title: Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate.
abstract: BACKGROUND
  In the phase 3 DEFINE and CONFIRM trials, flushing and gastrointestinal (GI) events were associated with delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) treatment in people with relapsing-remitting multiple sclerosis (MS). To investigate these events, a post hoc analysis of integrated data from these trials was conducted, focusing on the initial treatment period (months 0-3) with the recommended DMF dosage (240 mg twice daily).
  
  
  METHODS
  Eligibility criteria included age 18 to 55 years, relapsing-remitting MS diagnosis, and Expanded Disability Status Scale score 0 to 5.0. Patients were randomized and received treatment with placebo (n = 771) or DMF (n = 769) for up to 2 years. Adverse events were recorded at scheduled clinic visits every 4 weeks.
  
  
  RESULTS
  The incidence of GI and flushing events was highest in the first month of treatment. In months 0 to 3, the incidence of GI events was 17% in the placebo group and 27% in the DMF group and the incidence of flushing and related symptoms was 5% in the placebo group and 37% in the DMF group. Most GI and flushing events were of mild or moderate severity and resolved during the study. The events were temporally associated with the use of diverse symptomatic therapies (efficacy not assessed) and infrequently led to DMF discontinuation.
  
  
  CONCLUSIONS
  This integrated analysis indicates that in a clinical trial setting, GI and flushing events associated with DMF treatment are generally transient and mild or moderate in severity and uncommonly lead to treatment discontinuation.
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: J Theodore
authors.initials: JT
authors.lastname: Phillips
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Heather
authors.initials: H
authors.lastname: Abourjaily
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Amy
authors.initials: A
authors.lastname: Pace
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Mark
authors.initials: M
authors.lastname: Novas
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Christophe
authors.initials: C
authors.lastname: Hotermans
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Vissia
authors.initials: V
authors.lastname: Viglietta
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA (JTP); Medical University of Lodz, Lodz, Poland (KS); St. Josef Hospital, Ruhr University, Bochum, Germany (RG); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (EH); Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK (GG); and Biogen, Cambridge, MA, USA (HA, AP, MN, CH, VV, LM).
authors.forename: Leslie
authors.initials: L
authors.lastname: Meltzer