Improving the Standard of Care for Patients With Idiopathic Pulmonary Fibrosis Requires Participation in Clinical Trials
2009; Elsevier BV; Volume: 136; Issue: 2 Linguagem: Inglês
10.1378/chest.09-0848
ISSN1931-3543
Autores Tópico(s)Eosinophilic Disorders and Syndromes
ResumoIdiopathic pulmonary fibrosis (IPF) is an irreversible, fatal lung disease. Although the etiology of IPF is unknown, it is currently believed to occur as a result of repeated insults to the lungs over a period of years in individuals with occult, genetically determined, predisposing factors. Symptoms leading to diagnosis typically manifest in patients > 50 years old. Following diagnosis of IPF by surgical lung biopsy, the median survival is 2.8 years.1Bjoraker JA Ryu JH Edwin MK et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (971) Google Scholar While lung transplantation may improve survival for some patients, this option is appropriate for only a minority of patients with this debilitating disease.In 2000, a panel of experts representing the American Thoracic Society (ATS) and the European Respiratory Society (ERS) provided a consensus statement2American Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar regarding the diagnosis and treatment of IPF. This document provided a set of criteria for the accurate diagnosis of IPF that has been widely used to enroll well-defined IPF patients into clinical studies. Subsequently, several clinical trials have been performed in pursuit of improving outcomes for patients with IPF, although results to date have been disappointing, and an effective treatment regimen for IPF remains elusive. Nonetheless, significant advances in our understanding of the natural course of IPF and the pathogenesis of lung fibrosis have been made. Indeed, there is a need for the statement to be updated based on new evidence compiled over the last decade.Our present understanding of the cellular and molecular mechanisms of pulmonary fibrosis has resulted in the testing of treatment strategies that modulate specific inflammatory and fibrotic mediators and pathways currently implicated in the pathogenesis of IPF. These treatment strategies have included agents to inhibit the proinflammatory and profibrotic effects of tumor necrosis factor-α, transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor, tyrosine kinases, oxidants, endothelin, chemokines, and blood coagulation. Phase I, II, and III clinical trials have utilized etanercept,3Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar β- and γ-interferons,4Raghu G Bozic CR Brown KK et al.Feasibility of a trial of interferon beta-1a (IFNB-1a) in the treatment of idiopathic pulmonary fibrosis (IPF) [abstract].Am J Respir Crit Care Med. 2001; 163: A707Google Scholar, 5Raghu G Brown KK Bradford WZ et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (619) Google Scholar, 6King Jr, TE Albera C Bradford WZ et al.Effect of γ1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre randomised, placebo-controlled trial.Lancet. June 30, 2009; ([Epub ahead of print])Google Scholar a TGF-β antibody,7Brown KK Flaherty KR Daniels C et al.Safety and tolerability of GC1008, a human monoclonal antibody against TGFβ, in patients with idiopathic pulmonary fibrosis [abstract].Am J Respir Crit Care Med. 2008; 177: A768Google Scholar an anti-CTGF monoclonal antibody,8Mageto Y Flaherty K Brown K et al.Safety and tolerability of human monoclonal antibody FG-3019, anti-connective tissue growth factor, in patients with idiopathic pulmonary fibrosis.Chest [abstract]. 2004; 126: 773SAbstract Full Text Full Text PDF Google Scholar imatinab (Joseph Lasky, MD; personal communication; January 2009), pirfenidone,9Raghu G Johnson WC Lockhart D et al.Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study.Am J Respir Crit Care Med. 1999; 159: 1061-1069Crossref PubMed Scopus (449) Google Scholar, 10Azuma A Nukiwa T Tsuboi E et al.Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2005; 171: 1040-1047Crossref PubMed Scopus (786) Google Scholar, 11Ogura T Ebina M Taniguchi H et al.A phase III, double-blind, placebo-controlled clinical trial of perfenidone in patients with idiopathic pulmonary fibrosis in Japan [abstract].Am J Respir Crit Care Med. 2008; 177: A768Google Scholar N-acetylcysteine (NAC),12Demedts M Behr J Buhl R et al.High-dose acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2005; 353: 2229-2242Crossref PubMed Scopus (838) Google Scholar bosentan,13King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (454) Google Scholar and warfarin.14Kubo H Nakayama K Yanai M et al.Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest. 2005; 128: 1475-1482Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar While the results of these important clinical trials have not resulted in survival benefits, important new hypotheses and signals from subgroup analyses have been generated. This research has prompted a new wave of larger, randomized clinical trials that will test other potential inhibitors of lung fibrogenesis and target mechanisms of pulmonary hypertension that commonly manifests in patients with IPF.In view of the currently poor prognosis of patients afflicted with IPF, the desire to “try anything,” even without evidence, is understandable. Since no treatment regimen has been proven to be effective compared with no specific treatment (ie, true placebo controls), current treatment paradigms have evolved more from subjective perceptions of physicians and patients based on signals from trials rather than from scientific evidence. For example, the original long-term clinical trial15Raghu G Depaso WJ Cain K et al.Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.Am Rev Respir Dis. 1991; 144: 291-296Crossref PubMed Scopus (393) Google Scholar that combined low-dose prednisone plus azathioprine and compared this combination to prednisone alone in a prospective, double-blind, randomized study of patients with newly diagnosed IPF produced significant positive signals. Pending the results of additional studies and based on the observations published to date, the ATS/ERS statement2American Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar published in 2000 suggested low-dose prednisone plus azathioprine as a treatment option, and this evolved as a “standard of care.” However, there is currently widespread belief that corticosteroids and immunosuppressive agents such as azathioprine are ineffective in treating patients with IPF. Concerns regarding the efficacy of prednisone and azathioprine for IPF are compounded by inevitable side effects associated with these immune-modulating agents, but to date the risk-benefit analysis of this regimen has not been directly tested in a well-designed clinical trial with adequate sample size and true placebo controls. The Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual (IFIGENIA) study11Ogura T Ebina M Taniguchi H et al.A phase III, double-blind, placebo-controlled clinical trial of perfenidone in patients with idiopathic pulmonary fibrosis in Japan [abstract].Am J Respir Crit Care Med. 2008; 177: A768Google Scholar added NAC to the “standard regimen” of prednisone and azathioprine, and the effects of these combined agents were compared with the prednisone plus azathioprine. While measures of pulmonary function (vital capacity and diffusing capacity of the lung for carbon monoxide) were better preserved in patients receiving the three agents (NAC, prednisone, and azathioprine) compared to prednisone plus azathioprine without NAC, there were no true placebo controls in this study and several questions regarding the use of NAC remain to be answered. For instance, it is not known if NAC alone is better than either of the treatment regimens used in the IFIGENIA study or compared to no specific treatment (ie, true placebo controls). Despite these concerns, a “new” standard of care for IPF (treatment with NAC, prednisone, and azathioprine) seems to be evolving.16Wells AU Hirani N Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society.Thorax. 2008; 63: 1-58Crossref PubMed Scopus (697) Google ScholarIt is time for us to go back to square one and design clinical studies that will refute the myths and establish the facts while testing positive signals from pilot and phase II studies and hypotheses generated by subgroup and post hoc analyses of phase II/III studies. These queries can only be settled with well-performed clinical trials using a true placebo patient control group and appropriate end points. While enhanced survival is undoubtedly the most robust primary end point, considerations of large sample size and duration of study necessitate use of surrogate markers for survival benefit. IPF trial results must be interpreted cautiously when suboptimal end points are used.17Johnson WC Raghu G Clinical trials in idiopathic pulmonary fibrosis: a word of caution concerning choice of outcome measures.Eur Respir J. 2005; 26: 755-758Crossref PubMed Scopus (16) Google Scholar Based on results of several clinical trials,3Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar, 5Raghu G Brown KK Bradford WZ et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (619) Google Scholar, 13King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (454) Google Scholar, 18King Jr, TE Safrin S Starko KM et al.Analyses of efficacy end points in a controlled trial of interferon-γ1b for idiopathic pulmonary fibrosis.Chest. 2005; 127: 171-177Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 19Martinez FJ Safrin S Weycker D et al.The clinical course of patients with idiopathic pulmonary fibrosis.Ann Intern Med. 2005; 142: 963-967Crossref PubMed Google Scholar we now understand that the natural course of many IPF patients with mild-to-moderate functional impairment includes relative stability during the first 1 to 2 years following enrollment, and thus studies with true placebo control groups are feasible. Indeed, in a recent study3Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar using etanercept, the feasibility for enrolling patients to receive absolutely no specific treatment for IPF (ie, the true placebo control) has been demonstrated.Currently, pirfenidone is available for clinical use for patients with IPF in Japan, and it is unknown if the results of the phase III clinical trials using pirfenidone in the western hemisphere (CAPACITY trials I and II), as disclosed to the public by the sponsor (press release; InterMune, Brisbane, CA; February 3, 2009, and May 26, 2009; data presented by Paul Noble, MD, on May 26, 2009, during the International Conference of the American Thoracic Society, San Diego, CA), will meet approval by the US Food and Drug Administration for IPF. Pending availability of the results from other phase III clinical trials that have just been completed or will be completed in future and the subsequent availability of the drug(s) after approval by regulatory agencies for clinical use in IPF, the need for clarification of the ongoing current “standard of care” with conventional treatment modalities such as prednisone plus azathioprine or cyclophosphamide and the recent consideration of using NAC can be met with new studies that compare the regimen with a true placebo-control arm.The National Institutes of Health (NIH) in the United States is committed to improving the current standard of care for patients with IPF through NIH-sponsored clinical trials using a network of highly selected, specialized centers of excellence: the Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). Community and academic pulmonologists have also enrolled patients in clinical trials sponsored by pharmaceutical industries and other agencies, and these are currently underway in selected sites (see www.clinicaltrials.gov). Until a regimen is clearly demonstrated to be effective for IPF, well-designed, prospective, randomized, multicenter, clinical trials with true placebo controls are the only way to provide evidence for treatments that improve outcomes for IPF patients.Accomplishing the goal of improving the standard of care for patients with IPF will require the continued commitment and efforts of well-informed patient volunteers, cooperative interactions with community physicians, and expert investigators supported by worldwide sponsors. Thus, clinicians and patients need to be fully aware of all available clinical trials and urged to participate in the global effort to find efficacious treatment regimens for IPF. Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal lung disease. Although the etiology of IPF is unknown, it is currently believed to occur as a result of repeated insults to the lungs over a period of years in individuals with occult, genetically determined, predisposing factors. Symptoms leading to diagnosis typically manifest in patients > 50 years old. Following diagnosis of IPF by surgical lung biopsy, the median survival is 2.8 years.1Bjoraker JA Ryu JH Edwin MK et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (971) Google Scholar While lung transplantation may improve survival for some patients, this option is appropriate for only a minority of patients with this debilitating disease. In 2000, a panel of experts representing the American Thoracic Society (ATS) and the European Respiratory Society (ERS) provided a consensus statement2American Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar regarding the diagnosis and treatment of IPF. This document provided a set of criteria for the accurate diagnosis of IPF that has been widely used to enroll well-defined IPF patients into clinical studies. Subsequently, several clinical trials have been performed in pursuit of improving outcomes for patients with IPF, although results to date have been disappointing, and an effective treatment regimen for IPF remains elusive. Nonetheless, significant advances in our understanding of the natural course of IPF and the pathogenesis of lung fibrosis have been made. Indeed, there is a need for the statement to be updated based on new evidence compiled over the last decade. Our present understanding of the cellular and molecular mechanisms of pulmonary fibrosis has resulted in the testing of treatment strategies that modulate specific inflammatory and fibrotic mediators and pathways currently implicated in the pathogenesis of IPF. These treatment strategies have included agents to inhibit the proinflammatory and profibrotic effects of tumor necrosis factor-α, transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor, tyrosine kinases, oxidants, endothelin, chemokines, and blood coagulation. Phase I, II, and III clinical trials have utilized etanercept,3Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar β- and γ-interferons,4Raghu G Bozic CR Brown KK et al.Feasibility of a trial of interferon beta-1a (IFNB-1a) in the treatment of idiopathic pulmonary fibrosis (IPF) [abstract].Am J Respir Crit Care Med. 2001; 163: A707Google Scholar, 5Raghu G Brown KK Bradford WZ et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (619) Google Scholar, 6King Jr, TE Albera C Bradford WZ et al.Effect of γ1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre randomised, placebo-controlled trial.Lancet. June 30, 2009; ([Epub ahead of print])Google Scholar a TGF-β antibody,7Brown KK Flaherty KR Daniels C et al.Safety and tolerability of GC1008, a human monoclonal antibody against TGFβ, in patients with idiopathic pulmonary fibrosis [abstract].Am J Respir Crit Care Med. 2008; 177: A768Google Scholar an anti-CTGF monoclonal antibody,8Mageto Y Flaherty K Brown K et al.Safety and tolerability of human monoclonal antibody FG-3019, anti-connective tissue growth factor, in patients with idiopathic pulmonary fibrosis.Chest [abstract]. 2004; 126: 773SAbstract Full Text Full Text PDF Google Scholar imatinab (Joseph Lasky, MD; personal communication; January 2009), pirfenidone,9Raghu G Johnson WC Lockhart D et al.Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study.Am J Respir Crit Care Med. 1999; 159: 1061-1069Crossref PubMed Scopus (449) Google Scholar, 10Azuma A Nukiwa T Tsuboi E et al.Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2005; 171: 1040-1047Crossref PubMed Scopus (786) Google Scholar, 11Ogura T Ebina M Taniguchi H et al.A phase III, double-blind, placebo-controlled clinical trial of perfenidone in patients with idiopathic pulmonary fibrosis in Japan [abstract].Am J Respir Crit Care Med. 2008; 177: A768Google Scholar N-acetylcysteine (NAC),12Demedts M Behr J Buhl R et al.High-dose acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2005; 353: 2229-2242Crossref PubMed Scopus (838) Google Scholar bosentan,13King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (454) Google Scholar and warfarin.14Kubo H Nakayama K Yanai M et al.Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest. 2005; 128: 1475-1482Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar While the results of these important clinical trials have not resulted in survival benefits, important new hypotheses and signals from subgroup analyses have been generated. This research has prompted a new wave of larger, randomized clinical trials that will test other potential inhibitors of lung fibrogenesis and target mechanisms of pulmonary hypertension that commonly manifests in patients with IPF. In view of the currently poor prognosis of patients afflicted with IPF, the desire to “try anything,” even without evidence, is understandable. Since no treatment regimen has been proven to be effective compared with no specific treatment (ie, true placebo controls), current treatment paradigms have evolved more from subjective perceptions of physicians and patients based on signals from trials rather than from scientific evidence. For example, the original long-term clinical trial15Raghu G Depaso WJ Cain K et al.Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.Am Rev Respir Dis. 1991; 144: 291-296Crossref PubMed Scopus (393) Google Scholar that combined low-dose prednisone plus azathioprine and compared this combination to prednisone alone in a prospective, double-blind, randomized study of patients with newly diagnosed IPF produced significant positive signals. Pending the results of additional studies and based on the observations published to date, the ATS/ERS statement2American Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (982) Google Scholar published in 2000 suggested low-dose prednisone plus azathioprine as a treatment option, and this evolved as a “standard of care.” However, there is currently widespread belief that corticosteroids and immunosuppressive agents such as azathioprine are ineffective in treating patients with IPF. Concerns regarding the efficacy of prednisone and azathioprine for IPF are compounded by inevitable side effects associated with these immune-modulating agents, but to date the risk-benefit analysis of this regimen has not been directly tested in a well-designed clinical trial with adequate sample size and true placebo controls. The Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual (IFIGENIA) study11Ogura T Ebina M Taniguchi H et al.A phase III, double-blind, placebo-controlled clinical trial of perfenidone in patients with idiopathic pulmonary fibrosis in Japan [abstract].Am J Respir Crit Care Med. 2008; 177: A768Google Scholar added NAC to the “standard regimen” of prednisone and azathioprine, and the effects of these combined agents were compared with the prednisone plus azathioprine. While measures of pulmonary function (vital capacity and diffusing capacity of the lung for carbon monoxide) were better preserved in patients receiving the three agents (NAC, prednisone, and azathioprine) compared to prednisone plus azathioprine without NAC, there were no true placebo controls in this study and several questions regarding the use of NAC remain to be answered. For instance, it is not known if NAC alone is better than either of the treatment regimens used in the IFIGENIA study or compared to no specific treatment (ie, true placebo controls). Despite these concerns, a “new” standard of care for IPF (treatment with NAC, prednisone, and azathioprine) seems to be evolving.16Wells AU Hirani N Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society.Thorax. 2008; 63: 1-58Crossref PubMed Scopus (697) Google Scholar It is time for us to go back to square one and design clinical studies that will refute the myths and establish the facts while testing positive signals from pilot and phase II studies and hypotheses generated by subgroup and post hoc analyses of phase II/III studies. These queries can only be settled with well-performed clinical trials using a true placebo patient control group and appropriate end points. While enhanced survival is undoubtedly the most robust primary end point, considerations of large sample size and duration of study necessitate use of surrogate markers for survival benefit. IPF trial results must be interpreted cautiously when suboptimal end points are used.17Johnson WC Raghu G Clinical trials in idiopathic pulmonary fibrosis: a word of caution concerning choice of outcome measures.Eur Respir J. 2005; 26: 755-758Crossref PubMed Scopus (16) Google Scholar Based on results of several clinical trials,3Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar, 5Raghu G Brown KK Bradford WZ et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2004; 350: 125-133Crossref PubMed Scopus (619) Google Scholar, 13King Jr, TE Behr J Brown KK et al.BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: 75-81Crossref PubMed Scopus (454) Google Scholar, 18King Jr, TE Safrin S Starko KM et al.Analyses of efficacy end points in a controlled trial of interferon-γ1b for idiopathic pulmonary fibrosis.Chest. 2005; 127: 171-177Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 19Martinez FJ Safrin S Weycker D et al.The clinical course of patients with idiopathic pulmonary fibrosis.Ann Intern Med. 2005; 142: 963-967Crossref PubMed Google Scholar we now understand that the natural course of many IPF patients with mild-to-moderate functional impairment includes relative stability during the first 1 to 2 years following enrollment, and thus studies with true placebo control groups are feasible. Indeed, in a recent study3Raghu G Brown KK Costabel U et al.Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial.Am J Respir Crit Care Med. 2008; 178: 948-955Crossref PubMed Scopus (286) Google Scholar using etanercept, the feasibility for enrolling patients to receive absolutely no specific treatment for IPF (ie, the true placebo control) has been demonstrated. Currently, pirfenidone is available for clinical use for patients with IPF in Japan, and it is unknown if the results of the phase III clinical trials using pirfenidone in the western hemisphere (CAPACITY trials I and II), as disclosed to the public by the sponsor (press release; InterMune, Brisbane, CA; February 3, 2009, and May 26, 2009; data presented by Paul Noble, MD, on May 26, 2009, during the International Conference of the American Thoracic Society, San Diego, CA), will meet approval by the US Food and Drug Administration for IPF. Pending availability of the results from other phase III clinical trials that have just been completed or will be completed in future and the subsequent availability of the drug(s) after approval by regulatory agencies for clinical use in IPF, the need for clarification of the ongoing current “standard of care” with conventional treatment modalities such as prednisone plus azathioprine or cyclophosphamide and the recent consideration of using NAC can be met with new studies that compare the regimen with a true placebo-control arm. The National Institutes of Health (NIH) in the United States is committed to improving the current standard of care for patients with IPF through NIH-sponsored clinical trials using a network of highly selected, specialized centers of excellence: the Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). Community and academic pulmonologists have also enrolled patients in clinical trials sponsored by pharmaceutical industries and other agencies, and these are currently underway in selected sites (see www.clinicaltrials.gov). Until a regimen is clearly demonstrated to be effective for IPF, well-designed, prospective, randomized, multicenter, clinical trials with true placebo controls are the only way to provide evidence for treatments that improve outcomes for IPF patients. Accomplishing the goal of improving the standard of care for patients with IPF will require the continued commitment and efforts of well-informed patient volunteers, cooperative interactions with community physicians, and expert investigators supported by worldwide sponsors. Thus, clinicians and patients need to be fully aware of all available clinical trials and urged to participate in the global effort to find efficacious treatment regimens for IPF. Financial/nonfinancial disclosures: Dr. Raghu has received research grant monies from Actelion, Genzyme, and InterMune, for patient-related costs to conduct clinical studies in patients with IPF at the University of Washington Medical Center, Seattle, WA. He has been a consultant for Actelion, Amira, Boehringer-Ingelheim, Celgene, Centocor, Genzyme, Gilead Sciences, and Stromedix. He has received honoraria from Shionogi and Actelion for continuing medical education lectures on IPF. He is a recipient of RO-1 grant (principal investigator) from the National Institutes of Health (NIH), Bethesda, MD, to conduct IPF clinical trials through IPFnet, sponsored by the NIH. AppendixThe IPFnet is a National Institutes of Health-sponsored IPF clinical trials network. The IPFnet Steering Committee includes Kevin K. Brown, MD, National Jewish Medical and Research Center, Denver, CO; Robert J. Kaner, MD, Weill Medical College of Cornell University, New York, NY; Talmadge E. King, Jr, MD, University of California, San Francisco, CA; Joseph A. Lasky, MD, Tulane University, New Orleans, LA; James E. Loyd, MD, Vanderbilt University, Nashville, TN; Fernando J. Martinez, MD, University of Michigan, Ann Arbor, MI; Imre Noth, MD, University of Chicago, Chicago, IL; Mitchell A. Olman, MD, Cleveland Clinic, Cleveland, OH; Ganesh Raghu, MD, University of Washington, Seattle, WA; Jesse Roman, MD, Emory University School of Medicine, Atlanta, GA; Jay H. Ryu, MD, Mayo Clinic, Rochester, MN; David A. Zisman, MD, University of California, Los Angeles, CA; Data Coordinating Center, Kevin J. Anstrom, PhD, Duke University, Durham, NC; Committee Chair, Gary W. Hunninghake, MD, University of Iowa, Iowa City, IA; and Project Officer, Herbert Y. Reynolds, MD, National Heart, Lung, and Blood Institute, Bethesda, MD. The IPFnet is a National Institutes of Health-sponsored IPF clinical trials network. The IPFnet Steering Committee includes Kevin K. Brown, MD, National Jewish Medical and Research Center, Denver, CO; Robert J. Kaner, MD, Weill Medical College of Cornell University, New York, NY; Talmadge E. King, Jr, MD, University of California, San Francisco, CA; Joseph A. Lasky, MD, Tulane University, New Orleans, LA; James E. Loyd, MD, Vanderbilt University, Nashville, TN; Fernando J. Martinez, MD, University of Michigan, Ann Arbor, MI; Imre Noth, MD, University of Chicago, Chicago, IL; Mitchell A. Olman, MD, Cleveland Clinic, Cleveland, OH; Ganesh Raghu, MD, University of Washington, Seattle, WA; Jesse Roman, MD, Emory University School of Medicine, Atlanta, GA; Jay H. Ryu, MD, Mayo Clinic, Rochester, MN; David A. Zisman, MD, University of California, Los Angeles, CA; Data Coordinating Center, Kevin J. Anstrom, PhD, Duke University, Durham, NC; Committee Chair, Gary W. Hunninghake, MD, University of Iowa, Iowa City, IA; and Project Officer, Herbert Y. Reynolds, MD, National Heart, Lung, and Blood Institute, Bethesda, MD.
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