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7. 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

8. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis

Author

Cohen, J, Barkhof, F, Comi, G, Hartung, H, Khatri, B, Montalban, X, Pelletier, J, Capra, R, Gallo, P, Izquierdo, G, Tiel Wilck, K, de Vera, A, Jin, J, Stites, T, Wu, S, Aradhye, S, Kappos, L, TRANSFORMS Study Group, Contributor, Centonze, D, Cohen, Ja, Barkhof, F, Comi, Giancarlo, Hartung, Hp, Khatri, Bo, Montalban, X, Pelletier, J, Capra, R, Gallo, P, Izquierdo, G, TIEL WILCK, K, DE VERA, A, Jin, J, Stites, T, Wu, S, Aradhye, S, KAPPOS L., TRANSFORM STUDY GROUP, Cohen, J. A., Barkhof, F., Comi, G., Hartung, H., Khatri, B. O., Montalban, X., Pelletier, J., Capra, R., Gallo, P., Izquierdo, G., Tiel-Wilck, K., Vera, A. d., Jin, J., Stites, T., Wu, S., Aradhye, S., Kappos, L., Brescia Morra, V., Altri, Jeffrey A. Cohen, Frederik Barkhof, Giancarlo Comi, Hans-Peter Hartung, Bhupendra O. Khatri, Xavier Montalban, Jean Pelletier, Ruggero Capra, Paolo Gallo, Guillermo Izquierdo, Klaus Tiel-Wilck, Ana de Vera, James Jin, Tracy Stite, Stacy Wu, Shreeram Aradhye, Ludwig Kappo, for the TRANSFORMS Study Group, Alessandra Lugaresi, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, and Ben Dahan, David

Subjects
Male, Medizin, Administration, Oral, Arrhythmias, Relapsing-Remitting, drug therapy/pathology, Disability Evaluation, chemistry.chemical_compound, 0302 clinical medicine, Sphingosine, Teriflunomide, Propylene Glycols/adverse effects/*therapeutic use, Interferon-beta/adverse effects/*therapeutic use, Intramuscular, 0303 health sciences, Statistics, Brain, General Medicine, Middle Aged, Magnetic Resonance Imaging, Fingolimod, Intention to Treat Analysis, 3. Good health, adverse effects/therapeutic use, Administration, chemically induced, Disease Progression, intramuscular interferon, Settore MED/26 - Neurologia, Female, Young Adult, Double-Blind Method, Humans, Injections, Intramuscular, Interferon-beta, Multiple Sclerosis, Relapsing-Remitting, Immunosuppressive Agents, Adult, Propylene Glycols, Adolescent, Statistics, Nonparametric, Arrhythmias, Cardiac, Cardiac, medicine.drug, Oral, medicine.medical_specialty, Multiple Sclerosis, Injections, adverse effects/analogs /&/ derivatives/therapeutic use, 03 medical and health sciences, Relapsing-Remitting/*drug therapy/pathology, Internal medicine, Fingolimod Hydrochloride, medicine, Brain/pathology, Nonparametric, fingolimod, Cardiac/chemically induced, 030304 developmental biology, business.industry, Multiple sclerosis, fingolimod, multiple sclerosis, therapy, Interferon beta-1a, relapsing multiple sclerosis, Management of multiple sclerosis, medicine.disease, Immunosuppressive Agents/adverse effects/*therapeutic use, Oral, Adolescent, Adult, Arrhythmias, chemically induced, Brain, pathology, Disability Evaluation, Disease Progression, Double-Blind Method, Female, Humans, Immunosuppressive Agents, adverse effects/therapeutic use, Injections, Intramuscular, Intention to Treat Analysis, Interferon-beta, adverse effects/therapeutic use, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, drug therapy/pathology, Propylene Glycols, adverse effects/therapeutic use, Sphingosine, adverse effects/analogs /&/ derivatives/therapeutic use, Statistics, Nonparametric, Young Adult, Surgery, Siponimod, chemistry, Ponesimod, Sphingosine/adverse effects/*analogs & derivatives/therapeutic use, pathology, business, 030217 neurology & neurosurgery
Abstract

1533-4406 (Electronic) 0028-4793 (Linking) Comparative Study Journal Article Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't; BACKGROUND: Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS: In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS: A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P

Published
2010
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9. 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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14. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study

Author

Khatri, B, Barkhof, F, Comi, G, Hartung, Hp, Kappos, L, Montalban, X, Pelletier, J, Stites, T, Wu, S, Holdbrook, F, Zhang auberson, L, Francis, G, Cohen, Ja, Cohen, J, Easton, Jd, Calandra, T, Dimarco, J, Hudson, L, Kesselring, J, Laupacis, A, Temkin, N, Weinshenker, B, Zarbin, M, Poppe, P, Luetic, G, Cristiano, E, Caceres, F, Garcea, O, Correale, J, Ballario, C, Piedrabuena, R, Pollard, J, Beran, R, Hodgkinson, S, Schwartz, R, Heard, R, King, J, Butzkueven, H, Maida, Em, Vass, K, Franta elmer, C, Berger, T, Aichner, F, Ladurner, G, Bissay, V, Sindic, C, D'Hooghe, M, Mulleners, E, Damasceno, B, Barreira, A, Naylor, R, Alvarenga, R, Bacellar, A, Haussen, S, Duquette, P, Antel, J, Lamontagne, A, Grand'Maison, F, Freedman, M, Christie, S, O'Connor, P, Vorobeychik, G, Devonshire, V, Ramadan, M, Hamdy, S, Reda, E, Hashem, S, Fouad, M, Lebrun frenay, C, Clanet, M, Brochet, B, Debouverie, M, Heinzlef, O, Ziemssen, T, Koehler, W, Tiel wilck, K, Bachus, R, Altmann, N, Faiss, J, Baum, K, Dressel, A, Luckner, K, Ebke, M, Stangel, M, Diener, Hc, Bethke, F, Limmroth, V, Maschke, M, Thoemke, F, Reifschneider, G, Diehm, R, Wildemann, B, Melms, A, Rauer, S, Karlbauer, G, Berthele, A, Lang, M, Tumani, H, Krauseneck, P, Klein, M, Papadimitriou, A, Karageorgiou, K, Liakopoulos, D, Tascos, N, Plaitakis, A, Papathanasopoulos, P, Panczel, G, Jakab, G, Csiba, L, Komoly, S, Csanyi, A, Bartos, L, Centonze, D, Pozzilli, C, Marrosu, Mg, Bertolotto, A, Mancardi, GIOVANNI LUIGI, Scarpini, E, Protti, A, Ghezzi, A, Capra, R, Bergamaschi, R, Gallo, P, Stecchi, S, Montanari, E, Tola, Mr, Amato, Mp, Silvestrini, M, Lugaresi, A, Trojano, M, Morra, Vb, Ruggieri, S, Patti, F, Kim, Sm, Lee, Kh, Kim, Hj, Park, Sp, Ginestal, R, Salgado, Av, Fontoura, P, Cunha, L, Sousa, L, Mj, Sá, Pedrosa, R, Arbizu, T, Arroyo, R, Merino, Ja, Fernandez, O, Izquierdo, G, Casanova, B, Antigüedad, A, Goebels, N, Young, C, Lee, M, Chaudhuri, A, Nicholas, R, Martinez, Ac, Preiningerova, J, Greco, D, Gross, J, Newman, S, Mitchell, G, Pawar, G, Freedman, Sm, Kaufman, M, Absher, J, Kantor, D, Ayala, R, Honeycutt, W, Shafer, S, Steingo, B, Delgado, S, Cascione, M, Brock, C, Keegan, A, Laganke, C, Hunter, S, Wilson, E, Mazhari, A, Bauer, W, Singer, B, Lynch, S, Rowe, V, Hutton, G, Gazda, S, Dihenia, B, Campagnolo, D, Chippendale, T, Ash, P, Jung, L, Olek, M., Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, Pelletier J, Stites T, Wu S, Holdbrook F, Zhang-Auberson L, Francis G, Cohen JA, TRANSFORMS Study Group, Lugaresi A, Diener, Hans Christoph (Beitragende*r), Khatri, B, Barkhof, F, Comi, G, Hartung, Hp, Kappos, L, Montalban, X, Pelletier, J, Stites, T, Wu, S, Holdbrook, F, Zhang Auberson, L, Francis, G, Cohen, Ja, BRESCIA MORRA, Vincenzo, Comi, Giancarlo, TRANSFORMS Study, Group, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, medicine.medical_specialty, multiple sclerosis, interferon beta, fingolimod, treatment, Multiple Sclerosis, Adolescent, Medizin, Phases of clinical research, Relapsing-Remitting, Injections, Intramuscular, Young Adult, Humans, Adjuvants, Immunologic, Interferon-beta, Immunosuppressive Agents, Multiple Sclerosis, Relapsing-Remitting, Treatment Outcome, Middle Aged, Propylene Glycols, Sphingosine, Female, law.invention, Injections, Randomized controlled trial, law, Immunologic, analogs /&/ derivatives/therapeutic use, Internal medicine, Fingolimod Hydrochloride, Medicine, Adjuvants, Young adult, Intramuscular, business.industry, Multiple sclerosis, Interferon beta-1a, medicine.disease, Fingolimod, Surgery, drug therapy/pathology/physiopathology, Clinical research, therapeutic use, Adolescent, Adult, Female, Humans, Immunosuppressive Agents, therapeutic use, Injections, Intramuscular, Interferon-beta, therapeutic use, Male, Middle Aged, Multiple Sclerosis, drug therapy/pathology/physiopathology, Propylene Glycols, therapeutic use, Sphingosine, analogs /&/ derivatives/therapeutic use, Treatment Outcome, Young Adult, therapeutic use, Settore MED/26 - Neurologia, Neurology (clinical), business, medicine.drug
Abstract

In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod. METHODS: Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834. FINDINGS: 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p

Published
2011
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17. Inanspruchnahme medizinischer Leistungen und Versorgungsmuster von Parkinson-Patienten in neurologischen Schwerpunktpraxen in Berlin (NeuroPa-Studie)

Author

Reese, JP, primary, Balzer-Geldsetzer, M, additional, Dodel, R, additional, Becker, E, additional, Christopher, A, additional, Friedrich, H, additional, Kraemer, S, additional, Lüer, W, additional, Müngersdorf, M, additional, Puzich, R, additional, Rohr, A, additional, Schultes-Platzek, I, additional, Siefjediers, V, additional, Tiel-Wilck, K, additional, and Ehret, R, additional

Published
2009
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18. Versorgung von Parkinson-Patienten in neurologischen Schwerpunktpraxen in Berlin (NeuroPa-Studie)

Author

Ehret, R, primary, Balzer-Geldsetzer, M, additional, Reese, J.P, additional, Dodel, I, additional, Becker, E, additional, Christopher, A, additional, Friedrich, H, additional, Kraemer, S, additional, Lüer, W, additional, Müngersdorf, M, additional, Puzich, R, additional, Schultes-Platzek, I, additional, Siefjediers, V, additional, Tiel-Wilck, K, additional, and Dodel, R, additional

Published
2008
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19. The Faces Symbol Test, a newly developed screening instrument to assess cognitive decline related to multiple sclerosis: first results of the Berlin Multi-Centre FST Validation Study

Author

Scherer, P., primary, Penner, I.K., additional, Rohr, A., additional, Boldt, H., additional, Ringel, I., additional, Wilke-Burger, H., additional, Burger-Deinerth, E., additional, Isakowitsch, K., additional, Zimmermann, M., additional, Zahrnt, S., additional, Hauser, R., additional, Hilbert, K., additional, Tiel-Wilck, K., additional, Anvari, K., additional, Behringer, A., additional, Peglau, I., additional, Friedrich, H., additional, Plenio, A., additional, Benesch, G., additional, Ehret, R., additional, Nippert, I., additional, Finke, G., additional, Schulz, I., additional, Bergtholdt, B., additional, Breitkopf, S., additional, Kaskel, P., additional, Reischies, F., additional, and Kugler, J., additional

Published
2007
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22. A positional maneuver for treatment of horizontal-canal benign positional vertigo.

Author

Lempert T, Tiel-Wilck K, Lempert, T, and Tiel-Wilck, K

Abstract

Horizontal-canal benign positional vertigo (HC-BPV) is characterized by brief attacks of intense vertigo that are induced by mainly rolling over in bed. Examination shows a burst of purely horizontal nystagmus beating toward the undermost ear when the head is turned from supine to either lateral position. Two patients with typical HC-BPV were treated by a new positional procedure that aims to clear particles from the affected canal. The maneuver starts with the patient in the supine position and consists of three 90-degree head rotations toward the unaffected ear. Both patients had immediate and sustained relief of their attacks. No positional nystagmus could be elicited after the maneuver. The rapid cessation of positional vertigo and nystagmus adds evidence that HC-BPV is caused by dense particles that move within the canal whenever its orientation toward gravity is changed. [ABSTRACT FROM AUTHOR]

Published
1996

23. Drug-resistant MS spasticity treatment with Sativex® add-on and driving ability.

Author

Freidel, M., Tiel‐Wilck, K., Schreiber, H., Prechtl, A., Essner, U., and Lang, M.

Subjects
*MULTIPLE sclerosis treatment, *MULTIPLE sclerosis, *NEUROPLASTICITY, *DRUG resistance, *TETRAHYDROCANNABINOL, *SELF-evaluation, *PATIENTS
Abstract

Objective The aim of the present observational study was to determine the effects of a delta-9-tetrahydrocannabinol ( THC) and cannabidiol ( CBD) oromucosal spray (Sativex® spray), brand name Sativex®, indicated for drug-resistant MS spasticity, on the driving ability of treated MS patients. Methods The study was conducted over a period of 4-6 weeks. Thirty-three MS patients with moderate to severe treatment-resistant spasticity and planned to begin add-on treatment with Sativex® were enrolled at three specialized MS centres in Germany. A set of five driving test procedures from a validated computerized test battery was used to evaluate the driving ability of eligible patients. Tests were performed by patients at baseline and repeated after 4-6 weeks of treatment with Sativex® oromucosal spray. According to German normative data, the test thresholds achieved by the general population served as a reference to allow for a fitness/unfitness to drive classification. Results Patients showed comparable driving test results at baseline and at final visits. Only two patients changed classification shifting from 'unfit' to drive to 'fit' and vice versa. The mean severity of spasticity, as self-reported by the patients, improved with statistical significance. Sativex® was generally well tolerated. Conclusions Treatment of MS patients with Sativex® does not negatively impact on driving ability and may improve moderate to severe treatment-resistant MS spasticity. [ABSTRACT FROM AUTHOR]

Published
2015
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27. Efficacy and Safety of Teriflunomide in Multiple Sclerosis across Age Groups: Analysis from Pooled Pivotal and Real-world Studies.

Author

Oh J, Vukusic S, Tiel-Wilck K, Inshasi JS, Rog D, Baker DP, Pyatkevich Y, Poole EM, and Vermersch P

Abstract

Background: Evidence suggests that efficacy and safety of disease-modifying treatments for multiple sclerosis may differ with age. We evaluate efficacy and safety of teriflunomide across age subgroups of patients from pooled clinical trials and real-world studies., Methods: Post hoc analyses of patients who received teriflunomide 14 mg in the pooled phase II and III TEMSO, TOWER, TENERE, and TOPIC core and extension studies (n = 1978), and the real-world Teri-PRO (n = 928) and TAURUS-MS I (n = 1126) studies were conducted. Data were stratified by age at study entry: ⩽25, >25 to ⩽35, >35 to ⩽45, and >45 years. In Teri-PRO and TAURUS-MS I, an additional group, >55 years, was assessed., Results: In the pooled core studies, teriflunomide reduced annualized relapse rate (ARR) versus placebo across all ages. Unadjusted ARRs remained low across age groups in pooled extensions (0.18-0.30), Teri-PRO (0.10-0.35), and TAURUS-MS I (0.14-0.35). Baseline Expanded Disability Status Scale scores were higher with age, but stable through core and extension studies (mean increases over 7 years: ⩽25 years, +0.59; >25 to ⩽35 years, +0.46; >35 to ⩽45 years, +0.35; >45 years, +0.81). Across age groups, adverse event (AE) incidences were 78.4% to 90.7% in pooled core and extension studies and Teri-PRO, and 29.2% to 37.7% in TAURUS-MS I; serious AE incidences were ⩽21.3% in all studies. In pooled phase III and Teri-PRO studies, lymphocyte count decreases over 1 year after initiating teriflunomide, and proportions of patients developing lymphopenia, were small across age groups., Conclusions: Teriflunomide efficacy was demonstrated regardless of age. Safety was generally consistent across age groups., Competing Interests: Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JO received consulting or speaking fees from Alexion, Biogen Idec, Celgene, EMD Serono, Genzyme, Novartis, and Roche, and received research support from Biogen Idec, EMD Serono, and Roche. SV has received grants, personal fees, and nonfinancial support from Biogen, Celgene, Genzyme, MedDay, Merck Serono, Novartis, Roche, Sanofi, and Teva. KT-W received honoraria for lectures, studies, and consultancy from Almirall, Bayer, Biogen, Genzyme, Ipsen, Merck Serono, Merz Pharma, Novartis, Roche, Sanofi, and Teva. JSI reports nothing to disclose. DR received consulting fees from Bayer, Biogen, Celgene, MedDay, Merck Serono, Novartis, Roche, Sanofi, and Teva, and received research support from Actelion, Biogen, Genzyme, GW Pharma, Merck Serono, Mitsubishi, Novartis, Teva, and TG Therapeutics. DPB is an employee of Sanofi with ownership interest. YP and EMP were employees of Sanofi at the time the analysis was done. PV received consulting and/or speaking fees, and research support from Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, and Teva., (© The Author(s) 2021.)

Published
2021
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28. Reasons to switch: a noninterventional study evaluating immunotherapy switches in a large German multicentre cohort of patients with relapsing-remitting multiple sclerosis.

Author

Mäurer M, Tiel-Wilck K, Oehm E, Richter N, Springer M, Oschmann P, Manzel A, Hieke-Schulz S, Zingler V, Kandenwein JA, Ziemssen T, and Linker RA

Abstract

Background: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies., Methods: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014-2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman's wish to become pregnant. Expectations of the new DMT and patients' assessment of the decision maker were also recorded., Results: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients., Conclusions: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden., Competing Interests: Conflict of interest statement: All authors received support for their contribution to this study as well as medical writing support for the development of this manuscript from Roche Pharma AG, Grenzach-Wyhlen, Germany. RAL received compensation for activities with Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis Pharma, Roche and TEVA as well as research support from Biogen, Merck, and Novartis. MM received compensation for activities with Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, and TEVA. EO received honoraria for studies from Abbvie, Allergan, Bayer, Biogen, Genzyme, Merck & Co., Merck Serono, Merz, Novartis, Roche, Sanofi, TEVA, UCB, and Zambon. PO received compensation for activities with Bayer, Biogen, Genzyme, Merck, Novartis, Roche, and TEVA. NR has no additional disclosures. MS received honoraria for lectures, studies and consulting from Merck, Sanofi, Novartis, and Genzyme. KTW received honoraria for lectures, studies, and consultancy from Almirall, Bayer, Biogen, Genzyme, Merck Serono, Novartis, Roche, Sanofi, and TEVA. TZ received reimbursements for participation in scientific advisory boards from Almirall, Bayer Healthcare, Biogen, Celgene, Novartis, Merck Serono, TEVA, Genzyme, and Roche; he also received speaker honoraria from Almirall, Bayer Healthcare, Biogen, Celgene, Genzyme, Novartis, Roche, TEVA, and research support from Bayer Healthcare, BAT, Biogen, Genzyme, Novartis, and TEVA. AM, SHS, JAK are current employees of Roche Pharma AG. VZ is a current employee of F. Hoffmann-La Roche., (© The Author(s), 2019.)

Published
2019
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29. Real-life outcomes of teriflunomide treatment in patients with relapsing multiple sclerosis: TAURUS-MS observational study.

Author

Kallmann BA, Tiel-Wilck K, Kullmann JS, Engelmann U, and Chan A

Abstract

Background: Teriflunomide is a once-daily oral immunomodulatory agent approved for the treatment of relapsing-remitting multiple sclerosis (MS). We aimed to obtain data on the effectiveness, tolerability, and subject satisfaction with teriflunomide (Aubagio®) under clinical practice conditions in unselected MS patients., Methods: This work was a non-interventional, prospective, longitudinal, observational study in 307 sites in Germany., Results: A total of 1128 patients were eligible for the efficacy analysis [67.5% female; mean age (± standard deviation) 44.9 ± 9.7 years, range 20-73 years]. Time since first MS symptoms was 10.6 ± 8.2 years, and time since MS diagnosis was 8.9 ± 7.6 years. Expanded Disability Status Scale (EDSS) score at inclusion was 2.3 ± 1.5 (70.4% with score < 3.5). The mean observation period was 16.3 ± 9.1 months. A total of 75.2% had received previous disease-modifying therapies (DMTs) at any time. Of these patients, 504 (44.7%) received no DMT within 6 months of study entry, 593 patients (52.6%) had DMT discontinued prior to study entry [glatiramer acetate in 10.6%, subcutaneous interferon-beta 1a (IFNβ-1a) in 9.3%, intramuscular IFNβ-1a or IFNβ-1b in 6.6% each, azathioprine oral in 0.4%, other in 7.3%, last medication not known in 12.0%]. The mean annualized relapse rate decreased from 0.87 in the 24 months prior to study entry to 0.35 in the 24 months after study entry ( n = 468; p ⩽ 0.001). EDSS and Fatigue Severity Scale remained stable. In patients who received previous MS treatments, Treatment Satisfaction Questionnaire (TSQM-9) values (maximum = 100), for the observation at 24 months improved by 8.1 points for effectiveness, 17.0 points for convenience, and 15.3 points for global satisfaction ( p ⩽ 0.001 each, compared with study entry). In the safety cohort ( n = 1139), the proportion of patients with adverse events (AEs) of any severity was 35.8%, and with serious events 13.0%. The most frequently reported AEs were diarrhea ( n = 55), followed by MS relapse ( n = 48), hair thinning ( n = 38), and viral upper respiratory tract infection ( n = 31)., Conclusions: Relapse rate was halved during the observation period in comparison with the same time period before study entry. Patient satisfaction with teriflunomide was high in this real-world observation of patients, the majority of whom switched from other DMTs. The safety and tolerability profile of teriflunomide was similar to that reported in previous clinical trials., Competing Interests: Conflict of interest statement: BAK has received compensation for activities with Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. KTW has received honoraria for lectures, studies, and consultancy from Almirall, Bayer, Biogen, Genzyme, Ipsen, Merck Serono, Merz Pharma, Novartis, Roche, Sanofi, and Teva. AC has received compensation for activities with Actelion, Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, and Teva for use of university research funds. He receives research support from UCB, and from Sanofi for basic research on drug transport mechanisms relevant to teriflunomide. UE and JK are full-time employees of Sanofi-Aventis Deutschland GmbH.

Published
2019
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30. Determination of Seminal Concentration of Fingolimod and Fingolimod-Phosphate in Multiple Sclerosis Patients Receiving Chronic Treatment With Fingolimod.

Author

David OJ, Berwick A, Pezous N, Lang M, Tiel-Wilck K, Ziemssen T, Li P, Hara H, and Schmouder R

Subjects
Adult, Fingolimod Hydrochloride blood, Fingolimod Hydrochloride therapeutic use, Humans, Immunosuppressive Agents blood, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Multiple Sclerosis drug therapy, Phosphates blood, Phosphates therapeutic use, Fingolimod Hydrochloride pharmacokinetics, Immunosuppressive Agents pharmacokinetics, Multiple Sclerosis metabolism, Phosphates pharmacokinetics, Semen chemistry
Abstract

The safety profile of fingolimod 0.5 mg, approved therapy for relapsing multiple sclerosis, is well established in clinical and real-world studies. As fingolimod is teratogenic in rats, it was considered important to assess the concentrations of fingolimod and its active metabolite, fingolimod-phosphate, in the semen of male patients on treatment and the risk of harming a fetus in a pregnant partner. In this multicenter open-label study, 13 male patients receiving fingolimod for at least 6 months provided 1 semen and 1 blood sample for analyte concentration measurements. The steady-state seminal concentrations of fingolimod and fingolimod-phosphate were close to those simultaneously observed in blood. The amount of fingolimod-related material in 10 mL of ejaculate was estimated to be 47.5 ng. The estimated fingolimod and fingolimod-phosphate blood C max values in a woman having regular sexual intercourse with a male patient treated with fingolimod 0.5 mg were approximately 400 and 2400 times smaller than the estimated values in the embryo-fetal development study in rats at the no-observed-adverse-event level. Consequently, the risk of harming a fetus in a pregnant woman is considered extremely unlikely., (© 2017 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Published
2018
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32. [Migraine: differential diagnosis in episodic vertigo].

Author

Lempert T, Menzhausen L, and Tiel-Wilck K

Subjects
Adult, Diagnosis, Differential, Epilepsy, Temporal Lobe complications, Epilepsy, Temporal Lobe diagnosis, Female, Humans, Male, Meniere Disease etiology, Middle Aged, Migraine Disorders diagnosis, Neurologic Examination, Vestibular Function Tests, Migraine Disorders complications, Vertigo etiology
Abstract

Vestibular symptoms can be the predominant feature of migraine both in children and adults. Attacks of spontaneous or positional vertigo lasting from minutes to days may occur with or without concomitant headache. In the literature three syndromes of vestibular migraine have evolved: basilar artery migraine, benign recurrent vertigo and benign recurrent vertigo of childhood. In clinical practice, however, variants seem to be more frequent than the pure syndromes. Diagnosis is based on the individual constellation of typical precipitants and symptoms of migraine and the efficacy of pharmacological migraine prophylaxis. Nine cases are presented.

Published
1993

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