BACKGROUND: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. METHODS: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. FINDINGS: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). INTERPRETATION: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis.
Lublin, F., Miller, D., Freedman, M., Cree, B., Wolinsky, J., Weiner, H., et al. (2016). Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. THE LANCET, 387(10023), 1075-1084.
|Tipologia:||Articolo su rivista|
|Citazione:||Lublin, F., Miller, D., Freedman, M., Cree, B., Wolinsky, J., Weiner, H., et al. (2016). Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. THE LANCET, 387(10023), 1075-1084.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/S0140-6736(15)01314-8|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||12-mar-2016|
|Titolo:||Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial|
|Autori:||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; Freedman, M; 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; Lubetzki, C; 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; Montalban, X; 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; Kappos, L; 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|
|Appare nelle tipologie:||01 - Articolo su rivista|