An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.

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. Supported by InterMune Inc., which became a wholly owned subsidiary of F. Hoffmann-La Roche Ltd. in 2014. C.A. has received consulting fees from InterMune. E.S. has received a grant from InterMune to conduct this study. D.C., M.T., and E.G. were employees of InterMune at the time this study was conducted. J.R.S. has received consulting fees from InterMune. 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. Dr. Seibold and Dr. Gorina are joint senior authors. Address correspondence to Dr. D. Khanna, Professor of Medicine, Director, University of Michigan Scleroderma Program, Division of Rheumatology and Department of Internal Medicine, 300 North Ingalls St., SPC 5422, Ann Arbor, Michigan 48109, USA. E-mail: khannad@med.umich.edu. Full Release Article. For details see Reprints/Permissions at jrheum.org. Accepted for publication May 27, 2016.