A NEW ERA in IPF: Trials and Treatments Craig Thurm, MD Director, Pulmonary Medicine Director, Pulmonary Fellowship Medical Director, Respiratory Care Jamaica Hospital Medical Center Disclosure of Relevant Financial Relationships It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all conflicts of interest prior to the release of this activity. Faculty Disclosures Craig Thurm, MD has received research and grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, and Forest Pharmaceuticals. He has served as a consultant for Meda Pharmaceuticals and Sunovion Pharmaceuticals, and is a shareholder with Teva Pharmaceuticals. He has received honoraria from Boehringer Ingelheim, CSL Behring, Forest Pharmaceuticals, GlaxoSmithKlein, InterMune, Janssen Pharmaceuticals, and Merck. Activity Staff Disclosures The planners, reviewers, editors, staff, or other members at The France Foundation who control content have no relevant financial relationships to disclose. Educational Support Supported by educational grants from Boehringer Ingelheim and InterMune. Accreditation / Designation Statements The France Foundation is accredited with commendation by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The France Foundation designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. How to Receive CME Credit • Complete the pretest (page one of your handout) and give this page to the coordinator when you leave • Keep page two of your handout and follow the instructions to go online to claim CME credit • Your CME certificate will be available to download Educational Activity Learning Objective Upon completion of this course, the participants should be able to: • Explain the considerations associated with clinical evaluation, imaging, and surgical biopsy in differentially diagnosing IPF • Identify opportunities for interdisciplinary collaboration and consultation and key aspects of guideline recommendations that can facilitate early and accurate IPF diagnosis • Summarize the current understanding of the IPF disease process and strategies that can help measure disease progression and treatment response • Evaluate clinical trial data on available and emerging treatments for IPF • Identify opportunities for referral as part of multidisciplinary IPF management plan Outline • Diagnosis • Pathophysiology model • IPF drug trials – PANTHER (NAC) – ASCEND (pirfenidone) – INPULSIS (nintedanib) • Recent drug approvals! • Referral of patients with IPF Idiopathic Pulmonary Fibrosis • Peripheral lobular fibrosis of unknown cause • Clinical impact • • – Exertional dyspnea – Cough – Functional and exercise limitation – Impaired quality-of-life – Risk for acute respiratory failure and death Median survival time of 3-5 years Two new drugs approved by the FDA in October 2014 ‒ Nintedanib (Ofev) ‒ Pirfenidone (Esbriet) Diffuse Parenchymal Lung Disease (DPLD) Idiopathic interstitial pneumonias DPLD of known cause, eg, drugs or association, eg, collagen vascular disease Idiopathic pulmonary fibrosis Granulomatous DPLD, eg, sarcoidosis Other forms of DPLD, eg, LAM, HX, etc IIP other than idiopathic pulmonary fibrosis Desquamative interstitial pneumonia Respiratory bronchiolitis interstitial lung disease Acute interstitial pneumonia Cryptogenic organizing pneumonia Nonspecific interstitial pneumonia (provisional) Lymphocytic interstitial pneumonia ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:277-304. Major Idiopathic Interstitial Pneumonias Category Chronic fibrosing Smokingrelated Acute/ subacute Clinical-Radiologic-Pathologic Diagnosis Associated Radiographic and/or Pathologic pattern IPF UIP Idiopathic nonspecific interstitial Pneumonia (iNSIP) NSIP Respiratory bronchiolitis-ILD (RB-ILD) Respiratory bronchiolitis Desquamative interstitial pneumonia (DIP) Desquamative interstitial pneumonia Cryptogenic organizing pneumonia (COP) Organizing pneumonia Acute interstitial pneumonia (AIP) Diffuse alveolar damage Travis et al. Am J Respir Crit Care Med. 2013;188:733-748. Diagnostic Algorithm for IPF Suspected IPF Identifiable causes for ILD? No HRCT Possible UIP Inconsistent w/ UIP Surgical Lung Biopsy UIP Probable UIP Non-classifiable fibrosis MDD IPF IPF/Not IPF Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824. Not IPF 2011 ATS/ERS Diagnostic Criteria for IPF UIP pattern on HRCT without surgical biopsy Exclusion of known causes of ILD* AND *also known as diffuse parenchymal lung disease, DPLD Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824. OR Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP Idiopathic Pulmonary Fibrosis Normal Lungs Usual Interstitial Pneumonia Idiopathic Pulmonary Fibrosis Normal Lung Usual Interstitial Pneumonia Idiopathic Pulmonary Fibrosis Normal Lung Fibroblastic Focus in Usual Interstitial Pneumonia Clinical-Radiologic-Pathologic Approach to ILD Radiologic pattern (HRCT) Pathologic pattern (lung biopsy) Clinical picture Specific diagnosis ILD Disease Progression Exogenous and Endogenous stimuli Dust Fumes Cigarette smoke Autoimmune conditions Drugs Infections-viruses Radiation Other diseases Microscopic lung injury: Separated spatially and temporally Intact Wound healing Aberrant Genetic predisposition Lung homeostasis Steele MP, Schwartz DA. Annu Rev Med. 2013;64:265-276. Interstitial lung disease Eras of Care for IPF Pre-ATS Statement 2011 ATS Statement 2011 2011-2013 2014 Completed Trials for IPF: Prior to 2011 Consensus Statement Trial N Primary Endpoint Result Interferon-beta (1999) 167 Progression-free survival time Negative Interferon-gamma (GIPF-001) 330 Progression-free survival Negative Interferon-gamma (Inspire) 826 Survival time Negative Pirfenidone (CAPACITY 1) 344 Change in FVC Negative Pirfenidone (CAPACITY 2) 435 Change in FVC Positive Pirfenidone (Ogura) 275 Change in FVC Positive Etanercept 100 Change in DLco, FVC Negative Imatinib Mesylate 120 Progression-free survival Negative Bosentan (BUILD 1 and 2) 132 Change in 6MW Negative Bosentan (BUILD 3) 390 Progression-free survival time Negative Anticoagulation 56 N-acetylcysteine (NAC) (IFIGENIA) 184 Sildenafil (STEP) 29 Subsequent Survival trials showed that warfarin Positive and NAC/azathioprine/prednisone Change in FVC, DLco Positive should not be used for IPF Change in 6MWD, Borg dyspnea index Noth I, et al. Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95.\ Negative 2011 Guidelines on Management of IPF Treatment Strong For Weak For Weak Against Strong Against Corticosteroid X Colchicine X Cyclosporine A X Interferon γ 1b X Bosentan X Etanercept X NAC/Azathioprine/Prednisone X NAC X Anticoagulation X Pirfenidone X Mechanical ventilation X Pulmonary rehab X Long-term oxygen X Lung transplantation X Three Recent IPF Clinical Trials American Thoracic Society 2014 • PANTHER • ASCEND • INPULSIS N-acetylcysteine (NAC) pirfenidone nintedanib (BIBF1120) PANTHER N-acetylcysteine (NAC) NAC Does Not Reduce FVC Decline Conclusion: NAC offered no significant benefit with respect to the preservation of FVC in patients with IPF with mild-to-moderate impairment in lung function Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101. ASCEND Pirfenidone Possible Mechanisms of Pirfenidone Action • Antifibrotic • Molecular target • unclear Active in several animal models of fibrosis (lung, liver, kidney) Hilberg O, et al. Clin Respir J. 2012;6:131-143. Pirfenidone TNF-α IL-6 TGF-β IL-6 MMPs Collagenases Collagen ROIs Pre-2011 ATS 2011 2011-2013 CAPACITY 2011 CAPACITY-2 CAPACITY-1 • One pirfenidone trial was positive, one was negative • CAPACITY-1 placebo group FVC declined more slowly than expected Noble P, et al. Lancet. 2011;377:1760-1769. 2014 CAPACITY Endpoints Endpoint CAPACITY-2 CAPACITY-1 FVC X Overall survival X X Progression-free survival X Six-minute walk distance X DLCO X X Dyspnea X X Exertional desaturation X X Noble P, et al. Lancet. 2011;377:1760-1769. Pre-2011 ASCEND 2014 ATS 2011 2011-2013 2014 ASCEND Study Design 52 Weeks Inclusion Criteria • • • • • • Age 40-80 Confirmed IPF 50 - 90% FVC pred 30 - 90% DLCO pred FEV1/FVC ≥ 0.80 6-MWD ≥ 150 m 555 Patients PFS - Progression-free survival King TE, et al. N Engl J Med. 2014;370(22):2083-2092. Endpoints Oral Pirfenidone 2403 mg Daily Placebo 10: Δ FVC or death 20: 6-MWD PFS Dyspnea Death Primary ASCEND Endpoint Achieved Patients with ≥ 10% FVC Decline or Death (%) Primary Endpoint 48% Relative Reduction Week King TE, et al. N Engl J Med. 2014;370(22):2083-2092. Pirfenidone Increased Progression-Free Survival* *Progression is first occurrence of death, 10% ↓ FVC, or 50 m ↓ 6MWD King TE, et al. N Engl J Med. 2014;370(22):2083-2092. Mean Change (ml) Pirfenidone Reduces Loss of FVC 235 ml Rank ANCOVA P-value < 0.00001 at each indicated time point 428 ml Week King TE, et al. N Engl J Med. 2014;370(22):2083-2092. <0.000001 Proportion of Patients with ≥50 m Decline or Death (%) More Pirfenidone Patients Maintain Walk Distance or Survive King TE, et al. N Engl J Med. 2014;370(22):2083-2092. Week ASCEND Adverse Events Adverse Event Nausea Rash Dyspepsia Anorexia GERD Weight Loss Insomnia Dizziness Vomiting Pirfenidone (%) Placebo (%) (N = 278) (N = 277) 36 13.4 28.1 8.7 17.6 6.1 15.8 6.5 11.9 6.5 12.6 7.9 11.2 6.5 17.6 13 12.9 8.7 … Dyspnea Cough IPF King TE, et al. N Engl J Med. 2014;370(22):2083-2092. Δ (%) 22.6 19.4 11.5 9.3 5.4 4.7 4.7 4.6 4.2 … … … 14.7 25.2 9.4 17.7 29.6 18.1 -3 -4.4 -8.7 Pirfenidone Associated with Less Mortality ASCEND and CAPACITY data From randomization to 28 days after last dose Cox proportional hazard model Log-rank test King TE, et al. N Engl J Med. 2014;370(22):2083-2092. ASCEND Summary • Treatment with pirfenidone for 52 weeks significantly reduced disease progression, as measured by – Changes in % predicted FVC (P < 0.001) – Changes in 6-minute walk distance (P = 0.04) – Progression-free survival (P < 0.001) • Treatment with pirfenidone reduced all-cause mortality and treatment emergent IPF-related mortality in pooled analyses at week 52 • Pirfenidone was generally safe and well tolerated King TE, et al. N Engl J Med. 2014;370(22):2083-2092. ASCEND Conclusions • Pirfenidone, as compared with placebo, reduced disease progression in patients with IPF • Treatment was generally safe, had an acceptable side effect profile, and was associated with fewer deaths 37 FDA Approval of Pirfenidone (Esbriet) • Approved October 15, 2014 • Indicated for the treatment of IPF • Dosage and administration – 801 mg (three 267 mg capsules) three times daily with food – Doses should be taken at the same time each day – Initiate with titration • Days 1 through 7: 1 capsule 3x per day • Days 8 through 14: 2 capsules 3x per day • Days 15 onward: 3 capsules 3x per day – Consider temporary dosage reduction, treatment • interruption, or discontinuation for management of adverse reactions. Prior to treatment, conduct liver function tests. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. DrugDetails/. Accessed October 2014. 38 Pirfenidone Warnings and Precautions Temporary dosage reductions or discontinuations may be required • Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with pirfenidone. Monitor ALT, AST, and bilirubin before and during treatment. • Photosensitivity and rash: Photosensitivity and rash have been noted with pirfenidone. Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing daily. • Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastro-esophageal reflux disease, and abdominal pain have occurred with pirfenidone. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. DrugDetails/. Accessed October 2014. Pirfenidone: Other Considerations • Post-marketing experience (reactions of unknown frequency) – Agranulocytosis – Angioedema – Bilirubin increased in combination with increases of ALT and AST • Drug interactions – Metabolized primarily via CYP1A2 – Activators and inhibitors of CYP1A2 should be used with caution with pirfenidone • Use with caution with mild/moderate hepatic impairment, not • • recommended for patients with severe impairment Use with caution with mild/moderate/severe renal impairment, not recommended for patients with ESRD requiring dialysis Smoking causes decreased exposure to pirfenidone. Instruct patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. DrugDetails/. Accessed October 2014. INPULSIS Nintedanib Possible Mechanisms of Nintedanib Action • Triple kinase inhibitor • Phosphatase activator • Antiangiogenic, antitumor activity Nintedanib VEGF PDGF FGF Pleiotropic Effects Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782. Tai WT, et al. J Hepatol. 2014;61(1):89-97. SHP-1 Nintedanib Showed Promise for FVC Endpoint Richeldi L, et al. N Engl J Med.2011:365;1079-1089. Pre-2011 ATS 2011 2011-2013 2014 Pre-2011 INPULSIS 2014 ATS 2011 2011-2013 2014 INPULSIS-1 and INPULSIS-2 Study Design 52 Weeks Inclusion Criteria • • • • • Age > 40 IPF ≤ 5y ≥ 50% FVC pred 30 - 79% DLCO pred HRCT within 1y 3 Nintedanib 300 mg Daily 2 1066 Patients AE – Acute Exacerbation SGRQ – St. George’s Respiratory Questionnaire Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. Placebo Endpoints 10: ΔFVC 20: Time to first AE Δ SGRQ Primary INPULSIS Endpoint Achieved Annual Rate of Change of FVC INPULSIS-1 INPULSIS-2 45% Relative Reduction 52% Relative Reduction Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. Nintedanib Placebo Mean Observed Change from Baseline in FVC (mL) Nintedanib Reduces Loss of FVC Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. INPULSIS-1 INPULSIS-2 Week Cumulative Incidence of First Acute Exacerbation (%) Mixed Findings for Time to First Acute Exacerbation Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. INPULSIS-1 INPULSIS-2 Days Common Nintedanib Adverse Events INPULSIS-1 Event INPULSIS-2 Nintedanib (n = 309) Placebo (n = 204) Nintedanib (n = 329) Placebo (n = 219) Any (%) 96 89 94 90 Diarrhea (%) 62 19 63 18 Nausea(%) 23 6 26 7 Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. INPULSIS Summary • Nintedanib had significant benefit in adjusted annual rate of • • change in FVC • INPULSIS-1 Δ = 125.3 ml P < 0.001 • INPULSIS-2 Δ = 93.7 ml P < 0.001 Nintedanib had significant benefit in time to the first acute exacerbation in INPULSIS-2 • INPULSIS-1 HR = 1.15 P = 0.67 • INPULSIS-2 HR = 0.38 P = 0.005 Significant difference in favor of nintedanib for the change from baseline in the total SGRQ score in INPULSIS-2 but not INPULSIS-1 Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. INPULSIS Conclusions • Nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression • Nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. FDA Approval of Nintedanib (Ofev) • Approved October 15, 2014 • Indicated for the treatment of IPF • Dosage and administration – 150 mg twice daily approximately 12 hours apart taken with food – Consider temporary dose reduction to 100 mg, temporary interruption, or discontinuation for management of adverse reactions. – Prior to treatment, conduct liver function tests. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search. DrugDetails/. Accessed October 2014. 52 Nintedanib Warnings and Precautions • Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with • • • • • nintedanib. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required. GI disorders: Diarrhea, nausea, and vomiting have occurred with nintedanib. Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue nintedanib if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment. Embryofetal toxicity: Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known CAD. Bleeding events have been reported. Use nintedanib in patients with known bleeding risk only if anticipated benefit outweighs the potential risk. GI perforation has been reported. Use nintedanib with caution when treating patients with recent abdominal surgery. Discontinue nintedanib in patients who develop GI perforation. Only use nintedanib in patients with known risk of GI perforation if the anticipated benefit outweighs the potential risk. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014. 53 Nintedanib: Other Considerations • Drug interactions – Nintedanib is a substrate of P-glycoprotein (P-gp) and CYP3A4 – Concomitant use of P-gp and CYP3A4 inducers with nintedanib should – be avoided Patients treated with P-gp and CYP3A4 inhibitors and nintedanib should be monitored closely for adverse reactions • Nintedanib is a VEGFR inhibitor, and may increase the risk of • • bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary. Nintedanib not recommended for patients with moderate or severe hepatic impairment < 1% excreted via the kidney; no data on patients with severe renal impairment and ESRD http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014. 54 Current Phase 2 Trials for IPF Next Generation Therapy? Trial Target N Primary Endpoint Co-trimoxazole (Ph 3) Pneumocystis jiroveci 56 Change in FVC or respir. Hospital’n FG-3019 Anti-CTGF 90 Change in FVC from baseline Rituximab CD-20 58 Titers of anti-HEp-2 autoantibodies Simtuzumab Anti-LOXL2 500 PFS GC-1008 TGF- 25 Safety, tolerability, PK QAX576 Anti-IL-13 40 Safety, tolerability, FVC Tralokinumab Anti-IL-13 302 Change in FVC from baseline STX-100 αvβ6 32 Adverse events BMS-986020 LPA Receptor 300 Rate of change in FVC Clinical Trial Conclusions • 2014 is a watershed year in IPF – NAC did not show efficacy (PANTHER) – Pirfenidone (ASCEND) and nintedanib (INPULSIS) showed efficacy in mild/moderate IPF – Pirfenidone and nintedanib approved 10/15/14 for the treatment of IPF – Still need data on advanced disease, combination therapy, long-term safety, adherence • Implications of having approved drug(s) – Need early and accurate diagnosis – Role of IPF and ILD Centers of Excellence is evolving EARLY REFERRAL for SPECIALTY CARE Why refer early to an ILD Center? • Diagnostic expertise – Standardized assessment – Confirmation of diagnosis • Management expertise – Choice of an appropriate therapy – Oxygen prescription – Pulmonary rehabilitation – Attention to obesity and sarcopenia/frailty – Potential enrollment in a clinical trial – Transplant evaluation Flaherty et al. Am J Respir Crit Care Med 2004;170:904-10. Flaherty et al. Am J Respir Crit Care Med 2007;175:1054-60. Lamas et al. Am J Respir Crit Care Med 2011;184:842-7. ILD Checklist • • • • • • • • • • Therapeutic options Supplemental oxygen Age-appropriate vaccinations Risk factor reduction Pulmonary rehabilitation Clinical trials Lung transplant evaluation Patient education Advocacy group involvement Mental health needs Referral Opportunity? x x x x x x x Delayed Care Associated with Higher Mortality P for trend = 0.04 Lamas et al. Am J Respir Crit Care Med. 2011;184:842-847. Lung Transplantation is Increasing 3,000 CF IPF COPD Alpha-1 IPAH Re-Tx Number of Transplants 2,500 2,000 COPD 1,500 1,000 IPF 500 CF 0 http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry. Accessed August 2014. Lung Transplantation for IPF: 2014 Referral Guidelines • Histopathologic or radiographic evidence of usual • • • interstitial pneumonitis (UIP) Abnormal lung function: FVC < 80% predicted or DLCO < 40% predicted Any dyspnea or functional limitation attributable to lung disease Any oxygen requirement, even if only during exertion Weill D, et al. J Heart Lung Transplant.2014 Jun 26. [Epub ahead of print]. Conclusions • Pirfenidone and nintedanib are FDA approved for treatment of IPF • Diagnosis of IPF requires a patient history, physical exam, lab tests, HRCT, and sometimes a biopsy • Patients should be referred early – Pulmonary rehabilitation – ILD center – Lung transplantation evaluation To Receive Credit for this Activity: Please Complete the Evaluation and Posttest at www.pilotforipf.org/credit/## Supplemental Slides Possible NAC Mechanisms of Action • Increase glutathione antioxidation • Downregulate lysyl oxidase (LOX) activity, (essential for collagen deposition) Li S, et al. Respiration. 2012;84(6):509-517. Rushworth GF, et al. Pharmacol Ther. 2014;141(2):150-159. Pre-2011 ATS 2011 2011-2013 2014 Early Evidence for a NAC Cocktail + azathioprine + steroids Acetylcysteine + azathioprine + steroids Placebo ++azathioprine azathioprine++steroids steroids Demedts M, et al. New Engl J Med. 2005;353:2229-2242. Pre-2011 PANTHER 2012 Raghu G, et al. N Engl J Med. 2012;366:1968-1977. ATS 2011 2011-2013 2014 Pre-2011 ATS 2011 2011-2013 2014 PANTHER 2012 Interim Results Primary Triple Therapy Placebo P-value FVC (liters) -0.24 -0.23 0.85 Time to Death Kaplan–Meier Analysis no benefit for FVC • Increased risk of death Probability • Triple therapy has HR 9.26 (95% CI 1.16-74.1) P = 0.01 Weeks Since Randomization Raghu G, et al. N Engl J Med. 2012;366:1968-1977. Pre-2011 ATS 2011 2011-2013 2014 • Triple therapy has higher incidence of adverse events than placebo Percentage PANTHER 2012 Adverse Events 35 30 25 20 15 10 5 0 P-values < 0.05 Placebo Pred/Aza/NAC P-value for each comparison < 0.05 Raghu G, et al. N Engl J Med. 2012;366:1968-1977. IPFNet writing committee. N Engl J Med 2012;366;1968-77. PANTHER 2012 Conclusions • Compelling evidence against the use of the triple combination for patients with mild-tomoderate IPF • Next steps – Combination arm terminated – Two arms of study continued (NAC vs placebo) Raghu G, et al. N Engl J Med. 2012;366:1968-1977. Pre-2011 PANTHER 2014 Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101. ATS 2011 2011-2013 2014 PANTHER Study Design • Subjects: 264 patients with IPF (2 arm • • • • continuation of PANTHER-IPF) Treatment: acetylcysteine (600 mg) or placebo 3 times daily Duration: 60 weeks Primary end point: change in FVC Secondary end points – Time to the first acute exacerbation – Change from baseline in the total score on the St. George’s Respiratory Questionnaire Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101. To Receive Credit for this Activity, Please Complete the Evaluation and Posttest: PILOTforIPF.org/credit/13