondents agreed that they would not treat the patients in the RIS or CIS cases but would treat a patient with a relatively mild form of RRMS. Choice of treatment was evenly distributed among first-line injectables and oral treatments for mild RRMS, and moved to second-line treatment as the RRMS case increased in severity. Additional results on RRMS with breakthrough disease are presented.CONCLUSIONS: Although there was general agreement on some aspects of treatment, responses to other management and clinical practice questions varied considerably. These results, which reflect current clinical practice patterns, highlight the need for additional MS treatment education and awareness and may help inform the development of MS practice guidelines in Europe.
Published: 2017

112. Interferon beta-1b-neutralizing antibodies 5 years after clinically istolated syndrome

Author: Hartung HP, Freedman MS, Polman CH, Edan G, Kappos L, Miller DH, Montalban X, Barkhof F, Petkau J, White R, Sahajpal V, Knappertz V, Beckmann K, Lanius V, Sandbrink R, Pohl C, BENEFIT Study Group, COMI , GIANCARLO, Hartung, Hp, Freedman, M, Polman, Ch, Edan, G, Kappos, L, Miller, Dh, Montalban, X, Barkhof, F, Petkau, J, White, R, Sahajpal, V, Knappertz, V, Beckmann, K, Lanius, V, Sandbrink, R, Pohl, C, Comi, Giancarlo, and BENEFIT Study, Group
Published: 2011

113. lomg-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 2 BENEFIT trial

Author: KAPPOS L, FREEDMAN MS, POLMAN CH, EDAN G. HARTUUNG HP, MILLER DH, MONTALBAN X, BARKHOF F, RADU EW, METZIG C, BAUER L, LANIUS V, SANDBRINK R, COMI , GIANCARLO, Kappos, L, Freedman, M, Polman, Ch, EDAN G., HARTUUNG HP, Miller, Dh, Montalban, X, Barkhof, F, Radu, Ew, Metzig, C, Bauer, L, Lanius, V, Sandbrink, R, and Comi, Giancarlo
Published: 2009

114. Double-blind randomized multicenter dose-comparison study of interferon-β-1a (AVONEX): rationale, design and baseline data

Author: Kristoferitsch, W, Seeldrayers, P, Kyriallis, K, Brochet, B, Confavreux, C, Clanet, M, Cesaro, P, Defer, G, Edan, G, Lyon-Caen, O, Pelletier, J, Rumbach, L, Roullet, E, Vermersch, P, Dengler, R, Zschenderlein, R, Storch-Hagenlocher, B, Sailer, M, Hohlfeld, R, Kunze, KP, Heesen, C, Bamborschke, P, Grunwald, F, Hartung, HP, Rieckmann, P, DeKeyser, J, Montalban, [No Value], Fernandez, U, Arbizu, T, Sandberg, M, Kappos, L, Bates, D, Campbell, MJ, Capildeo, R, Compston, A, McLellan, DL, Wroe, S, Young, C, Radue, EW, Polman, C, Kesselring, J, Thompson, A, Wekerle, H, and Whitehead, J
Subjects: Adult, Male, interferon-beta-1a, Multiple Sclerosis, Interferon-beta, MRI follow-up, Middle Aged, Magnetic Resonance Imaging, dose-comparison study design, 03 medical and health sciences, 0302 clinical medicine, Adjuvants, Immunologic, Double-Blind Method, Neurology, MAGNETIC-RESONANCE, Humans, Multicenter Studies as Topic, Female, 030212 general & internal medicine, Neurology (clinical), RELAPSING MULTIPLE-SCLEROSIS, Interferon beta-1a, 030217 neurology & neurosurgery, Follow-Up Studies, Randomized Controlled Trials as Topic
Abstract: We describe the rationale and design of a double-blind, randomized multicenter, dose-comparison study of interferon-beta-Ia (IFN-beta -Ia: AVONEX(R) in the treatment of relapsing multiple sclerosis (MS). The study is expected to provide quantitative insights on the dose range for optimal clinical benefits in MS. The study involves 802 patients in 10 European countries who have EDSS scores 2.0-5.5, and who have experienced at least two relapses within the 3 years prior to enrolment Patients ore randomized to receive once-weekly intramuscular injections of IFN-beta -Ia 30 or 60 mcg for at least 3 years. The primary endpoint of the study is the effect of IFN-beta -Ia therapy on the time to sustained progression of disability. For patients with a baseline EDSS less than or equal to 4.5, sustained progression of disability is defined as a I point increase in EDSS from baseline, maintained for 6 months. For patients with baseline EDSS less than or equal to 5, sustained progression of disability is defined as reaching on EDSS greater than or equal to 6.0 maintained for 6 months. EDSS scores will be determined every 3 months. A series of prospectively defined secondary and tertiary efficacy endpoints will be examined Safety will be monitored throughout the study. Magnetic resonance imaging (MRI) with and without gadolinium-enhancement has been Performed in at least 358 patients at baseline and repeated annually after enrolment In a subset of these patients, a frequent MRI study is also being performed.
Published: 2001
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115. Adress from the President, January 2017

Author: Edan, G., primary
Published: 2017
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116. treatment with Interferon-Beta-1b delays conversion to clinically definite and MC Donald MS in patients with clinically isolated syndromes

Author: KAPPOS L, POLMAN CH FREEDMAN MS, EDAN G, HARTUNG HP, MILLER DH, MONTALBAN X. BARKHOF F, BAUER L, JAKOBOS P, POHL C, SANDBRINK R, COMI , GIANCARLO, Kappos, L, POLMAN CH FREEDMAN, M, Edan, G, Hartung, Hp, Miller, Dh, MONTALBAN X., BARKHOF F, Bauer, L, Jakobos, P, Pohl, C, Sandbrink, R, and Comi, Giancarlo
Published: 2006

117. Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans

Author: Games Collaborative Group, Ban, M, Booth, D, Heard, R, Stewart, G, Goris, A, Vandenbroeck, K, Dubois, B, Laaksonen, M, Ilonen,J, Alizadeh, M, Edan, G, Babron, MC, Brassat, D, Clanet, M, Cournu Rebeix, I, Fontaine, B, Semana, G, Goedde, R, Epplen, J, Weber, A, Infante Duarte, C, Zipp, F, Rajda, C, Bencsik, K, Vécsei, L, Heggarty, S, Graham, C, Hawkins, S, Liguori,M, Momigliano Richiardi,P, Caputo, D, Grimaldi, LM, Leone, M, Massacesi, L, Milanese, C, Salvetti, M, Trojano, M, Bielecki, B, Mycko, MP, Selmaj, K, Santos, M, Maciel,P, Pereira,C, Silva,A, Silva,BM, Coraddu,F, Marrosu,MG, Akesson,E, Hillert,J, Datta,P, Oturai, A, Harbo, HF, Spurkland,A, Goertsches,R, Villoslada, P, Eraksoy, M, Hensiek,A, Compston,A, Setakis,E, Gray,J, Yeo,TW, Sawcer, S., SAVETTIERI, Giovanni, Games Collaborative Group, Ban, M, Booth, D, Heard, R, Stewart, G, Goris, A, Vandenbroeck, K, Dubois, B, Laaksonen, M, Ilonen,J, Alizadeh, M, Edan, G, Babron, MC, Brassat, D, Clanet, M, Cournu-Rebeix, I, Fontaine, B, Semana, G, Goedde, R, Epplen, J, Weber, A, Infante-Duarte, C, Zipp, F, Rajda, C, Bencsik, K, Vécsei, L, Heggarty, S, Graham, C, Hawkins, S, Liguori,M, Momigliano-Richiardi,P, Caputo, D, Grimaldi, LM, Leone, M, Massacesi, L, Milanese, C, Salvetti, M, Savettieri, G, Trojano, M, Bielecki, B, Mycko, MP, Selmaj, K, Santos, M, Maciel,P, Pereira,C, Silva,A, Silva,BM, Coraddu,F, Marrosu,MG, Akesson,E, Hillert,J, Datta,P, Oturai, A, Harbo, HF, Spurkland,A, Goertsches,R, Villoslada, P, Eraksoy, M, Hensiek,A, Compston,A, Setakis,E, Gray,J, Yeo,TW, and Sawcer, S.
Subjects: Multiple sclerosis, Genome screen, Linkage disequilibrium, Meta-analysi, Settore MED/26 - Neurologia, JAG1, POU2AF1
Abstract: By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them — D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.
Published: 2006

118. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis?

Author: Bonenfant, J., primary, Bajeux, E., additional, Deburghgraeve, V., additional, Le Page, E., additional, Edan, G., additional, and Kerbrat, A., additional
Published: 2016
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119. Journées d’enseignement supérieur de neurologie – Nantes 2016

Author: Damier, P., primary, Derkinderen, P., additional, Edan, G., additional, Boutoleau-Bretonnière, C., additional, Verny, C., additional, Desal, H., additional, and Laplaud, D., additional
Published: 2016
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120. Magnetic resonance imaging outcomes from a phase III trial of teriflunomide

Author: Wolinsky, Js, Narayana, Pa, Nelson, F, Datta, S, O'Connor, P, Confavreux, C, Comi, G, Kappos, L, Olsson, Tp, Truffinet, P, Wang, L, Miller, A, Freedman MSMaida, E, Auff, E, Fazekas, F, Berger, T, Bhan, V, Bouchard, Jp, Duquette, P, Freedman, M, Grand'Maison, F, Kremenchutzky, M, Bourque, C, Marrie, Ra, Melanson, M, Patry, D, Oger, J, Stefanelli, M, Jacques, F, Venegas, P, Miranda, M, Barrientos, N, Tenhamm, E, Gloger, S, Rohde, G, Mares, J, Frederiksen, J, Stenager, E, Haldre, S, Gross Paju, K, Elovaara, I, Sumelahti, Ml, Erälinna, Jp, Färkkilä, M, Harno, H, Reunanen, M, Jolma, T, Camu, W, Clavelou, P, Magy, L, Debouverie, M, Edan, G, Lebrun Frenay, C, Moreau, T, Pelletier, J, Roullet, E, Alamowitch, S, Clanet, M, Hautecoeur, P, Damier, P, Rumbach, L, Chan, A, Schimrigk, S, Haas, J, Lensch, E, Diener, H, Limmroth, V, Anders, D, Berghoff, M, Oschmann, P, Stangel, M, Frese, A, Kiefer, R, Marziniak, M, Zettl, U, Stark, E, Jendroska, K, Reifschneider, G, Amato, Mp, Cosi, V, Gallo, Paolo, Gasperini, C, Ghezzi, A, Trojano, M, Pozzilli, C, Montanari, E, Zwanikken, Cp, Jongen, Pj, Centrum, Ms, Van Munster ET, Hupperts, Rm, Anten, B, Sanders, Ea, Celius, E, Hovdal, H, Krogseth, Sb, Kozubski, W, Kwiecinski, H, Czlonkowska, A, Stelmasiak, Z, Selmaj, K, Hasiec, T, Fryze, W, Drozdowski, W, Kochanowicz, J, Cunha, L, De Sá, J, Harrington Sena, A, Odinak, M, Skoromets, A, Gusev, E, Boiko, A, Lashch, N, Stolyarov, I, Belova, A, Malkova, N, Doronin, B, Yakupov, E, Brundin, L, Hillert, J, Karabudak, R, Irkec, C, Idiman, E, Turan, O, Efendi, H, Gedizlioglu, M, Buchakchyyska, N, Goloborodko, A, Ipatov, A, Kobets, S, Lebedynets, V, Moskovko, S, Yushchenko, Oi, Sanotskyy, Y, Smolanka, V, Yavorskaya, V, Bates, D, Evangelou, N, Hawkins, C, Mclean, B, O'Riordan, J, Price, S, Turner, B, Barnes, D, Zajicek, J, Honeycutt, W, Khan, O, Spikol, L, and Stevens, J.
Published: 2013

121. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study

Author: Comi, G., Filippi, M., Barkhof, F., Durelli, L., Edan, G., Fernandez, O., Hartung, H. -P., Seeldrayers, P., Sorensen, P. S., Rovaris, M., Martinelli, V., Hommes, O. R., Uccelli, A., Comi, Giancarlo, Filippi, Massimo, Barkhof, F, Durelli, L, Edan, G, Fernandez, O, Hartung, Hp, Seeldrayers, P, Sorensen, P, Rovaris, M, Martinelli, V, and Hommes, Or
Subjects: Adult, Male, medicine.medical_specialty, Randomization, Multiple Sclerosis, Adolescent, Injections, Subcutaneous, Pathofysiologie van Hersenen en Gedrag, Pathophysiology of Brain and Behaviour, Placebo, Gastroenterology, Severity of Illness Index, Drug Administration Schedule, Central nervous system disease, Double-Blind Method, Recurrence, Reference Values, Internal medicine, medicine, Humans, Optic neuritis, Physical Examination, First episode, Clinically isolated syndrome, medicine.diagnostic_test, business.industry, Multiple sclerosis, Magnetic resonance imaging, General Medicine, Interferon-beta, medicine.disease, Magnetic Resonance Imaging, Surgery, Europe, Logistic Models, Treatment Outcome, Multivariate Analysis, Female, business, Follow-Up Studies
Abstract: Item does not contain fulltext BACKGROUND: Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis. METHODS: Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 microg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections. FINDINGS: 241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0.034). The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment. INTERPRETATION: Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes.
Published: 2001

122. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome

Author: Hartung, Hp, 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, Stourac, P, Taláb, R, Zapletalová, O, Kováøová, I, Medová, 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, Pirttilä, T, Ruutiainen, J, Koivisto, K, Reunanen, M, Elovaara, I, Villringer, A, Altenkirch, H, Wessel, K, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoffmann, F, Baum, K, Jung, S, Petereit, Hf, Reske, D, Sailer, M, Köhler, J, Sommer, N, Hohlfeld, R, Henn, Kh, Steinbrecher, A, Tumani, H, Gold, R, Rieckmann, P, Komoly, R, Gács, G, Jakab, G, Csiba, L, Vécsei, L, Miller, A, Karussis, D, Chapman, J, Ghezzi, A, Comi, G, Gallo, Paolo, Cosi, V, Durelli, L, Anten, B, Visser, L, Myhr, Km, Szczudlik, A, Selmaj, K, Stelmasiak, Z, Podemski, R, Maciejek, Z, Cunha, L, Sega Jazbec, S, Montalba, X, Arbizu, T, Saiz, A, Bárcena, J, Arroyo, R, Fernández, O, Izquierdo, G, Casanova, B, Lycke, J, Kappos, L, Mattle, H, Beer, K, Coleman, R, Chataway, J, O'Riordan, J, and Howell, S. .
Published: 2012

123. Die frühzeitige Behandlung von Patienten nach dem ersten Schub einer Multiplen Sklerose mit Interferon beta-1b verzögert die Entwicklung bleibender neurologischer Schäden

Author: Hartung, HP, Kappos, L, Edan, G, Freedman, MS, Miller, D, Montalban, X, Polman, C, Barkhof, F, Bauer, L, Dahms, S, Pohl, C, and Sandbrink, R
Published: 2024
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124. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome

Author: Hartung, Hp, 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, Stourac, P, Taláb, R, Zapletalová, O, Kováøová, I, Medová, 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, Pirttilä, T, Ruutiainen, J, Koivisto, K, Reunanen, M, Elovaara, I, Villringer, A, Altenkirch, H, Wessel, K, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoffmann, F, Baum, K, Jung, S, Petereit, Hf, Reske, D, Sailer, M, Köhler, J, Sommer, N, Hohlfeld, R, Henn, Kh, Steinbrecher, A, Tumani, H, Gold, R, Rieckmann, P, Komoly, R, Gács, G, Jakab, G, Csiba, L, Vécsei, L, Miller, A, Karussis, D, Chapman, J, Ghezzi, A, Comi, G, Gallo, Paolo, Cosi, V, Durelli, L, Anten, B, Visser, L, Myhr, Km, Szczudlik, A, Selmaj, K, Stelmasiak, Z, Podemski, R, Maciejek, Z, Cunha, L, Sega Jazbec, S, Montalba, X, Arbizu, T, Saiz, A, Bárcena, J, Arroyo, R, Fernández, O, Izquierdo, G, Casanova, B, Lycke, J, Kappos, L, Mattle, H, Beer, K, Coleman, R, Chataway, J, O'Riordan, J, Howell, S. ., Neurology, Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie
Subjects: Multiple Sclerosis, Injections, Subcutaneous, Relapse rate, Brain mri, Medicine, Humans, Longitudinal Studies, Prospective Studies, Clinically isolated syndrome, biology, business.industry, Immunogenicity, Interferon-beta, Antibodies, Neutralizing, Titer, Interferon β 1b, Cross-Sectional Studies, Immunology, biology.protein, Neurology (clinical), Antibody, business, Demyelinating Diseases, Follow-Up Studies, Interferon beta-1b
Abstract: To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b).In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer20 NU/mL was considered NAb-positive, with low (≥20-100 NU/mL), medium (≥100-400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years.NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers.Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.
Published: 2011
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125. Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis

Author: O'Connor, P, Wolinsky, Js, Confavreux, C, Comi, G, Kappos, L, Olsson, Tp, Benzerdjeb, H, Truffinet, P, Wang, L, Miller, A, Freedman, Ms, Reingold, S, Cutter, G, Antel, J, Barkhof, F, Maddrey, W, Ravnborg, M, Schenker, S, Narayana, Pa, Nelson, F, Vainrub, I, Datta, S, He, R, Gates, B, Ton, K, Wamil, B, Igau, B, Nicolas, V, Notelet, L, Payrard, S, Wijnand, P, Devore, S, Li, Hh, Osho, T, Wei, L, Dukovic, D, Ling, Y, Mednikova, Z, Trabelsi, N, Musset, M, Merrill, D, Turpault, S, Williams, B, Nortmeyer, H, Kirst, E, Witthaus, E, Chen, S, Maida, E, Auff, E, Fazekas, F, Berger, T, Bhan, V, Bouchard, Jp, Duquette, P, Grand'Maison, F, Kremenchutzky, M, Bourque, C, Marrie, Ra, Melanson, M, Patry, D, Oger, J, Stefanelli, M, Jacques, F, Venegas, P, Miranda, M, Barrientos, N, Tenhamm, E, Gloger, S, Rohde, G, Mares, J, Frederiksen, J, Stenager, E, Haldre, S, Gross Paju, K, Elovaara, I, Sumelahti, Ml, Erälinna, Jp, Färkkilä, M, Harno, H, Reunanen, M, Jolma, T, Camu, W, Clavelou, P, Magy, L, Debouverie, M, Edan, G, Lebrun Frenay, C, Moreau, T, Pelletier, J, Roullet, E, Alamowitch, S, Clanet, M, Hautecoeur, P, Damier, P, Rumbach, L, Chan, A, Schimrigk, S, Haas, J, Lensch, E, Diener, H, Limmroth, V, Anders, D, Berghoff, M, Oschmann, P, Stangel, M, Frese, A, Kiefer, R, Marziniak, M, Zettl, U, Stark, E, Jendroska, K, Reifschneider, G, Amato, Mp, Cosi, V, Gallo, Paolo, Gasperini, C, Ghezzi, A, Trojano, M, Pozzilli, C, Montanari, E, Zwanikken, Cp, Jongen, Pj, Van Munster ET, Hupperts, Rm, Anten, B, Sanders, Ea, Celius, E, Hovdal, H, Krogseth, Sb, Kozubski, W, Kwiecinski, H, Czlonkowska, A, Stelmasiak, Z, Selmaj, K, Hasiec, T, Fryze, W, Drozdowski, W, Kochanowicz, J, Cunha, L, De Sá, J, Sena, Ah, Odinak, M, Skoromets, A, Gusev, E, Boiko, A, Lashch, N, Stolyarov, I, Belova, A, Malkova, N, Doronin, B, Yakupov, E, Brundin, L, Hillert, J, Karabudak, R, Irkec, C, Idiman, E, Turan, O, Efendi, H, Gedizlioglu, M, Buchakchyyska, N, Goloborodko, A, Ipatov, A, Kobets, S, Lebedynets, V, Moskovko, S, Sanotskyy, Y, Smolanka, V, Yavorskaya, V, Bates, D, Evangelou, N, Hawkins, C, Mclean, B, O'Riordan, J, Price, S, Turner, B, Barnes, D, Zajicek, J, Honeycutt, W, Khan, O, Spikol, L, and Stevens, J.
Published: 2011

126. Prognostic implications of a carefully performed neurological assessment in patients with a first event suggestive of multiple sclerosis (vol 9, pg 19, 2009)

Author: Nielsen, J.M., Pohl, C., Polman, C.H., Barkhof, F., Freedman, M.S., Edan, G., Miller, D. H., Bauer, L., Sandbrink, R., Kappos, L., Uitdehaag, B.M.J., Neurology, Radiology and nuclear medicine, Epidemiology and Data Science, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases
Published: 2011
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127. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

Author: Ernst Wilhelm, Radue, William, H. Stuart, Peter, A. Calabresi, Christian, Confavreux, Steven, L. Galetta, Richard, A. Rudick, Fred, D. Lublin, Bianca, Weinstock Guttman, Daniel, R. Wynn, Elizabeth, Fisher, Athina, Papadopoulou, Frances, Lynn, Michael, A. Panzara, Alfred, W. Sandrock, For, the SENTINEL Investigators including F. Fazekas, Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Deisenhammer, F., Decoo, D, Lampaert, J., Bartholome, E., Bier, J., Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Finland:, J. Eralinna, Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, Ferriby, D., Debouverie, M., Pittion Vouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach, L., Decavel, P., Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, Guttman, Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher E. Rothenfusser Körber, A. Steinbrecher E. Rothenfusser Körber, Zellner, Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Israel:, O. Abramsky, Karusiss, D., Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, : C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fernandez Fernandez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Switzerland:, L. Kappos, Achtnichts, L., Wilmes, S., Turkey:, R. Karabudak, Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni, G., Lim, E. T., Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss, M., Gupta, V., Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel, A., Babu, A., Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor, P., Humphries, S., Wynn, D., Nagar, C., O'Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Javerbaum, J., Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo, B., Kishner, R., Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan, S., Yerby, M., Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., Ko, M., Gelber, D., Fortin, C., Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir J. Brockington, K. Bashir J. Brockington, Nicholas, A., Slaughter, R., Archer S. Harik, R. Archer S. Harik, Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Chandler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., Tandon, R., Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O'Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair, M., Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases
Subjects: Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Relapsing-Remitting, Placebo, Antibodies, Monoclonal, Humanized, Gastroenterology, Antibodies, Central nervous system disease, Pharmacotherapy, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, pathology/therapy, Drug Therapy, Internal medicine, Monoclonal, Medicine, Humans, Immunologic Factors, Humanized, medicine.diagnostic_test, business.industry, Multiple sclerosis, Patient Selection, Interferon beta-1a, Antibodies, Monoclonal, Brain, Magnetic resonance imaging, Interferon-beta, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Surgery, Treatment Outcome, Neurology, therapeutic use, Combination, Drug Therapy, Combination, pathology, Female, Neurology (clinical), Adolescent, Adult, Antibodies, Humanized, Antibodies, therapeutic use, Brain, pathology, Drug Therapy, Combination, Female, Humans, Immunologic Factors, therapeutic use, Interferon-beta, therapeutic use, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, pathology/therapy, Patient Selection, Treatment Outcome, business, medicine.drug
Abstract: The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.
Published: 2010
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128. daclizumab in active relapsing multiple clerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta

Author: Jacques, F, Melanson, M, Kremenchutzky, M, Lapierre, Y, O'Connor, P, Blevins, G, Wandinger, K, Sommer, N, Heesen, C, Pozzilli, C, Gallo, Paolo, Comi, G, Arbizu, T, Fernandez, O, Montalban, X, Casanova, B, Garcia Moreno, A, Absher, J, Cooper, J, Khatri, B, Fox, E, Wynn, D, Picone, M, Herbert, J, Lynch, S, Minagar, A, Carter, J, Sullivan, H, Martin, J, Ford, C, Phillips, T, Kasper, L, Dunn, J, English, J, Steingo, B, Edwards, K, Honeycutt, W, Jacobs, A, Kaufman, M, Freedman, M, Pugh, S, Vollmer, T, Thomas, F, Pirko, I, Markowitz, C, Rose, J, Storey, J, Jeffery, D, Kahn, O, Dickson, R, Gottesman, M, Miller, De, Reingold, Sc, Cutter, G, Wolinsky, J, Freedman, Ms, Edan, G., Wynn, D, Kaufman, M, Montalban, X, Vollmer, T, Simon, J, Elkins, J, O'Neil, G, Neyer, L, Sheridan, J, Wang, C, Comi, Giancarlo, and ROSE JW CHOICE, Investigator
Subjects: Adult, Male, medicine.medical_specialty, Daclizumab, Adolescent, T-Lymphocytes, Antibodies, Monoclonal, Humanized, Placebo, Gastroenterology, law.invention, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, Randomized controlled trial, law, Internal medicine, medicine, Clinical endpoint, Humans, Immunologic Factors, Lymphocytes, Cell Proliferation, Intention-to-treat analysis, business.industry, Multiple sclerosis, Antibodies, Monoclonal, Brain, Interferon-beta, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Magnetic Resonance Imaging, CD56 Antigen, eye diseases, Treatment Outcome, Immunoglobulin G, Pharmacodynamics, Immunology, Monoclonal, Female, Neurology (clinical), business, Immunosuppressive Agents, medicine.drug
Abstract: Summary Background Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. Methods We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161. Findings From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4·75 in the interferon beta and placebo group compared with 1·32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0·004) and 3·58 in the interferon beta and low-dose daclizumab group (25%, −76% to 68%; p=0·51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56 bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0·002; interferon beta and high-dose daclizumab group p Interpretation Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. Funding Facet Biotech and Biogen Idec.
Published: 2010

129. 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: 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, Stourac, P, Taláb, R, Zapletalová, O, Kovárová, I, Medová, 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, Pirttilä, T, Ruutiainen, J, Koivisto, K, Reunanen, M, Elovaara, I, Villringer, A, Altenkirch, H, Wessel, K, Hartung, Hp, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoff, F, Baum, K, Jung, S, Felicitas Petereit, H, Reske, D, Sailer, M, Köhler, J, Sommer, N, Hohlfeld, R, Henn, Kh, Steinbrecher, A, Tumani, H, Gold, R, Rieckmann, P, Komoly, R, Gács, G, Jakab, G, Csiba, L, Vécsei, L, Miller, A, Karussis, D, Chapman, J, Ghezzi, A, Comi, G, Gallo, Paolo, Cosi, V, Durelli, L, Anten, B, Visser, L, Myhr, Km, Szczudlik, A, Selmaj, K, Stelmasiak, Z, Podemski, R, Maciejek, Z, Cunha, L, Sega Jazbec, S, Montalbán, X, Arbizu, T, Saiz, A, Bárcena, J, Arroyo, R, Fernández, O, Izquierdo, G, Casanova, B, Lycke, J, Kappos, L, Mattle, H, Beer, K, Coleman, R, Chataway, J, O'Riordan, J, Howell, S, Miller, Dh, Polman, Ch, Bauer, L, Ghazi, M, Pohl, C, Sandbrink, R, Barkhof, F, Uitdehaag, B, de Vera, A, Wu, S, Radü, Ew, Mcfarland, Hf, Kesselring, J, Petkau, Aj, Toyka, K. V., Dubois, Bénédicte, Neurology, Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Adult, Male, Questionnaires, medicine.medical_specialty, Multiple Sclerosis, Kaplan-Meier Estimate, Placebo, Risk Assessment, Young Adult, Disability Evaluation, Double-Blind Method, Surveys and Questionnaires, Internal medicine, medicine, Humans, Proportional Hazards Models, Intention-to-treat analysis, Expanded Disability Status Scale, Clinically isolated syndrome, business.industry, Multiple sclerosis, Interferon beta-1b, Hazard ratio, Interferon-beta, medicine.disease, Magnetic Resonance Imaging, Surgery, Tolerability, Data Interpretation, Statistical, Disease Progression, Female, Neurology (clinical), business
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. ispartof: The Lancet Neurology vol:8 issue:11 pages:987-997 ispartof: location:England status: published
Published: 2009
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130. THE PREVENTION OF POST-PARTUM RELAPSES WITH PROGESTIN AND ESTRADIOL IN MULTIPLE SCLEROSIS (POPART'MUS) TRIAL: RATIONALE, OBJECTIVES AND STATE OF ADVANCEMENT

Author: Vukusic, S, Ionescu, I, El Etr, M, Schumacher, M, Baulieu, Ee, Cornu, C, Confavreux, C, Clanet, M, Brassat, D, Viala, F, Moreau, T, Couvreur, G, Madinier, G, Debouverie, M, Laplaud, D, Wiertlewski, S, Clavelou, P, Aufauvre, D, Pelletier, J, Rico Lamy, A, Edan, G, Le Page, E, Rumbach, L, Berger, E, Hautecoeur, P, Lebrun Frenay, C, Labauge, P, Castelnovo, G, Heinzlef, O, Brochet, B, Ouallet, Jc, Clerc, C, Rieu, L, Lauxerois, M, Hinzelin, G, Froment Sallansonnet, M, Stankoff, B, Borgel, F, Toureille Borlet, L, Minier, D, Coustans, M, Tourniaire, P, Durelli, Luca, Tavella, A, Trojano, M, Carrozzo, A, Patti, F, Zaffaroni, M, and Motti, L.
Published: 2009

131. 250 mu g or 500 mu g interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study

Author: O'Connor, P., Filippi, M., Arnason, B., Comi, G., Cook, S., Goodin, D., Hartung, H., Jeffery, D., Kappos, L., Boateng, F., Filippov, V., Groth, M., Knappertz, V., Kraus, C., Sandbrink, R., Pohl, C., BogumilAbramsky O, T., Achiron, A, Agius, M, Aichner, F, Altenkirch, H, Amato, Mp, Anten, B, Arbizu, T, Ash, P, Ballario, C, Bashir, K, Baum, K, Baumhackl, U, Beaver, G, Belova, A, Berger, J, Berger, T, Berlit, P, Beuche, W, Bhan, V, Bigley, K, Bissay, V, Blake, C, Bö, L, Boyko, A, Brochet, B, Brown, M, Callegaro, D, Carra, A, Carroll, W, Cascione, M, Christie, S, Clanet, M, Clavelou, P, Clementino, Vi, Confavreux, C, Cooper, J, Cross, A, Csanyi, A, Czlonkowska, A, D'Hooghe, M, Damier, P, Debouverie, M, Defer, G, Demina, T, Deri, N, Diem, R, Dressel, A, Dubois, B, Dunne, P, Duquette, P, Durelli, L, Edan, G, Elias, S, Elovaara, I, Esfahani, F, Evtushenko, S, Fabijan, Th, Fernández, O, Ferreira, Ml, Fink, A, Flechter, S, Ford, C, Francesconi, C, Freedman, M, Fryze, W, Gabbai, A, Gács, G, Gallo, Paolo, Gazda, S, Gerloff, C, Glyman, S, Goodman, A, Gottesman, M, Grand'Maison, F, Guarnaccia, J, Gutierrez, A, Haas, J, Hansen, Hj, Hardiman, O, Heard, R, Heidenreich, F, Herbert, J, Herminia Scola, R, Hodgkinson, S, Hoffmann, F, Holub, R, Huddlestone, J, Hughes, B, Hughes, M, Hunter, S, Hurwitz, B, Izquierdo, G, Jacobasch, E, Jacques, F, Jakab, G, Jongen, P, Karageorgiou, C, Karni, A, Kasper, L, Kaufman, M, Keidel, M, Khatri, B, Kiefer, R, Kirzinger, S, Kita, M, Komoly, S, Kotov, S, Kozubski, W, Kumlien, E, Kwiecinski, H, Labouge, P, Laganke, C, Lapierre, Y, Lebrun Frenay, C, Leist, T, Leon, Sa, Luetic, G, Lynch, S, Lynch, T, Malkova, N, Maltezou, M, Markowitz, C, Martin, C, Mattle, H, Mattson, D, Metra, M, Meyding Lamadé, U, Milo, R, Milonas, I, Miller, A, Miller, T, Minagar, A, Mitchell, G, Moreau, T, Mosberg, R, Murphy, R, Nehrych, T, Nikl, J, Odinak, M, Oschmann, P, Owen King, J, Pagani, L, Pereira Damasceno, B, Podemski, R, Pöhlau, D, Pozzilli, C, Rammohan, K, Reunanen, M, Rice, G, Richardson, P, Rivera, V, Rizvi, S, Rogozhyn, V, Rolak, L, Rosenkranz, T, Rotta, R, Sanders, E, Sater, R, Satgur Gupta, A, Schwartz, R, Sedal, L, Sega Jazbec, S, Selchen, D, Selmaj, K, Sheremata, W, Shvets, T, Silver, D, Simsarian, J, Skoromets, A, Smiroldo, J, Sokolova, L, Solovyova, Y, Sommer, N, Spirin, N, Stangel, M, Stark, E, Steinbrecher, A, Stemper, B, Stolyarov, I, Strasser Fuchs, S, Sweeney, B, Tettenborn, B, Thrower, B, Tilbery, Cp, Traboulsee, A, Trojano, M, Tubridy, N, Tyor, W, Valikovics, A, Vermersch, P, Vollmer, T, Voloshyna, N, Vrech, C, Wajgt, A, Weller, B, Wendt, J, Yakhno, N, Yeung, M, Zavalishin, I., O'Connor, P, Filippi, Massimo, Arnason, B, Comi, G, Cook, S, Goodin, D, Hartung, Hp, Jeffery, D, Kappos, L, Boateng, F, Filippov, V, Groth, M, Knappertz, V, Kraus, C, Sandbrink, R, Pohl, C, Bogumil, T., and Dubois, Bénédicte
Subjects: Adult, Male, medicine.medical_specialty, interferon beta-1b, Adolescent, Pharmacology, relapsing-remitting multiple sclerosis, law.invention, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Internal medicine, medicine, Humans, Immunologic Factors, Glatiramer acetate, Adverse effect, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Multiple sclerosis, Interferon beta-1b, Brain, Glatiramer Acetate, Interferon-beta, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Tolerability, glatiramer acetate, Female, Neurology (clinical), business, Peptides, medicine.drug
Abstract: BACKGROUND: The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. METHODS: Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. FINDINGS: We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p
Published: 2009

132. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL

Author: Calabresi, Pa, Giovannoni, G, Confavreux, C, Galetta, Sl, Havrdova, E, Hutchinson, M, Kappos, L, Miller, Dh, O'Connor, Pw, Phillips, Jt, Polman, Ch, Radue, Ew, Rudick, Ra, Stuart, Wh, Lublin, Fd, Wajgt, A, Weinstock Guttman, B, Wynn, Dr, Lynn, F, Panzara, Ma, Affirm, Investigators, Fazekas, SENTINEL Investigators including: F., Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Eisenhammer, F., Decoo J. Lampaert, D. Decoo J. Lampaert, Bartholome J. Bier, E. Bartholome J. Bier, Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittionvouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach P. Decavel, L. Rumbach P. Decavel, Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, A., Guttman, E., Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher, A., Rothenfusser Körber, E., Zellner, R., Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Abramsky D. Karusiss, O. Abramsky D. Karusiss, Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fern ez Fern ez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Kappos, L., Achtnichts, L., Wilmes, S., Karabudak, R., Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni ET Lim, G. Giovannoni E. T. Lim, Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss V. Gupta, M. Reiss V. Gupta, Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel A. Babu, A. Perel A. Babu, Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor S. Humphries, P. Fodor S. Humphries, Wynn, D., Nagar, C., O’Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., S. M, El, Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Kaiser, J. Javerbaum, Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo R. Kishner, B. Steingo R. Kishner, Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan M. Yerby, S. Cohan M. Yerby, Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., KoD Gelber C. Fortin, M. K. o. D. Gelber C. Fortin, Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, J., Nicholas, A., Slaughter, R., Archer, R., Harik, S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Ch ler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., R. T, On, Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Ari, D. B, Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O’Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair EW Radue, M. S. i. n. c. l. a. i. r. E. W. Radue, de Vera, A., Bacelar, O., Kuster, P., and Kappos, L. .
Subjects: medicine.medical_specialty, Multiple Sclerosis, Enzyme-Linked Immunosorbent Assay, Relapsing-Remitting, Antibodies, Monoclonal, Humanized, Gastroenterology, Antibodies, law.invention, Disability Evaluation, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Antibody Specificity, Internal medicine, Monoclonal, medicine, Secondary Prevention, Humans, Adverse effect, Antibodies, Blocking, Humanized, Antibodies, Monoclonal, Brain, Flow Cytometry, Interferon-beta, Magnetic Resonance Imaging, Placebo Effect, Treatment Outcome, Neuroscience (all), Expanded Disability Status Scale, business.industry, Multiple sclerosis, Incidence (epidemiology), Interferon beta-1a, medicine.disease, Blocking, Multiple sclerosis functional composite, Immunology, Neurology (clinical), business, medicine.drug
Abstract: Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. Methods: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon β-1a [INFβ1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as “transiently positive” if they had detectable antibodies (≥0.5 μg/mL) at a single time point or “persistently positive” if they had antibodies at two or more time points ≥6 weeks apart. Results: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression ( p ≤ 0.05), relapse rate ( p = 0.009), and MRI ( p ≤ 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant. Conclusions: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing. GLOSSARY: BLQ = below the limit of quantification; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; IFNβ1a = interferon β-1a; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OD = optical density.
Published: 2007

133. Health-related quality of life in multiple sclerosis: Effects of natalizumab

Author: Rudick, R. A., Miller, D., Hass, S., Hutchinson, M, Calabresi, P. A., Confavreux, C., Galetta, S. L., Giovannoni, G., Havrdova, E., Kappos, L., Lublin, F. D., Miller, D. H., O'Connor, P. W., Phillips, J. T., Polman, C. H., Radue, Ew, Stuart, W. H., Wajgt, A., Weinstock Guttman, B., Wynn, D. R., Lynn, F., Panzara, M. A., Affirm, Macdonell, SENTINEL Investigators including: R., Hughes, A., Taylor, I., Lee, Y. C., Ma, H., King, J., Kilpatrick, T., Butzkueven, H., Marriott, M., Pollard, J., Spring, P., Spies, J., Barnett, M., Dehaene, I., Vanopdenbosch, L., D’Hooghe, M., Van Zandijcke, M., Derijck, O., Seeldrayers, P., Jacquy, J., Piette, T., De Cock, C., Medaer, R., Soors, P., Vanroose, E., Vanderhoven, L., Nagels, G., Dubois, B., Deville, M. C., D’Haene, R., Jacques, F., Hallé, D., Gagnon, S., Likavcan, E., Murray, T. J., Bhan, V., Mackelvey, R., Maxner, C. E., Christie, S., Giaccone, R., Guzman, D. A., Melanson, M., Esfahani, F., Gomori, A. J., Nagaria, M. H., Grand’Maison, F., Berger, L., Nasreddine, Z., Duplessis, M., Brunet, D., Jackson, A., Pari, G., O’Connor, P., Gray, T., Hohol, M., Marchetti, P., Lee, L., Murray, B., Sahlas, J., Perry, J., Devonshire, V., Hooge, J., Hashimoto, S., Oger, J., Smyth, P., Rice, G., Kremenchutzky, M., Stourac, P., Kadanka, Z., Benesova, Y., Niedermayerova, I., Meluzinova, E., Marusic, P., M, Bojar, Zarubova, K., Houzvicková, E., Piková, J., Talab, R., Faculty, Hospital Olomouc, Olomouc, B. Muchova, Urbánek, K, Kettnerova, Z., Mares, J., Otruba, P., Zapletalová, O., Hradilek, P., Ddolezil, D. Dolezil, Woznicova, I., Höfer, R., Ambler J. Fiedler, Z. Ambler J. Fiedler, Sucha, J., Matousek, V., Rektor, I., Dufek, M., Mikulik, R., Mastik, J., Tyrlikova, I., General, Teaching Hospital, Prague, E. Havrdová, Horakova, D., Kalistová, H., Týblová, M., Ehler, E., Novotná, A., Geier, P., Soelberg Sorensen, P., Ravnborg, M., Petersen, B., Blinkenberg, M., Färkkilä, M., Harno, H., Kallela, M., Häppölä, O., Elovaara, I., Kuusisto, H., Ukkonen, M., Peltola, J., Palmio, J., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Edan, G., Le Page, E., Mérienne, M., Yaouanq, J., Clanet, M., Mekies, C., Azais Vuillemin, C., Senard, A., Lau, G., Steinmetz, G., Warter V. Wolff, J. Warter V. Wolff, Fleury, M., Tranchant, C., Stark, E., Buckpesch Heberer, U., Henn, K. H., Skoberne, T., Schimrigk, S., Hellwig, K., Brune, N., Weiller, C., Gbadamosi, J., Röther, J., Heesen, C., Buhmann, C., Karageorgiou, C., Korakaki, D., Giannoulis, D. r., Tsiara, S., Thomaides, T., Thomopoulos, I., Papageorgiou, H., Armakola, F., Komoly, S., Rózsa, C., Matolcsi, J., Szabó, G. y., Molnár, B., Lovas, G., Dioszeghy, P., Szulics, P., Magyar, Z., Incze, J., Farkas, J., Clemens, B., Kánya, J., Valicskó, Z. s., Bense, E., Nagy, Z. s., Geréby, G., Perényi, J., Simon, Z. s., Szapper, M., Gedeon, L., Csanyi, A., Rum, G., Lipóth, S., Szegedi, A., Jávor, L., Nagy, I., Adám, I., Szirmai, I., Simó, M., Ertsey, C., I, Amrein, Kamondi, A., Harcos, P., Dobos, E., Szabó, B., Balas, V., Guseo, A., Fodor, E., Jófejü, E., Eizler, K., Csiba, L., Csépány, T., Pallagi, E., Bereczki, D., Jakab, G., Juhász, M., Bszabó, B. Szabó I. Mayer, Katona, G., Hutchinson, M., O’Dwyer, J., O’Rourke, K., Sanders, E. A. C. M., Rijk van Andel, J. F., Bomhof, M. A. M., van Erven, P., Hintzen I. Hoppenbrouwers, R. Q. Hintzen I. Hoppenbrouwers, Neuteboom, R. F., Zemel, D., van Doorn, P. A., Jacobs, B. C., Munster, E. T. h. L. Van, ter Bruggen, J. P., Bernsen, R., Jongen, P. J. H., de Smet, E. A. A., Tacken, H. F. H., Polman, C., Zwemmer, J., Nielsen, J., Kalkers, N., Kragt, J., Jasperse, B., Willoughby, E., Anderson, N. E., Barber, A., Anderson, T., Parkin, P. J., Fink, J., Avery, S., Mason, D., Kwiecinski, H., Zakrzewska Pniewska, B., Kaminska, A., Podlecka, A., Nojszewska, M., Czlonkowska, A., Zaborski, J., Wicha, W., Kruszewska Ozimowska, J., Darda Ledzion, L., Selmaj, K., Mochecka Thoelke, A., Pentela Nowicka, J., Walczak, A., Stasiolek, M., Stelmasiak, Z., Bartosik Psujek, H., Mitosek Szewczyk, K., Belniak, E., Chyrchel, U., Maciejowski, M., Strzyzewska Lubos, L., Lubos, L., Matusik, E., Maciejek, Z., Niezgodzinska Maciejek, A., Sobczynska, D., Slotala, T., Wawrzyniak, S., Kochanowicz K. Kuczynski, J. Kochanowicz K. Kuczynski, Zimnoch, R., Pryszmont, M., Drozdowski, W., Baniukiewicz, E., Kulakowska, A., Borowik, H., Lewonowska, M., Szczudlik, A., Róg, T., Gryz Kurek, E., Pankiewicz, J., Furgal, J., Kimkowicz, A., Fryze, W., Wierbicki, T., Michalak, L., Kowalewska, J., Swiatkiewicz, J., Hillert, J., Åkesson, E, Fredrikson, S., Diener, P, Olsson, T., Wallström, E., Fpiehl, F. Piehl L. Hopia, Brundin, L., Marta, M., Andersson, M., Lycke, J., Runmarker, B., Malmeström, C., Vaghfeldt, P., Skoog, B., Schluep, M., Bogousslavskyr, J., Du Pasquier, R., Achtnichts, L., Kuhle, J., Buitrago Telez, C., Schläger, R., Naegelin, Y., Eraksoy, M., Bebek, N., Akman Demir, G., Topcuoglu, B., Kurtuncu, M., Istanbul, University, Istanbul:, A. Siva, Saip, S., Altintas, A., Kiyat, A., Sharief, M., Kasti, M., Lim, E. T., Rashid, W., Silber, E., Saldanha, G., Hawkins, C., Mamutse, G., Woolmore, J., Hawkes, C., Findley, L., Dasilva, R., Gunasekara, H., Palace, J., Cader, Z., Littleton, E., Burke, G., Sharrack O. Suliman, B. Sharrack O. Suliman, Klaffke, S., Swash, M., Dhillon, H., Bates, D., Westwood, M., Nichol, P., Barnes, D., Wren, D., Stoy, N., Robertson, N., Pickersgill, T., Pearson, O., Lawthom, C., Young, C., Mills, R., Lecky, B., Ford, C., Katzman, J., Rosenberg, G., Cooper, J., Wrubel, B., Richardson, B., Lynch, S., Ridings, L., Mcvey, A., Nowack, W., Rae Grant, A., Mackin, G. A., Castaldo, J. E., Spikol, L. J., Carter, J., Wingerchuk, D., Caselli, R., Dodick, D., Scarberry, S., Bailly, R., Garnaas, K., Haake, B., Rossman, H., Belkin, M., Boudouris, W. D., Pierce, R. P., Mass, M., Yadav, V., Bourdette, D., Whitham, R. H., Heitzman, D., Martin, A., Greenfield, C. F., Agius, M., Richman, D. P., Vijayan, N., Wheelock, V. L., Reder, A., Arnason, B., Noronha, A., Balabanov, R., Ray, A., Sheremata, W., Delgado, S., Shebert, B., Maldonado, J., Bowen, J., Garden, G. A., Distad, B. J., Carrithers, M., Rizzo, M., Vollmer, T., Reiningerova, J., Guarnaccia, J., Lo, A., Richardson, G. B., Fazekas, F., Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Deisenhammer, F., Decoo, : D, Lampaert, J., Bartholome, E., Bier, J., Stenager, : E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Soelberg Sørensen, P., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Eralinna, : J., Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, : T., Noblet, M., Rouaud, O., Couvreur, G., Lepage, E., Drapier, S., De Burghgraeve, V., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, Ferriby, D., Debouverie, M., Pittion Vouyouvitch, S., Lacour, J. C., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach, L., Decavel, P., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, : S., Grupe, A., Gutmann, E., Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher E. Rothenfusser Körber, A. Steinbrecher E. Rothenfusser Körber, Zellner, R., Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Abramsky, : O., Karusiss, D., Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, : C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, : C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Kragt, J. J., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fernandez Fernandez, : O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Kappos, : L., Wilmes, S., Karabudak, : R., Kurne, A., Erdem, S., Siva, A., Atamer, A., Bilgili, F., Topcular, B., Giovannoni, : G., Lava, : N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss, M., Gupta, V., Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel, A., Babu, A., Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor, P., Humphries, S., Wynn, D., Nagar, C., O’Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Javerbaum, J., Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Boudoris, W., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo, B., Kishner, R., Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan, S., Yerby, M., Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., Ko, M., Gelber, D., Fortin, C., Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir J. Brockington, K. Bashir J. Brockington, Nicholas, A., Slaughter, R., Archer S. Harik, R. Archer S. Harik, Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sherbert, R., Herndon, R., Uschmann, H., Chandler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., Tandon, R., Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Doherty, M., Wundes, A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O’Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair, M., Radue, E. W., de Vera, A., Bacelar, O., and Kuster, P.
Subjects: Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Visual analogue scale, Health Status, Population, Pain, Comorbidity, Placebo, Antibodies, law.invention, Natalizumab, Randomized controlled trial, Quality of life, Double-Blind Method, law, Internal medicine, Surveys and Questionnaires, Monoclonal, medicine, Prevalence, Humans, Longitudinal Studies, education, Humanized, education.field_of_study, Expanded Disability Status Scale, Neuroscience (all), business.industry, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Female, Patient Satisfaction, Treatment Outcome, United States, Quality of Life, Multiple sclerosis, medicine.disease, Neurology, Physical therapy, Neurology (clinical), business, medicine.drug
Abstract: Objective To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-β-1a) plus natalizumab 300mg (n = 589), or IFN-β-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. Ann Neurol 2007
Published: 2007

134. Effect of early versus delayed interferon beta-1b treatment on desability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study

Author: Kappos, L, Freedman, Ms, Polman, Ch, Edan, G, Hartung, Hp, Miller, Dh, Montalbán, X, Barkhof, F, Radü, Ew, Bauer, L, Dahms, S, Lanius, V, Pohl, C, Strasser Fuchs, Sandbrink R. investigators—Austria: S., Graz, T. Berger, Innsbruck, Vass, K., Sindic, V. i. e. n. n. a. Belgium: C., Brussels, B. Dubois, Leuven, D. Dive, Liège, Debruyne, J., Metz, G. h. e. n. t. Canada: L., Calgary, G. Rice, London, Duquette, P., Lapierre, Y., Montreal, M. Freedman, Ottawa, A. Traboulsee, Vancouver, O’Connor, P., Štourač, T. o. r. o. n. t. o. Czech Republic: P., Brno, R. Taláb, Hradec Kralove, O. Zapletalová, Ostrava, Kovářová, I., Medová, E., Prague, Fiedler, J., Frederiksen, P. l. z. e. n. Denmark: J., Brochet, G. l. o. s. t. r. u. p. France: B., Bordeaux, T. Moreau, Dijon, P. Vermersch, Lille, J. Pelletier, Marseille, G. Edan, Rennes, M. Clanet, Toulouse, P. Clavelou, Clermont Ferrand, C. Lebrun Frenay, Nice, Gout, O., Kallela, P. a. r. i. s. Finland: M., Helsinki, T. Pirttilä, Kuopio, J. Ruutiainen, Turku, K. Koivisto, Seinäjoki, M. Reunanen, Oulu, Elovaara, I., Villringer, T. a. m. p. e. r. e. Germany: A., Altenkirch, H., Berlin, K. Wessel, Braunschweig, Hartung, H. P., Steinke, W., Düsseldorf, H. Kölmel, Erfurt, P. Oschmann, Giessen, R. Diem, Göttingen, A. Dressel, Greifswald, F. Hoffmann, Halle/saale, K. Baum, Hennigsdorf, S. Jung, Homburg/saar, Petereit, H., Reske, D., Cologne, M. Sailer, Magdeburg, J. Köhler, Mainz, N. Sommer, Marburg, R. Hohlfeld, Munich, K. H. Henn, Offenbach, A. Steinbrecher, Regensburg, H. Tumani, Ulm, Gold, R., Rieckmann, P., Würzburg, Komoly, R., Gács, G., Jakab, G., Budapest, L. Csiba, Debrecen, Vécsei, L., Miller, S. z. e. g. e. d. Israel: A., Haifa, D. Karussis, Jerusalem, Chapman, J., Ghezzi, Tel H. a. s. h. o. m. e. r. Italy: A., Gallarate, G. Comi, Milan, Gallo, Paolo, V. Cosi, Pavia, Durelli, L., Anten, T. u. r. i. n. Netherlands: B., Sittard, Visser, L., Myhr, T. i. l. b. u. r. g. Norway: K. M., Szczudlik, B. e. r. g. e. n. Poland: A., Kraków, K. Selmaj, Łódź, Z. Stelmasiak, Lublin, R. Podemski, Wrocław, Maciejek, Z., Cunha, B. y. d. g. o. s. z. c. z. Portugal: L., Sega Jazbec, C. o. i. m. b. r. a. Slovenia: S., Montalbán, L. j. u. b. l. j. a. n. a. Spain: X., Arbizu, T., Saiz, A., Barcelona, J. Bárcena, Barakaldo, R. Arroyo, Madrid, O. Fernández, Málaga, G. Izquierdo, Seville, Casanova, B., Lycke, V. a. l. e. n. c. i. a. Sweden: J., Kappos, M. ö. l. n. d. a. l. Switzerland: L., Basel, H. Mattle, Bern, Beer, K., Coleman, St G. a. l. l. e. n. UK: R., Aberdeen, J. Chataway, London, J. O’Riordan, Dundee, and S. Howell, Sheffield
Published: 2007

135. The incidence and significance of anti-natalizumab antibodies. Results from the AFFIRM and SENTINEL

Author: Calabresi, Pa, Giovannoni, G, Confavreux, C, Galetta, Sl, Havrdova, E, Hutchinson, M, Kappos, L, Miller, Dh, O'Connor, Pw, Phillips, Jt, Polman, Ch, Radue, Ew, Rudick, Ra, Stuart, Wh, Lublin, Fd, Wajgt, A, Weinstock Guttman, B, Wynn, Dr, Lynn, F, Panzara, Ma, Fazekas, The following investigators participated in the SENTINEL study: F., Enzinger, * C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, * E., Egg, R., Deisenhammer, F., Lampaert, D. Decoo* J., Bier, E. Bartholome* J., Stenager, Denmark: E., Rasmussen, * M., Binzer, M., Ravnborg, M., Soelberg Sørensen, * P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, * E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, * J., Soilu Hänninen, M., Reunanen, M., Remes, * A., Keskinarkaus, I., Moreau, T., Noblet, * M., Rouaud, O., Couvreur, G., Edan, G., Lepage, * E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Gout, O., Deschamps, * R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, * J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittion Vouyouvitch, * S., Lacour, J. C., Pelletier, J., Feuillet, * L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, * K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, * D., Renouil Guy, N., Cesaro, P., Degos, * F., Benisty, S., Decavel, L. Rumbach* P., Confavreux, C., Blanc, * S., Aubertin, P., Riche, G., Brochet, B., Ouallet, * J. C., Anne, O., Menck, S., Grupe, * A., Guttman, E., Lensch, E., Fucik, * E., Heitmann, S., Hartung, H. P., Schröter, * M., Kurz, F. M. W., Heidenreich, F., Trebst, * C., Pul, R., Hohlfeld, R., Krumbholz, * M., Pellkofer, H., Haas, J., Segert, * A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, * K., Hoffmann, V., Zettl, U., Steinhagen, * V., Adler, S., Steinbrecher, A., Rothenfusser Körber, * E., Zellner, R., Baum, K., Günther, * A., Bläsing, H., Stoll, G., Gold, * R., Bayas, * A., Kleinschnitz, C., Limmroth, V., Katsarava, * Z., Kastrup, O., Haller, P., Stoeve, * S., Höbel, D., Oschmann, P., Voigt, * K., Burger, C. V., Karusiss, O. Abramsky* D., Achiron, A., Kishner, * I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, * D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, Paolo, Ranzato, * F., Tiberio, M., Perini, P., Laroni, A., Marrosu, M., Marchi, * E. Cocco P., Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, * A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, G., Pizzorno, * M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, * V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, * M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, * E., Tacken, H., Frequin, S. T. F. M., Siegers, * H. P., Mauser, H. W., Fernandez Fernandez, O., León, * A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, * C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, * L., Moral, E., Martinez, S., Kappos, L., Achtnichts, * L., Wilmes, S., Karabudak, R., Kurne, * A., Erdem, S., Siva, A., Saip, * S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, * F., Topcular, B., Lim, G. Giovannoni* E. T., Lava, N., Murnane, * M., Dentinger, M., Zimmerman, E., Gupta, M. Reiss* V., Scott, T., Brillman, * J., Kunschner, L., Wright, D., Babu, A. Perel* A., Rivera, V., Killian, * J., Hutton, G., Lai, E., Picone, Bernard W. M., Cadivid, * D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, * A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, * P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, * M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, * C., Tyler, R., Horvit, A., Humphries, P. Fodor* S., Wynn, D., Nagar, * C., O’Brien, D., Allen, N., Turel, A., Friedenberg, * S., Carlson, J., Hosey, J., Crayton, H., Richert, * J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, * Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, * C., Rorick, M., Reed, R., Elias, S., Feit, * H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, * K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, * C., Fleck, J., Horak, H., Javerbaum, J., Elmore, * R., Garcia, E., Tasch, E., Gruener, G., Celesia, * G., Chawla, J., Miller, A., Drexler, * E., Keilson, M., Wolintz, R., Drasby, E., Muscat, * P., Belden, J., Sullivan, R., Cohen, J., Stone, * L., Marrie, R. A., Fox, R., Hughes, B., Babikian, * P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, * W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, * G., Martin, J., Kaufman, D., Stuart, W., English, * J. B., Stuart, D. S., Gilbert, R. W., Kaufman, MS M., Putman, . *. S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, * E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, * H., Rizo, M., Kitaj, M., Blevins, Neurolo J., Smith, * T., Mcgee, F., Honeycutt, W., Brown, * M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, * J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, * S., Dorn, D., Groeschel, A., Kishner, B. Steingo* R., Cohen, B., Melen, * O., Simuni, T., Zee, P., Yerby, S. Cohan* M., Hendin, B., Levine, * T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, * R., Ferrell, W., Stefoski, D., Stevens, * S., Katsamakis, G., Topel, J., Ko, M., Fortin, D. Gelber* C., Green, B., Logan, * W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, * A., Sim, G., Mihai, C., Vertino, * M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, * A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, * A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, * J., Nicholas, A., Slaughter, R., Archer, R., Harik, * S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, * G., Olek, M., Demetriou, M., Shin, R., Cala bresi, * P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, * S., Sherbert, R., Herndon, R., Uschmann, * H., Chandler, A., Markowitz, C., Jacobs, * D., Balcer, L., Mitchell, G., Chakra vorty, * S., Heyman, R., Stauber, Z., Goodman, A., Segal, * B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, * M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, * M., Hawker, K., Ulrich, R., Panitch, H., Hamill, * R., Tandon, R., Dulaney, E., Simnad, V., Miller, * J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, * M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, * R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, * B., Hart, D., Moses, H., Sriram, * S., Fang, J., O’Duffy, A., Kita, M., Taylor, * L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, * S., Lefkowitz, D., Kumar, S., and Sinclair, M.
Published: 2007

136. Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans

Author: Ban M, Booth D, Heard R, Stewart G, Goris A, Vandenbroeck K, Dubois B, Laaksonen M, Ilonen J, Alizadeh M, Edan G, Babron MC, Brassat D, Clanet M, Cournu-Rebeix I, Fontaine B, Semana G, Goedde R, Epplen J, Weber A, Infante-Duarte C, Zipp F, Rajda C, and Bencsi
Published: 2006

137. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis

Author: Richard, A. Rudick, William, H. Stuart, Peter, A. Calabresi, Christian, Confavreux, Steven, L. Galetta, Ernst Wilhelm, Radue, Fred, D. Lublin, Bianca, Weinstock Guttman, Daniel, R. Wynn, Frances, Lynn, Msc, M. S. c., Michael, A. Panzara, Alfred, W. Sandrock, For, the SENTINEL Investigators including: F. Fazekas, Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Eisenhammer, F., Decoo J. Lampaert, D. Decoo J. Lampaert, Bartholome J. Bier, E. Bartholome J. Bier, Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Eralinna, J., Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, A., Ferriby, D., Debouverie, M., Pittionvouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach P. Decavel, L. Rumbach P. Decavel, Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, A., Guttman, E., Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher, A., Rothenfusser Körber, E., Zellner, R., Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Abramsky D. Karusiss, O. Abramsky D. Karusiss, Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fern ez Fern ez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Kappos, L., Achtnichts, L., Wilmes, S., Karabudak, R., Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni ET Lim, G. Giovannoni E. T. Lim, Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss V. Gupta, M. Reiss V. Gupta, Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel A. Babu, A. Perel A. Babu, Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor S. Humphries, P. Fodor S. Humphries, Wynn, D., Nagar, C., O’Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., S. M, El, Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Kaiser, J. Javerbaum, Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, A., Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo R. Kishner, B. Steingo R. Kishner, Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan M. Yerby, S. Cohan M. Yerby, Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., KoD Gelber C. Fortin, M. K. o. D. Gelber C. Fortin, Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir, K., Brockington, J., Nicholas, A., Slaughter, R., Archer, R., Harik, S., Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Ch ler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., R. T, On, Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Ari, D. B, Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O’Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair EW Radue, M. S. i. n. c. l. a. i. r. E. W. Radue, de Vera, A., Bacelar, O., Kuster, P., and Kappos, L. .
Subjects: Adult, Male, Infusions, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Combination therapy, Integrin alpha4, Peripheral edema, Progressive Multifocal, Relapsing-Remitting, Gastroenterology, Antibodies, Natalizumab, Drug Therapy, Leukoencephalopathy, Internal medicine, Monoclonal, Secondary Prevention, medicine, Humans, Humanized, Proportional Hazards Models, Expanded Disability Status Scale, business.industry, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Brain, Cell Adhesion Molecules, Disease Progression, Drug Therapy, Combination, Female, Infusions, Intravenous, Interferon-beta, JC Virus, Leukoencephalopathy, Progressive Multifocal, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Medicine (all), Progressive multifocal leukoencephalopathy, Multiple sclerosis, Hazard ratio, Interferon beta-1a, General Medicine, medicine.disease, Surgery, Combination, medicine.symptom, Intravenous, business, medicine.drug
Abstract: Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an α 4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P
Published: 2006

138. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity

Author: Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, and Miterski B
Subjects: MSSS, MS, EDSS
Abstract: BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.
Published: 2005

139. Interferon beta-1a in relapsing multiple sclerosis: four-year extension of the European IFNbeta-1a Dose-Comparison Study

Author: Clanet, M., Kappos, L., Hartung, H.P., Hohlfeld, R., Kristoferitsch, W., Schrieber, A., Schlederer, A., Seeldrayers, P., Piette, A., Papacostas, S., Kyriallis, K., Pantzaris, A., Brochet, B., Gayou, A., Rouanet, M., Rouant, F., Confavreux, C., Riche, G., Blanc, S., Achiti, J., Magnier, C., Aubertin, P., Mekies, C., Brassat, D., Thalamas, C., Vuilleman, C., Senard, A., Lau, G., Cesaro, P., Degos, F., Defer, G., Schaeffer, S., Edan, G., de Marco, A., Cahagne, V., Belliard, S., Lyon-Caen, O., Stankoff, B., Lubetzki, C., Arnulf, I., Damier, P., Pelletier, J., Tamman, D., Suchet, L., Dalecky, A., Rumbach, L., Moulin, A., Berger, E., Roullet, E., Pez, D., Heinzlef, O., Lecanuet, P., Vermersch, P., Engles, A., Dengler, R., Heidenreich, F., Lindert, A., Koehler, A., Windhagen, A., Steiner, A., Zschenderlein, R., Luenemann, J., Gelderblom, H., Kassim, N., Storch-Hagenlocher, B., Koerner, A., Vogt-Schaden, A., Stingle, A., Storch-Hagenlocher, A., Sailer, 27449, Matzke, A., Dose, A., Weiler, C., Kunze, K., Heesen, C., Bamborschke, P., Petereit, H., Liu, A., Nolden, A., Grunwald, F., Menck, A., Grupe, A., Rieckmann, P., Weilbach, A., Flachenecker, A., Chan, A., Maurer, A., de Keyser, Jacques, Zwanniken, G., Zorgdrager, A., Montalban, X., Nos, A., Fernandez, O., Tamayo, J.A., Romero, F., Arbizu, T., Martinez-Yelamos, A., Martin, A, and Casado, A.
Subjects: Adult, Male, medicine.medical_specialty, Injections, Intramuscular, Central nervous system disease, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Adjuvants, Immunologic, Internal medicine, Epidemiology, Clinical endpoint, medicine, Humans, 030212 general & internal medicine, Clinical efficacy, business.industry, Incidence (epidemiology), Multiple sclerosis, Interferon beta-1a, Interferon-beta, medicine.disease, Surgery, Europe, Interferon β 1a, Treatment Outcome, Neurology, Disease Progression, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug, Follow-Up Studies
Abstract: Background: Multiple sclerosis (MS) is a chronic disease requiring long-term monitoring of treatment. Objective: To assess the four-year clinical efficacy of intramuscular (IM) IFNb-1a in patients with relapsing MS from the European IFNb-1a Dose-C omparison Study. Methods: Patients who completed 36 months of treatment (Part 1) of the European IFNb-1a Dose-C omparison Study were given the option to continue double-blind treatment with IFNb-1a 30 mcg or 60 mcg IM once weekly (Part 2). Analyses of 48-month data were performed on sustained disability progression, relapses, and neutralizing antibody (NA b) formation. Results: O f 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. IFNb-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months. There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48% and 43%, respectively), and annual relapse rates; relapses tended to decrease over 48 months. The incidence of patients who were positive for NAbs at any time during the study was low in both treatment groups. Conclusion: C ompared with 60-mcg IM IFNb-1a once weekly, a dose of 30 mcg IM IFNb-1a once weekly maintains the same clinical efficacy over four years.
Published: 2004

140. Myélopathie postérieure par carence en cuivre acquise

Author: Videt-Gibou, D., Belliard, S., Rivalan, J., Ménard, D., and Edan, G.
Published: 2010
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141. Register‐based incidence of multiple sclerosis in Brittany (north‐western France), 2000–2001

Author: Yaouanq, J., primary, Tron, I., additional, Kerbrat, A., additional, Leray, E., additional, Hamonic, S., additional, Merienne, M., additional, Hinault, P., additional, and Edan, G., additional
Published: 2014
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142. Alemtuzumab dans une cohorte de 15 patients présentant une SEP agressive et antérieurement traités par Mitoxantrone : étude observationnelle

Author: Le page, E., primary, Deburghgraeve, V., additional, Lester, M.A., additional, Cardiet, I., additional, and Edan, G., additional
Published: 2014
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143. Suivi à 10ans d’une cohorte de patients ayant présenté un premier épisode neurologique évocateur de SEP en 2000–2001 en Bretagne

Author: Yaouanq, J., primary, Hamonic, S., additional, Leray, E., additional, Edan, G., additional, and Kerbrat, A., additional
Published: 2014
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144. Brain volume changes in patients at presentation with suspected Multiple Sclerosis: results from the Etoms Study

Author: Comi, G., Inglese, M., DE STEFANO, N., Smith, S., Barkhof, F., Durelli, Luca, Edan, G., Fernandez, O., Hartung, H. P., Matthews, P. M., Seeldrayers, P., Sorensen, P. S., Martinelli, V., Hommes, O. R., and Filippi, M.
Published: 2002

145. A short and validated multiple sclerosis-specific health-related quality of life measurement for routine medical practice

Author: UCL - SSH/ILSM - Louvain School of Management Research Institute, Devy, R., Lehert, Philippe, Varlan, E., Genty, M., Edan, G., UCL - SSH/ILSM - Louvain School of Management Research Institute, Devy, R., Lehert, Philippe, Varlan, E., Genty, M., and Edan, G.
Abstract: Background and purpose: Patient-reported health-related quality of life (Hr-QoL) is an essential end-point to assess the efficacy of multiple sclerosis (MS) treatment. Most QoL tools were developed for clinical research, for which measurement accuracy is required, irrespective of ease of use or the human resources needed. In routine medical practice (RMP), time and resources are limited, requiring simple and quick tools. Our objective was to set up a Hr-QoL measurement adapted for patients with MS, and providing an accurate estimate of Hr-QoL, whilst remaining easy to use and interpret in the RMP context. Methods: Literature searches, expert meetings and semi-structured interviews were used to gather relevant items and dimensions of existing scales. Scale development included item reduction and dimension identification through a cross-sectional observational study. The scale was validated on another independent representative sample. Statistically significant dimensions were identified using psychometric procedures, a Rasch polytomous model and iterative confirmatory factor analysis (CFA). Results: From 12 potential dimensions, based on a sample of 331 patients with MS, the backward CFA identified physical, mental and energy dimensions, and item optimization selected 10 items constituting our Hr-QoL scale prototype. Its validity was assessed in an independent study of 457 patients with MS, which provided statistical evidence of reliability, reproducibility in time, invariance with regard to population subgroups and overall fitting with a Rasch polytomous model. Conclusions: Compared with existing alternatives, our 10-item three-dimensional Hr-QoL measurement tool is adapted to RMP, and constitutes an adequate compromise between precision and ease of use in patients with MS. © 2013 EFNS.
Published: 2013

146. The results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing-remitting multiple sclerosis

Author: UCL - (SLuc) Service de neurologie, UCL - Cliniques universitaires Saint-Luc, De Stefano, N., Sindic, Christian, Filippi, M., Confavreux, C., Vermersch, P., Simu, M., Hupperts, R., Bajenaru, O., Edan, G., Grimaldi, L., Marginean, I., Medaer, R., Orefice, G., Pascu, I., Pelletier, J., Sanders, E., Scarpini, E., Mancardi, G. L., UCL - (SLuc) Service de neurologie, UCL - Cliniques universitaires Saint-Luc, De Stefano, N., Sindic, Christian, Filippi, M., Confavreux, C., Vermersch, P., Simu, M., Hupperts, R., Bajenaru, O., Edan, G., Grimaldi, L., Marginean, I., Medaer, R., Orefice, G., Pascu, I., Pelletier, J., Sanders, E., Scarpini, E., and Mancardi, G. L.
Abstract: Objective Two pilot studies were conducted to evaluate safety, tolerability, and efficacy of two doses of Protiramer (TV-5010) in patients with relapsing-remitting multiple sclerosis. Background Both glatiramer acetate and TV-5010 are synthetic copolymers comprised the same four amino acids in a defined molar ratio. TV-5010 has higher average molecular weight than Glatiramer acetate and might be hypothesized that glatiramoids with higher molecular weight might be more immunoreactive than lower molecular weight peptides, thus increasing therapeutic potential and allowing for less frequent dosing. Methods In the two separate studies, after a 10 week pretreatment period, TV-5010 was given subcutaneously once weekly at 15 mg and 30 mg for 36 weeks. The primary end point was a reduction in the number of magnetic resonance imaging active lesions (i.e., T1-weigthed gadolinium-enhancing and new T2-weighted lesions) between the pretreatment period and the end of study. Results Both TV-5010 doses were generally well tolerated. The treatment with TV-5010 at a dose of 15 mg/wk did not show any significant effect. In contrast, in patients treated with at a dose of 30 mg/wk, a significant reduction in the mean number of gadolinium-enhancing (-58.8%; P = 0.0013) and new T2-W (-50%; P = 0.0002) lesions was observed. However, a large decrease in the mean number of both gadolinium-enhancing (-55%) and new T2-W (-40%) lesions during the pretreatment period made difficult the interpretation of the efficacy assessments. Conclusions Further studies are needed to confirm these preliminary data on safety and efficacy of TV-5010 at a weekly dose of 30 mg. Multiple Sclerosis 2009; 15: 238-243. http://msj.sagepub.com
Published: 2009

147. Rate of pregnancy-related relapse in multiple sclerosis

Author: Confavreux C, Hutchinson M, Hours, Mm, Cortinovis Tourniaire, P, Alpérovitch, Moreau T. A., Carton, H., D’Hooghe, M. B., Hommes, O., Biron, A., Grimaud, J., Chauplannaz, G., Latombe, D., Clanet, M., Glau, G. Lau, Rumbach, L., Goas, J. Y., Rouhart, F., Ingue, A. Maz, Roullet, E., Madigand, M., Hautecoeur, P., Brunet, P., Edan, G., Allaire, C., Riffault, G., Leche, J., Benoit, T., Simonin, C., Ziegler, F., Baron, J. C., Rivrain, Y., Dumas, R., Loche, D., Bourrin, J. C., Huttin, B., Delisse, B., Gibert, I., Boulay, C., Verceletto, M., Durand, G., Bonneviot, G., Gil, R., Hedreville, M. A., Cbelair, C. Belair, Poitevin, R. J., Devoize, J. L., Pwyremblewski, P. Wyremblewski, Delestre, F., Setiey, A., Comi, G., Fillippi, M., Ghezzi, A., Martinelli, V., Rossi, P., Zaffaroni, M., Tola, M. R., Amato, M. P., Fioretti, C., Gmeucci, G. Meucci, Inglese, MARIA MATILDE, Mancardi, GIOVANNI LUIGI, Gambi, D., Thomas, A., Cavazzuti, M., Citterio, A., Aheltberg, A. Heltberg, Hansen, H. J., Fernandez, O., Romero, F., Arbizu, T., Hernandez, J. J., Frutos, C. De Andres de, Sclarky, D. Geffner, Benito, Y. Aladro, Yanez, P. Reyes, Aguilar, M., Burguera, J. A., Yaya, R., Dib, W. Bowakim, Sindic, C. J. M., Medaer, R., Roose, H., Geens, K. M. J., Guillaume, D., Zandycke, M. Van, Janssens, J., Cornette, M., Mol, L., Weilbach, F., Flachenecke, P., Hartung, H. P., Haas, J., Tendolkar, I., Sindern, E., Kölmel, H. W., Reichel, D., Rauch, M., Preuss, S., Poser, S., Mauch, E., Strasser Fuchs, S., Kollegger, H., Hawkins, S., Howell, S. J. L., Rees, J. E., Thompson, A., Johnson, M., Boggild, M., Gregory, R. P., Bates, D., Bone, I., Polman, C., Frequin, S., Jongen, P., J. Correia de, Sa, Rio, M. E., Huber, S., Lechner Scott, J., Confavreux, C, Hutchinson, M, Hours, Mm, Cortinovis Tourniaire, P, Moreau, T, the Pregnancy in Multiple Sclerosis, Group, Filippi, Massimo, and Comi, Giancarlo
Subjects: Adult, medicine.medical_specialty, Multiple Sclerosis, Obstetrical, Disease, Relapse rate, Kurtzke Expanded Disability Status Scale, Central nervous system disease, Pregnancy, Recurrence, medicine, Humans, Prospective Studies, Severe disability, Prospective cohort study, Post partum, Analgesia, Epidural, Analgesia, Obstetrical, Breast Feeding, Disease Progression, Female, Postpartum Period, Pregnancy Complications, Medicine (all), business.industry, Obstetrics, Multiple sclerosis, General Medicine, medicine.disease, Surgery, First trimester, Epidural, Gestation, Analgesia, business, Complication, Breast feeding, Postpartum period
Abstract: Background and Methods Multiple sclerosis often occurs in young women, and the effect of pregnancy on the disease is poorly understood. We studied 254 women with multiple sclerosis during 269 pregnancies in 12 European countries. The women were followed during their pregnancies and for up to 12 months after delivery to determine the rate of relapse per trimester and the score on the Kurtzke Expanded Disability Status Scale (range, 0 to 10, with higher scores indicating more severe disability). The relapse rate in each trimester was compared with the rate during the year before the pregnancy. The effects of epidural analgesia and breast-feeding on the frequency of relapse during the first three months post partum and the disability score at 12 months post partum were also determined. Results The mean (±SD) rate of relapse was 0.7±0.9 per woman per year in the year before pregnancy; it was 0.5±1.3 during the first trimester (P=0.03 for the comparison with the rate before pregnancy), 0.6±1.6 during the secon...
Published: 1998

148. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.

Author: Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R, Kappos, L, Polman, C H, Freedman, M S, Edan, G, Hartung, H P, Miller, D H, Montalban, X, and Barkhof, F
Published: 2006
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149. Benefit 11: Long-term follow-up study of patients with clinically isolated syndrome treated with interferon beta-1b

Author: Kappos, L., primary, Edan, G., additional, Freedman, M., additional, Montalbán, X., additional, Miller, D., additional, Polman, C., additional, Hartung, H.-P., additional, Hemmer, B., additional, Fox, E., additional, Barkhof, F., additional, Schippling, S., additional, Lanius, V., additional, Hermann, J., additional, Pohl, C., additional, Sandbrink, R., additional, Wicklein, E.-M., additional, and Pleimes, D., additional
Published: 2013
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150. Semi-automatic classification of lesion patterns in patients with clinically isolated syndrome

Author: Crimi, A., primary, Commowick, O., additional, Ferre, J.C., additional, Maarouf, A., additional, Edan, G., additional, and Barillot, C., additional
Published: 2013
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