title: Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies.
abstract: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years.
  
  
  
  Patients with RRMS were randomly assigned to receive delayed-release DMF 240 mg PO BID or TID or matching placebo for up to 2 years (96 weeks). As a tertiary end point in both studies, patient-reported HRQoL was assessed using the Physical and Mental Component Summaries (PCS and MCS, respectively) of the 36-item Short Form Health Survey (SF-36); global assessment of well-being, as measured on a visual analog scale (VAS); and the EuroQoL-5D (EQ-5D) VAS, administered at baseline and at weeks 24, 48, and 96. Higher scores suggested better HRQoL.
  
  
  
  The integrated analysis included 2301 patients treated with delayed-release DMF BID (n = 769) or TID (n = 761) or placebo (n = 771). The mean PCS and MCS scores at baseline were lower overall compared with those reported in the general US population and were ≥5 points lower (a clinically meaningful difference) in patients with a baseline Expanded Disability Status Scale (EDSS) score of ≥2.5 compared with those in patients with a baseline EDSS score of 0. At 2 years, mean PCS and MCS scores were increased from baseline in the patients treated with delayed-release DMF, whereas the mean PCS and MCS scores were decreased from baseline in the placebo group; the difference in PCS and MCS scores was significant for the delayed-release DMF BID and TID groups compared with placebo. SF-36 subscale scores generally remained stable or were improved relative to baseline in patients treated with delayed-release DMF and decreased in patients receiving placebo; improvements were significant for delayed-release DMF BID and TID versus placebo on most subscales. Compared with that in the placebo group, the proportions of patients in the delayed-release DMF groups exhibiting a ≥5-point improvement in SF-36 score were significantly higher. The following factors were found to be predictive of improved PCS and MCS scores at 2 years: delayed-release DMF treatment, lower baseline EDSS score, age ≤40 years (PCS only), and corresponding lower baseline PCS or MCS score. Changes from baseline in VAS and EuroQoL-5D scores were generally consistent with changes in SF-36 scores.
  
  
  
  These HRQoL benefits parallel the improvements in clinical and magnetic resonance imaging end points with delayed-release DMF, suggesting that delayed-release DMF treatment improves patient-perceived health status as well as neurologic and physical functioning. ClinicalTrials.gov identifiers: NCT0042012; NCT00451451.
authors.affiliation: Neuroscience Institute, Virginia Mason Medical Center, Seattle, Washington. Electronic address: mariko.kita@virginiamason.org.
authors.forename: Mariko
authors.initials: M
authors.lastname: Kita
authors.affiliation: Department of Neurology, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
authors.affiliation: Department of Neurology, Saint Josef-Hospital/Ruhr-University Bochum, Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.affiliation: Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, Texas.
authors.forename: J Theodore
authors.initials: JT
authors.lastname: Phillips
authors.affiliation: Biogen Idec Inc, Cambridge, Massachusetts.
authors.forename: Sujata P
authors.initials: SP
authors.lastname: Sarda
authors.affiliation: Biogen Idec Inc, Cambridge, Massachusetts.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kong
authors.affiliation: Biogen Idec Inc, Cambridge, Massachusetts.
authors.forename: Vissia
authors.initials: V
authors.lastname: Viglietta
authors.affiliation: Biogen Idec Inc, Cambridge, Massachusetts.
authors.forename: Sarah I
authors.initials: SI
authors.lastname: Sheikh
authors.affiliation: Biogen Idec Inc, Cambridge, Massachusetts.
authors.forename: Macaulay
authors.initials: M
authors.lastname: Okwuokenye
authors.affiliation: Departments of Neurology and Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
mesh_terms: D000293:Adolescent; D000328:Adult; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000627:therapeutic use*; D000069462:Dimethyl Fumarate / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006304:Health Status; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D010147:Pain Measurement; D011788:Quality of Life; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate
keywords: delayed-release dimethyl fumarate; multiple sclerosis; quality of life; randomized controlled trial