title: An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial.
abstract: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.
  
  
  
  All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.
  
  
  
  Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.
  
  
  
  Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD.
  
  
  
  ClinicalTrials.gov; www.clinicaltrials.gov NCT01933334.
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune. khannad@med.umich.edu.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Carlo
authors.initials: C
authors.lastname: Albera
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Aryeh
authors.initials: A
authors.lastname: Fischer
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Nader
authors.initials: N
authors.lastname: Khalidi
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Raghu
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Lorinda
authors.initials: L
authors.lastname: Chung
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Elena
authors.initials: E
authors.lastname: Schiopu
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Margit
authors.initials: M
authors.lastname: Tagliaferri
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: James R
authors.initials: JR
authors.lastname: Seibold
authors.affiliation: From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
authors.forename: Eduard
authors.initials: E
authors.lastname: Gorina
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000627:therapeutic use; D011728:Pyridones / Q000009:adverse effects* / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000150:complications*; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; C093844:pirfenidone; D009173:Mycophenolic Acid
keywords: INTERSTITIAL LUNG DISEASES; PIRFENIDONE; SAFETY; SCLERODERMA; SYSTEMIC SCLEROSIS; TOLERABILITY