title: Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions.
abstract: BACKGROUND
  Teriflunomide, a once-daily oral immunomodulator for the treatment of relapsing-remitting multiple sclerosis, has demonstrated consistent efficacy on clinical and MRI parameters in clinical trials.
  
  
  OBJECTIVE
  To summarize the safety and tolerability profile of teriflunomide based on data from four placebo-controlled trials.
  
  
  METHODS
  Safety and tolerability were assessed using two teriflunomide clinical program data pools. Pool 1 contained 3044 patients randomized to teriflunomide (14 mg or 7 mg) or placebo in the core studies of one phase 2 trial and three phase 3 trials, with cumulative treatment exposure >1500 patient-years per group. Pool 2 comprised 2338 patients who received teriflunomide treatment in the above trials, including those continuing in extension studies, with a duration of treatment up to 12 years, representing >6800 patient-years. Safety assessments included adverse events, laboratory parameters, and physical examinations.
  
  
  RESULTS
  In Pool 1, the number of patients experiencing adverse events and serious adverse events was similar in the three treatment groups. Common events occurring in ≥ 10% of patients in either teriflunomide group, and with an incidence ≥ 2% compared with placebo, were alanine aminotransferase (ALT) increase, headache, diarrhea, hair thinning, and nausea. Overall, the nature of events observed in Pool 2 was similar to Pool 1. The majority of events in both pools were of mild-to-moderate intensity, were self-limiting, and infrequently resulted in discontinuation of therapy. The most common reason for treatment discontinuation in all treatment groups was ALT elevation, reflecting the protocol requirement to discontinue treatment on confirmation of ALT > 3 × the upper limit of normal.
  
  
  CONCLUSIONS
  No new or unexpected safety signals beyond those detected in individual trials were identified in this pooled analysis with treatment duration exceeding 12 years and a cumulative exposure to teriflunomide exceeding 6800 patient-years. Overall, both doses of teriflunomide had consistent and manageable safety profiles.
authors: University Vita-Salute San Raffaele, Via Olgettina, 60, 20132 Milan, Italy. Electronic address: g.comi@hsr.it.
authors: Giancarlo
authors: G
authors: Comi
authors: University of Ottawa and the Ottawa Hospital Research Institute, The Ottawa Hospital - General Campus, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6. Electronic address: mfreedman@toh.on.ca.
authors: Mark S
authors: MS
authors: Freedman
authors: Neurology, Departments of Medicine and Clinical Research, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: Ludwig.Kappos@usb.ch.
authors: Ludwig
authors: L
authors: Kappos
authors: Department of Clinical Neurosciences, Karolinska Hospital, 17176 Stockholm, Sweden. Electronic address: Tomas.Olsson@ki.se.
authors: Tomas P
authors: TP
authors: Olsson
authors: Icahn School of Medicine at Mount Sinai-The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, 5 East 98th Street, New York, NY 10029, USA. Electronic address: aaron.miller@mssm.edu.
authors: Aaron E
authors: AE
authors: Miller
authors: University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA. Electronic address: Jerry.S.Wolinsky@uth.tmc.edu.
authors: Jerry S
authors: JS
authors: Wolinsky
authors: University of Toronto, St Michael's Hospital, 30 Bond Street, Toronto, ON, Canada M5B 1W8. Electronic address: opaul362@gmail.com.
authors: Paul W
authors: PW
authors: O'Connor
authors: Genzyme, a Sanofi company, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. Electronic address: Myriam.Benamor@sanofi.com.
authors: Myriam
authors: M
authors: Benamor
authors: Sanofi, 55 Corporate Drive, Bridgewater, NJ 08807, USA. Electronic address: Deborah.Dukovic@sanofi.com.
authors: Deborah
authors: D
authors: Dukovic
authors: Genzyme, a Sanofi company, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. Electronic address: Philippe.Truffinet@sanofi.com.
authors: Philippe
authors: P
authors: Truffinet
authors: Comprehensive Multiple Sclerosis Center, Thomas Jefferson University Hospital, 900 Walnut Street, Ste. 200, Philadelphia, PA 19107, USA. Electronic address: Thomas.Leist@jefferson.edu.
authors: Thomas P
authors: TP
authors: Leist
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D003437:Crotonates / Q000008:administration & dosage / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D009570:Nitriles; D010919:Placebos; D016032:Randomized Controlled Trials as Topic; D014052:Toluidines / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003437:Crotonates; D006885:Hydroxybutyrates; D007155:Immunologic Factors; D009570:Nitriles; D010919:Placebos; D014052:Toluidines; C527525:teriflunomide
keywords: Clinical trials; Multiple sclerosis; Relapsing-remitting multiple sclerosis; Safety analysis; Teriflunomide