title: Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study.
abstract: OBJECTIVE
  To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563).
  
  
  METHODS
  A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg.
  
  
  RESULTS
  By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5; probability of 12-week disability progression ≤0.48).
  
  
  CONCLUSIONS
  In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide.
  
  
  METHODS
  This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.). opaul362@gmail.com.
authors: Paul
authors: P
authors: O'Connor
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Giancarlo
authors: G
authors: Comi
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Mark S
authors: MS
authors: Freedman
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Aaron E
authors: AE
authors: Miller
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Ludwig
authors: L
authors: Kappos
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Jean-Pierre
authors: JP
authors: Bouchard
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Christine
authors: C
authors: Lebrun-Frenay
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Jan
authors: J
authors: Mares
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Myriam
authors: M
authors: Benamor
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Karthinathan
authors: K
authors: Thangavelu
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Jinjun
authors: J
authors: Liang
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Philippe
authors: P
authors: Truffinet
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Victoria J
authors: VJ
authors: Lawson
authors: From the University of Toronto (P.O.), Ontario, Canada; University Vita-Salute San Raffaele (G.C.), Milan, Italy; University of Ottawa and the Ottawa Hospital Research Institute (M.S.F.), Ontario, Canada; Icahn School of Medicine at Mount Sinai (A.E.M.), New York, NY; University Hospital Basel (L.K.), Switzerland; Laval University, Centre Hospitalier Universitaire de Québec (J.-P.B.), Québec, Canada; Hôpital Pasteur (C.L.-F.), Nice, France; Fakultni Nemocnice Olomouc (J.M.), Olomouc, Czech Republic; Sanofi Genzyme (M.B., P.T.), Chilly-Mazarin, France; Sanofi Genzyme (K.T.), Cambridge, MA; Sanofi (J.L.), Bridgewater, NJ; Fishawack Communications Ltd. (V.J.L.), Abingdon, UK; and University of Texas Health Science Center at Houston (J.S.W.).
authors: Jerry S
authors: JS
authors: Wolinsky
mesh_terms: D000284:Administration, Oral; D000328:Adult; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis; D003437:Crotonates / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006885:Hydroxybutyrates; D038622:Internationality; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology; D009570:Nitriles; D013997:Time Factors; D014052:Toluidines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D003437:Crotonates; D006885:Hydroxybutyrates; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide