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EVIDENCE BASED MANAGEMENT OF IPF (Based on ATS/ERS/JRS/ALAT Committee guidelines for IPF)DR.KALAIYARASAN6/10/2015

OverviewIntroductionPharmacological therapiesNon pharmacological therapiesTreatment of selected complications & comorbid conditions.Palliative careNewer AgentsConclusion

Idiopathic pulmonary fibrosis (IPF)A specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs.

Associated with the histopathologic and/or radiologic pattern of UIP.

Characterized by progressive worsening of dyspnea and lung function and is associated with a poor prognosis.

IPF - EtiologyUnknown

Potential risk factorsCigarette smokingEnvironmental exposuresMicrobial agents (EBV, HCV, CMV, HHV-7, HHV-8)Gastroesophageal refluxGenetic Factors (ELMOD2, on chromosome 4q31)

Signs & Symptoms of IPFUnexplained chronic exertional dyspneaCoughBibasilar inspiratory crackles (Velcro crackles)ClubbingWeight lossFeverFatigueMyalgiasArthralgia

The incidence increases with older age, with presentation typically occurring in the sixth and seventh decades.Male preponderance and the majority of patients have a history of cigarette smoking.

IPF Diagnosis (Based on 2011 guideliness)Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).

UIP pattern on HRCT

Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy.

Accuracy increases with multidisciplinary discussion between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD.

The major and minor criteria proposed in the 2000 ATS/ERS Consensus Statement have been eliminated.

Pharmacological Therapies

Corticosteroid monotherapyNo RCT have been conducted.

Retrospective, uncontrolled studies reported no survival benefits, but a minority of patients showed improvement in their pulmonary function1,2,3.

Controlled data have found no survival benefit4. There is substantial morbidity from long-term therapy2.1. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: response to corticosteroid treatment and its effect on survival. Thorax 1980;35:593599.2. Gay SE, Kazerooni EA, Toews GB, Lynch JP III, Gross BH, Cascade PN, Spizarny DL, Flint A, Schork MA, Whyte RI, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1998;157:10631072.3. Flaherty KR, Toews GB, Lynch JP III, Kazerooni EA, Gross BH, Strawderman RL, Hariharan K, Flint A, Martinez FJ. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med 2001;110:278282.4. Nagai S, Kitaichi M, Hamada K, Nagao T, Hoshino Y, Miki H, Izumi T. Hospital-based historical cohort study of 234 histologically proven Japanese patients with IPF. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:209214.

Recommendation (2011) Patients with IPF should not be treated with corticosteroid monotherapy (strong recommendation, very low-quality evidence).

ColchicineInhibits fibroblast proliferation & collagen synthesis in vitro1.

Several prospective clinical trials have compared colchicine to various treatment regimens showing no difference in clinical outcome2,3,4.

A retrospective study of 487 patients with IPF - no therapy Vs colchicine - no impact on survival5.1. Entzian P, Schlaak M, Seitzer U, Bufe A, Acil Y, Zabel P. Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis. Lung 1997;175:4151.2. Fiorucci E, Lucantoni G, Paone G, Zotti M, Li BE, Serpilli M, Regimenti P, Cammarella I, Puglisi G, Schmid G. Colchicine, cyclophosphamide and prednisone in the treatment of mild-moderate idiopathic pulmonary fibrosis: comparison of three currently available therapeutic regimens. Eur Rev Med Pharmacol Sci 2008;12:105111.3. Antoniou KM, Nicholson AG, Dimadi M, Malagari K, Latsi P, Rapti A, Tzanakis N, Trigidou R, Polychronopoulos V, Bouros D. Longterm clinical effects of interferon gamma-1b and colchicine in idiopathic pulmonary fibrosis. Eur Respir J 2006;28:496504.4. Douglas WW, Ryu JH, Swensen SJ, Offord KP, Schroeder DR, Caron GM, DeRemee RA; Lung Study Group. Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis: a randomized prospective study. Am J Respir Crit Care Med 1998;158:220225.5. Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 2000;161:11721178.

Recommendation (2011) Patients with IPF should not be treated with colchicine (strong recommendation, very low-quality evidence).

Cyclosporin ALimited data available.Early reports in small, uncontrolled groups of patients with IPF suggested a possible benefit1,2. Retrospective study of 10 patients with IPF showed no apparent benefit3.

Two studies of small groups of postlung transplant patients with IPF treated with cyclosporine-containing immunosuppressive regimens have shown progression of disease in the native lung4,5.1. Alton EW, Johnson M, Turner-Warwick M. Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A. Respir Med 1989;83:277279.2. Moolman JA, Bardin PG, Rossouw DJ, Joubert JR. Cyclosporin as a treatment for interstitial lung disease of unknown aetiology.Thorax 1991;46:592595.3. Homma S, Sakamoto S, Kawabata M, Kishi K, Tsuboi E, Motoi N, Yoshimura K. Cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia. Intern Med 2005;44:11441150.4. Grgic A, Lausberg H, Heinrich M, Koenig J, Uder M, Sybrecht GW, Wilkens H. Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native lung after single lung transplantation. Respiration 2008;76:139145.5. Wahidi MM, Ravenel J, Palmer SM, McAdams HP. Progression of idiopathic pulmonary fibrosis in native lungs after single lung transplantation. Chest 2002;121:20722076.

Recommendation (2011) Patients with IPF should not be treated with cyclosporine A (strong recommendation, very low quality evidence).

Corticosteroid and Immunomodulator therapy(e.g.,azathioprine or cyclophosphamide)A small randomized trial of corticosteroid Vs corticosteroid & azathioprine showed a trend toward a survival benefit with combination therapy1.

Corticosteroid & cyclophosphamide was compared with corticosteroid alone, and a survival benefit with cyclophosphamide was demonstrated2.

Results are confounded by the inclusion of patients that do not meet recent diagnostic criteria for IPF at that time. 1. Raghu G, Depaso WJ, Cain K, Hammar SP, Wetzel CE, Dreis DF, Hutchinson J, Pardee NE, Winterbauer RH. 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;144:291296.2. Johnson MA, Kwan S, Snell NJ, Nunn AJ, Darbyshire JH, Turner-Warwick M. Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989;44:280288.

Summary of evidence Contd.Two retrospective, controlled studies of cyclophosphamide have been published.

The first compared corticosteroid and cyclophosphamide Vs no therapy in 164 patients, and found no survival difference1.

The second compared corticosteroid and cyclophosphamide Vs corticosteroid alone in 82 patients, and found a survival benefit with combination therapy2.

1. Collard HR, Ryu JH, Douglas WW, Schwarz MI, Curran-Everett D, King TE Jr, Brown KK. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 2004;125:21692174.2. Pereira CAC, Malheiros T, Coletta EM, Ferreira RG, Rubin AS, Otta JS, Rocha NS. Survival in idiopathic pulmonary fibrosiscytotoxic agents compared to corticosteroids. Respir Med 2006;100:340347.

Recommendation (2011) Patients with IPF should not be treated with combination corticosteroid & immunomodulator therapy (strong recommendation, low-quality evidence).

Interferon- 1b (IFN-)Antifibrotic and immunomodulatory properties.

330 patients with IPF, randomized to receive IFN- 200 mg three times a week subcutaneously or placebo, with low-dose prednisone as concomitant medication in both groups1.

Objective: time to clinical worsening or death.

Result - no difference between groups.

post hoc analysis suggested a trend toward improved survival with IFN- in a subgroup of patients with less severe physiological disease at baseline.1. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr, Idiopathic Pulmonary Fibrosis Study Group. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125133.

INSPIRE TrialDouble blind RCT.

826 patients were randomly assigned in a 2:1 ratio to receive 200 g interferon gamma-1b (n=551) or equivalent placebo (n=275) subcutaneously, three times per week.

Primary end point - overall survival time

Showed no difference in overall mortality (14.5% in the IFN- group compared with 12.7% in the placebo arm).1. King TE Jr, Albera C, Bradford WZ, Costabel U, Hormel P, Lancaster L, Noble PW, Sahn SA, Szwarcberg J, Thomeer M, et al.; INSPIRE Study Group. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 2009;374:222228.

Recommendation (2011) Patients with IPF should not be treated with IFN- (strong recommendation, high-quality evidence).

EtanerceptRecombinant soluble human TNF receptor, binds to TNF & neutralizes its activity in vitro1.

A RCT of etanercept for patients with IPF failed to show a difference in the primary endpoint of change in FVC over 48 weeks, although the study was underpowered.

Non significant trends were observed in DLCO, 6MWT parameters or patient-centered outcomes2.1. Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993;151:15481561.2. Raghu G, Brown KK, Costabel U, Cottin V, du Bois RM, Lasky JA, ThomeerM, Utz JP, Khandker RK, McDermott L, et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med 2008;178:948955.

Recommendation (2011) Patients with IPF should not be treated with etanercept (strong recommendation, moderate-quality evidence).

ANTICOAGULATIONA procoagulant state may be involved in promoting fibrosis via cell-surface receptormediated pathways1,2.

Plausibility for a mechanistic link between thrombosis and lung fibrosis3,4.

It is less clear what role systemic anticoagulants may have in preventing this effect in patients with IPF.1 Chambers RC. Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? Br J Pharmacol 2008;153:S367S378.2 Navaratnam V, Fogarty AW, McKeever T, Thompson N, Jenkins G, Johnson SR, Dolan G, Kumaran M, Pointon K, Hubbard RB. Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case-control study. Thorax 2014;69:207215.3 Sode BF, Dahl M, Nielsen SF, Nordestgaard BG. Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide study. Am J Respir Crit Care Med 2010;181:10851092.4 Sprunger DB, Olson AL, Huie TJ, Fernandez-Perez ER, Fischer A, Solomon JJ, Brown KK, Swigris JJ. Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease. Eur Respir J 2012;39:125132.

SUMMARY OF EVIDENCEThe 2011 guideline included one study, an open randomized trial that compared oral warfarin & prednisolone against prednisolone alone in 56 patients with IPF1.

Treatment with warfarin led to a reduction in the secondary outcome of IPF acute exacerbation-associated mortality.

This trial was associated with significant methodological concerns.1 Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:14751482.

SUMMARY OF EVIDENCE Contd.One RCT published since the 2011 guideline randomized 145 patients with IPF to oral warfarin (target INR, 2.03.0) Vs placebo control1.

Stopped early after a mean follow-up of 28 weeks due to lack of benefit & a signal for potential harm with treatment.

No significant difference seen in terms of FVC change or percentage of patients with a greater than 10% decrease in FVC during the study period .

Trend toward more serious adverse events in patients receiving warfarin & significant increase in mortality was seen.1 Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186:8895.

RECOMMENDATION20112015The majority of patients with IPF should not be treated with anticoagulants, but this therapy may be a reasonable choice in a minority (weak recommendation,very low-quality evidence).Dont use warfarin anticoagulation in patients with IPF who do not have a known alternative indication for its use (strong recommendation against, low confidence in estimates of effect).

Patients who have an alternate and/or known indication for anticoagulation, such as venous thrombo-embolic disease or atrial fibrillation, should follow treatment guidelines for these conditions independent of their underlying IPF.

IMATINIBPotent inhibitor of lung fibroblastmyofibroblast differentiation and proliferation.

Inhibitor of extracellular matrix production through inhibition of PDGF and TGF- signaling.

SUMMARY OF EVIDENCEPlacebo-controlled RCT, randomized 119 patients and included a median follow-up of 96 weeks with oral Imatinib 600mg/OD1.

Primary outcome Disease progression (defined as a more than 10% decline in FVC) or death at 96 weeks

No difference in mortality was seen between groups.

Statistically significant increased risk of adverse events in the imatinib group compared with control.1 Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR; Imatinib-IPF Study Investigators. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010;181:604610.

RECOMMENDATIONDont use imatinib in patients with IPF (strong recommendation, moderate confidence in estimates of effect).

Combination of Prednisone, Azathioprine,N-AcetylcysteinePreviously, immune suppression was considered important in the treatment of IPF1.

It was thought that a two-drug regimen including glucocorticoids in addition to either azathioprine or cyclophosphamide may be superior to glucocorticoids alone1.

Given some early studies in favor of N-acetylcysteine2, clinicians and researchers have examined the potential benefit of this three-drug regimen for IPF.1. American Thoracic Society; European Respiratory Society. American Thoracic Society: idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646664.2. Tomioka H, Kuwata Y, Imanaka K, Hashimoto K, Ohnishi H, Tada K, Sakamoto H, Iwasaki H. A pilot study of aerosolized Nacetylcysteine for idiopathic pulmonary fibrosis. Respirology 2005;10:449455.

SUMMARY OF EVIDENCEPANTHER TrialMulticentric RCT, combination therapy Vs placebo1.

Stopped early after a signal for harm was seen in patients receiving combination therapy compared with placebo, with an increase in mortality (HR, 9.26; 95% CI, 1.1674.1) and hospitalization (P,0.001).

No significant difference between groups was seen in FVC change, DLCO change or quality-of-life indices.1 Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:19681977.

RECOMMENDATION20112015The majority of patients with IPF should not be treated with combination corticosteroid, azathioprine and acetylcysteine therapy, but this therapy may be a reasonable choice in a minority (weak recommendation, low quality evidence).Dont use the combination therapy of N-acetylcysteine, azathioprine and prednisone in patients with IPF. (strong recommendation, low confidence in estimates of effect).

Endothelin receptor antagonists (ERAs)Clinically available ERAs include:Selective ET-A antagonists (e.g., ambrisentan) Dual antagonists that affect both ET-A and ET-B receptors (e.g., bosentan and macitentan).

Increased ET-A and ET-B receptor levels have been found in IPF-affected fibrotic lung1.1 Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997;156:600608.

SUMMARY OF EVIDENCEAmbrisentan is the only selective ERA with RCT evidence, with a single study that randomized 492 patients with IPF in a 2:1 ratio to either drug or placebo1.

Stratified randomization based on the presence or absence of PH by right heart catheterization at baseline.

Ambrisentan increased disease progression, assessed as worsening DLCO or FVC, independent of the presence or absence of PH.

Study was stopped early for lack of benefit and a high likelihood of harm seen with intervention.

1 Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, Martinez FJ, Nathan SD, Wells AU, Collard HR, et al.; ARTEMIS-IPF Investigators*. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013;158: 641649.

RECOMMENDATIONDont use ambrisentan, a selective ER-A endothelin receptor antagonist, in patients with IPF, regardless of the presence or absence of PH (strong recommendation against, low confidence in estimates of effect).

NintedanibPreviously known as molecule BIBF 1120

An intracellular inhibitor of several tyrosine kinases that targets multiple growth factor receptors, including VEGF, fibroblast growth factor and PDGF.

SUMMARY OF EVIDENCENintedanib treatment in patients with IPF was evaluated in three RCTs published in two separate reports1,2.

The first was a phase 2 safety and efficacy trial that studied four different doses of nintedanib (50 mg once daily, 50 mg twice daily, 100 mg twice daily, and 150 mg twice daily) Vs placebo1.

No significant difference between groups was seen in terms of mortality. 1 Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:10791087.2 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, et al.; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:20712082.

SUMMARY OF EVIDENCE Contd.The percentage of patients with more than 10% FVC decline during the 12 month follow up period was lower with the highest dose of nintedanib (P = 0.004) but was not significantly different at the other doses when compared with placebo.

Patients treated with any dose of nintedanib did have fewer acute exacerbations compared with controls.

There were more adverse events & serious adverse events in the patients receiving nintedanib; however, statistically insignificant.

SUMMARY OF EVIDENCE Contd.INPULSIS-1 & INPULSIS-2 Phase 3 RCTs that enrolled a total of 1,066 patients in a 3:2 ratio to receive 150 mg of nintedanib twice daily versus placebo1.

Follow-up for both of these studies was 52 weeks.

Primary end point - annual rate of decline in forced vital capacity (FVC).

Key secondary end points - time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire.1 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, et al.; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:20712082.

SUMMARY OF EVIDENCE Contd.Few patients treated with nintedanib had a more than 10% absolute reduced decline in FVC during the study period.

The adjusted annual rate of change in FVC was 2114.7 ml (nintedanib) Vs 2239.9 ml (placebo).

Significantly more patients treated with nintedanib reported an adverse event; however, no significant increase in serious adverse events.

Patients treated with nintedanib did report significantly more diarrhea and nausea compared with those receiving placebo.

SUMMARY OF EVIDENCE Contd.Pooled analysis of these three trials showed benefit with nintedanib therapy for the outcome number of patients with more than 10% absolute reduced decline in FVC (RR, 1.15; 95% CI, 1.061.25; moderate confidence).

RECOMMENDATIONUse nintedanib in patients with IPF (conditional recommendation, moderate confidence in estimates of effect).

PirfenidonePirfenidone is an oral anti-fibrotic drug.

Shown to regulate important profibrotic and pro inflammatory cytokine cascades in vitro1.

Reduces fibroblast proliferation & collagen synthesis in animal models of lung fibrosis2-4.1. Nakazato H, Oku H, Yamane S, Tsuruta Y, Suzuki R. A novel antifibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. Eur J Pharmacol 2002;446:177185.2. Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis.J Pharmacol Exp Ther 1999;291:367373.3. Iyer SNGG, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999;289:211218.4. Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, Matsushima S, Torii M, Arimura A. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 2008;590:400408.

SUMMARY OF EVIDENCE Contd.The 2011 guideline document reported on two relatively small RCTs that compared pirfenidone Vs placebo in Japanese patients with IPF who had mild to moderate impairment in PFTs 1,2.

One of these trials1 was stopped early for potential benefit, as acute exacerbation, a secondary outcome, was found to occur more frequently in the placebo group.

A benefit with pirfenidone was seen when evaluating the frequency of oxygen desaturation during 6-minute-walk test and the decline in vital capacity (VC) over time.Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, Itoh H, Ohi M, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:10401047.Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, et al.; Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821829.

SUMMARY OF EVIDENCE Contd.The second trial1 had significant methodological concerns, including a highly selected enrolment and alteration of the primary endpoint mid study.

It also demonstrated a benefit of pirfenidone treatment in terms of a reduction in the rate of decline in VC (290 ml vs. 2160 ml; P = 0.04) and improved progression-free survival (P =0.03). Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, et al.; Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821829.

SUMMARY OF EVIDENCE Contd.CAPACITY trial1

The CAPACITY trial reported on two independent study protocols:

Study 004 included 435 patients randomized to one of three treatment groups (high-dose pirfenidone [2,403 mg/d], low-dose pirfenidone [1,197 mg/d], placebo)

Study 006 had 344 patients randomized to only two treatment groups (high-dose pirfenidone [2,403 mg/d] and placebo).

The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72.

1. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, et al.; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:17601769.

SUMMARY OF EVIDENCE Contd.Study 004 - showed a reduction in decline of FVC during the 72-week treatment period.

Study 006 - did not show a benefit in the same outcome during the same period.

Importantly, patients from both studies who were assigned to receive high-dose pirfenidone reported increased rates of nausea, dyspepsia, vomiting, anorexia, photosensitivity, and rash compared with placebo.

SUMMARY OF EVIDENCE Contd.The ASCEND trialA Randomized, Double-Blind, Placebo Controlled Trial of Pirfenidone.

Randomized 555 patients with IPF to either high-dose pirfenidone (2,403 mg/d) or placebo.

As opposed to the CAPACITY trials, the ASCEND trial had stricter patient selection criteria.

Primary end point - change in FVC or death at week 52. Secondary end points - 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.

ACEND Trial - ResultsPirfenidone significantly reduced the proportion of patients who had a more than 10% decline in their FVC during the 52-week follow-up period.

Pirfenidone treatment increased 6-minute-walk distance and progression-free survival when compared with placebo.

Mortality or dyspnea scores did not differ.

Consistent with previous studies, patients randomized to pirfenidone reported more treatment related adverse effects.

SUMMARY OF EVIDENCE Contd.Pooled results from these trials1-4 suggested improved mortality with pirfenidone (RR, 0.70; 95% CI, 0.471.02; moderate confidence).

Pirfenidone reduced the rate of FVC decline. 1. Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, Itoh H, Ohi M, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:10401047.2. Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, et al.; Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821829.3. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, et al.; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:17601769.4. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, et al.; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370: 20832092.

RECOMMENDATION20112015The majority of patients with IPF should not be treated with pirfenidone, but this therapy may be a reasonable choice in a minority (weak recommendation, low- to moderate-quality evidence)Use pirfenidone in patients with IPF (conditional recommendation, moderate confidence in estimates of effect).

Antiacid MedicationAbnormal GER, including clinically silent acidity has been observed in up to 90% of patients with IPF1.

GER is a risk factor for aspiration and microaspiration, which could subsequently cause pneumonitis, a mechanism that has been postulated to cause or worsen IPF.

PPIs or H2 receptor antagonists, may decrease this risk for micro aspiration-associated lung injury or damage2,3.1. Tobin RW, Pope CE II, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;158: 18041808.2. Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, Yow E, Raghu G; IPFnet Investigators. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013;1:369376.3. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J 2012;39:242245.

SUMMARY OF EVIDENCE Contd.124 patients receiving a PPI or H2 blocker Vs 118 patients not receiving anti-acid treatment or other study medications.

Significantly smaller decrease in FVC during the study period for those receiving anti-acid treatment at baseline.

However, no differences in all-cause mortality or all-cause hospitalization.Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, Yow E, Raghu G; IPFnet Investigators. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013;1:369376.

RECOMMENDATION20112015Asymptomatic gastroesophageal reflux disease should be medically treated in the majority of patients with IPF, but treatment may not be reasonable in a minority (weak recommendation, very low-quality evidence).Use regular antiacid treatment for patients with IPF (conditional recommendation, very low confidence in estimates of effect).

SildenafilSildenafil, an oral PDE-5 inhibitor, has been studied in two RCTs that enrolled patients with IPF1,2.

STEP-IPF2(Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis) Phase 3 RCT.180 patients with advanced IPF (DLCO, 35% predicted) randomized to either sildenafil (20 mg three times daily) or placebo for 12 weeks, with a subsequent 12-week open-label phase during which all patients received active drug1. 1. Jackson RM, Glassberg MK, Ramos CF, Bejarano PA, Butrous G, G omez-Marn O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 2010;188:115123.2. Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW; Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;363:620628.

SUMMARY OF EVIDENCEPrimary end point: more than 20% improvement in their 6-minute-walk distance after the initial 12-week period.

Results:No significant benefit of sildenafil on the primary outcome.

Small benefits seen with sildenafil on the secondary outcomes, with improved shortness of breath, improved quality of life, improved DLCO, and improved arterial oxygen saturation, all at the end of the 12-week randomized period.

There was no difference in serious adverse events.1. Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW; Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;363:620628.

SUMMARY OF EVIDENCE Contd.The second, smaller study randomized 29 patients with mild or moderate disease (average DLCO, 42% predicted) to receive either sildenafil (20 mg three times daily) or placebo for a 6-month treatment period1.

Patients with known PH or RV dysfunction were excluded.

In this small study, no significant benefit of sildenafil treatment was seen on 6-minute-walk test distance, Borg dyspnea scores, FVC, DLCO, or arterial oxygen saturation.

More adverse events occurred in the sildenafil group; however, not serious.1. Jackson RM, Glassberg MK, Ramos CF, Bejarano PA, Butrous G, Gomez-Marn O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 2010;188:115123.

SUMMARY OF EVIDENCE Contd.Pooled analysis of these two trials1,2 showed no significant benefit of sildenafil treatment on mortality or acute exacerbation.

There was a significant improvement in quality of life with sildenafil when assessed by the St George Respiratory Questionnaire (moderate confidence).

Similar to the individual trials, no significant benefit with treatment was seen on the outcomes of FVC, DLCO, Borg dyspnea score, oxygen saturation, or 6-minute-walk distance.Jackson RM, Glassberg MK, Ramos CF, Bejarano PA, Butrous G, G omez-Marn O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 2010;188:115123.Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW; Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;363:620628.

RECOMMENDATIONDont use sildenafil, a phosphodiesterase-5 inhibitor, for treatment of IPF (conditional recommendation against, moderate confidence in estimates of effect).

Dual Endothelin ReceptorAntagonists (ER-A and ER-B)BUILD-1 Trial(Bosentan Use in Interstitial Lung Disease)

158 patients randomized to either bosentan or placebo and followed patients for 12 months1.

No significant benefit was seen in mortality, as measured by worsening PFTs or clinical status.

There was no statistically significant increase in adverse events or serious adverse events with bosentan therapy. 1. King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, Sta hler G, Leconte I, Roux S, Raghu G. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008;177:7581.

SUMMARY OF EVIDENCE Contd.BUILD-3 StudyRandomized, double-blind, placebo-controlled trial.

Included a larger sample (n = 616) & only patients with biopsy-proven UIP, a pathologic diagnosis consistent with IPF1.

Objectives - To demonstrate that bosentan delays IPF worsening or death.Primary endpoint - Time to IPF worsening (a confirmed decrease from baseline in FVC 10% and DLCO 15%, or acute exacerbation of IPF) or death up to end of study.

Bosentan did not show a conclusive effect on mortality or disease progression or change in FVC.

1. King TE Jr, Brown KK, Raghu G, du Bois RM, Lynch DA, Martinez F, Valeyre D, Leconte I, Morganti A, Roux S, et al. BUILD-3:a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;184:9299.

SUMMARY OF EVIDENCE Contd.Macitentan, a novel dual-receptor ERA, was compared with placebo in a phase 2 study of 178 patients with lung biopsy proven IPF1.

No significant difference was seen in mortality or disease progression or change in FVC.

No difference in rates of reported adverse or serious adverse events was seen.1. Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J; MUSIC Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J 2013;42:16221632.

SUMMARY OF EVIDENCE Contd.Pooled for analysis13 showed no overall effect on mortality was seen using dual ERAs for patients with IPF.

No important difference between groups was seen in FVC change or in the rates of adverse events or serious adverse events.1. King TE Jr, Brown KK, Raghu G, du Bois RM, Lynch DA, Martinez F, Valeyre D, Leconte I, Morganti A, Roux S, et al. BUILD-3:a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;184:9299.2. King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, Sta hler G, Leconte I, Roux S, Raghu G. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008;177:7581.3. Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J; MUSIC Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J 2013;42:16221632.

RECOMMENDATION20112015Patients with IPF should not be treated with bosentan (strong recommendation, moderate-quality evidence).Dont use bosentan or macitentan, both dual ER-A and ER-B endothelin receptor antagonists, for the treatment of IPF (conditional recommendation against, low confidence in estimates of effect).

N-Acetylcysteine MonotherapyThe only RCT in the 2011 guideline document - randomized 30 patients to receive either aerosolized N-acetylcysteine or bromhexine hydrochloride for 12 months.

Documented significant improvement in the extent of ground glass on HRCT & reduction in KL-6 levels1.

No differences in physiologic measurements or walk distance were found.1. Tomioka H, Kuwata Y, Imanaka K, Hashimoto K, Ohnishi H, Tada K, Sakamoto H, Iwasaki H. A pilot study of aerosolized Nacetylcysteine for idiopathic pulmonary fibrosis. Respirology 2005;10:449455.

SUMMARY OF EVIDENCETwo new RCTs have been included in 2015 update.

A multicenter, prospective RCT done in Japan randomly assigned 76 patients to receive 352.4 mg inhaled N-acetylcysteine twice daily Vs control during a period of 48 weeks1.

No significant difference was seen in the primary outcome of change in FVC between groups. 1. Homma S, Azuma A, Taniguchi H, Ogura T, Mochiduki Y, Sugiyama Y, Nakata K, Yoshimura K, Takeuchi M, Kudoh S; Japan NAC Clinical Study Group. Efficacy of inhaled N-acetylcysteine monotherapy in patients with early stage idiopathic pulmonary fibrosis. Respirology 2012;17:467477.

SUMMARY OF EVIDENCE Contd.264 patients were randomized to receive 600 mg oral N-acetylcysteine three times a day or placebo.

Results of this two-group analysis (including both pre- and post study design change) showed no significant difference in the FVC change with N-acetylcysteine monotherapy.

No significant differences seen in the rates of death or acute exacerbation.Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G; Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:20932101.

SUMMARY OF EVIDENCE Contd.Pooled results of these three RCTs1,2 showed no significant benefit on mortality.

No significant differences in FVC change, quality of life or adverse outcomes.

However the studies reported significant improvement on 6-minute-walk test distance.Tomioka H, Kuwata Y, Imanaka K, Hashimoto K, Ohnishi H, Tada K, Sakamoto H, Iwasaki H. A pilot study of aerosolized Nacetylcysteine for idiopathic pulmonary fibrosis. Respirology 2005;10:449455.2. Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G; Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:20932101.

RECOMMENDATION20112015The majority of patients with IPF should not be treated with acetylcysteine monotherapy, but this therapy may be a reasonable choice in a minority (weak recommendation, low-quality evidence).Dont use N-acetylcysteine monotherapy in patients with IPF (conditional recommendation, low confidence in estimates of effect).

Non pharmacological Therapies

Bilateral Lung Transplantation Vs Single-Lung TransplantationLung transplantation is commonly considered for patients with moderate to severe disease due to progressive & incurable nature of IPF.

Lacking RCT evidence to guide this recommendation, 2015 update considered observational studies that assessed the survival of patients with IPF, accepting bilateral lung transplantation versus single lung transplantation.

SUMMARY OF EVIDENCEPooled survival analysis of three observational studies showed no difference single Vs bilateral lung transplantation.

Four additional studies were not included in the pooled analysis, also showed no significant difference in terms of survival between bilateral Vs single-lung transplantation.1. Force SD, Kilgo P, Neujahr DC, Pelaez A, Pickens A, Fernandez FG, Miller DL, Lawrence C. Bilateral lung transplantation offers better long-term survival, compared with single-lung transplantation, for younger patients with idiopathic pulmonary fibrosis. Ann Thorac Surg 2011;91:244249.2. Mason DP, Brizzio ME, Alster JM, McNeill AM, Murthy SC, Budev MM, Mehta AC, Minai OA, Pettersson GB, Blackstone EH. Lung transplantation for idiopathic pulmonary fibrosis. Ann Thorac Surg 2007;84:11211128.3. Neurohr C, Huppmann P, Thum D, Leuschner W, von Wulffen W, Meis T, Leuchte H, Baumgartner R, Zimmermann G, Hatz R, et al;Munich Lung Transplant Group. Potential functional and survival benefit of double over single lung transplantation for selected patients with idiopathic pulmonary fibrosis. Transpl Int 2010;23:887896.

RECOMMENDATIONThe committee did not make a recommendation regarding single Vs bilateral lung transplantation in patients with IPF.

The committee acknowledged that additional evidence should be evaluated to guide this clinical decision.

The shortage of organs is a universal problem, and the decision to give bilateral lung transplantation to a single patient rather than give single-lung transplantation to two patients, including the effect on health inequity, must be considered.

Should patients with IPF and resting hypoxemia receive long-term oxygen therapy?One study has retrospectively compared survival in a cohort of patients with IPF, many of whom (27%) received oxygen therapy1.

In multivariate analysis, no survival benefit was demonstrated with oxygen use.

Indirect evidence from two large randomized trials in obstructive lung disease has demonstrated a clear survival benefit with long-term oxygen therapy2,3.1.Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis:Impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 2000;161:11721178.2. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease:a clinical trial. Ann Intern Med 1980;93:391398.3. Longterm domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema: report of the Medical Research Council Working Party. Lancet 1981;1:681.

RECOMMENDATION (2011) Patients with IPF and clinically significant resting hypoxemia should be treated with long-term oxygen therapy (strong recommendation, very low-quality evidence).

Should patients with respiratory failure due to IPF receive mechanical ventilation?Several small studies in patients with IPF and respiratory failure showed a high hospital mortality rate.

A representative study of 23 patients with IPF and respiratory failure who required mechanical ventilation reported a hospital mortality rate of 96%1.

The only survivor underwent lung transplantation 6 hours after intubation.

A systematic review reports a similarly poor hospital mortality of 87% among the 135 reported cases2.1. Stern JB, Mal H, Groussard O, Brugiere O, Marceau A, Jebrak G, Fournier M. Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure. Chest 2001;120:213219.2. Mallick S. Outcome of patients with idiopathic pulmonary fibrosis (IPF) ventilated in intensive care unit. Respir Med 2008;102:13551359.

RECOMMENDATION (2011)The majority of patients with respiratory failure due to IPF should not receive mechanical ventilation, but mechanical ventilation may be a reasonable intervention in a minority (weak recommendation, low quality evidence).

Pulmonary rehabilitationPulmonary rehabilitation programs involve aerobic conditioning, strength & flexibility training, educational lectures, nutritional interventions & psychosocial support.

Two controlled trials have demonstrated an improvement in walk distance and symptoms or quality of life1,2.

Other uncontrolled studies have found similar findings.

The beneficial effects may be more pronounced in patients with worse baseline functional status.1. Holland AE, Hill CJ, Conron M, Munro P, McDonald CF. Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease. Thorax 2008;63:549554.2. Nishiyama O, Kondoh Y, Kimura T, Kato K, Kataoka K, Ogawa T, Watanabe F, Arizono S, Nishimura K, Taniguchi H. Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. Respirology 2008;13:394399.

RECOMMENDATION (2011)The majority of patients with IPF should be treated with pulmonary rehabilitation, but pulmonary rehabilitation may not be reasonable in a minority (weak recommendation, low-quality evidence).

TREATMENT OF SELECTED COMPLICATIONS ANDCOMORBID CONDITIONS

Should patients with acute exacerbation of IPF betreated with corticosteroids?Although high-dose corticosteroids are commonly prescribed for the treatment of acute exacerbation of IPF, there are no controlled trials on which to judge efficacy.

Cyclosporin A and anticoagulation have also been used without conclusive results1,2,3.1. Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:14751482.2. Homma S, Sakamoto S, Kawabata M, Kishi K, Tsuboi E, Motoi N, Yoshimura K. Cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia. Intern Med 2005;44:11441150.3. Sakamoto S, Homma S, Miyamoto A, Kurosaki A, Fujii T, Yoshimura K. Cyclosporin A in the treatment of acute exacerbation of idiopathic pulmonary fibrosis. Intern Med 2010;49:109115.

RECOMMENDATION (2011)The majority of patients with acute exacerbation of IPF should be treated with corticosteroids, but corticosteroids may not be reasonable in a minority (weak recommendation, very low-quality evidence).

Should PH Be Treated inPatients with IPF?Co-morbid PH is commonly seen in patients with IPF and contributes to a worsened clinical prognosis.

The 2011 guideline considered the very limited available evidence at the time in suggesting against treatment of PH in patients with IPF.

SUMMARY OF EVIDENCEThere are limited data available.

A single dose trial of IV & aerosolized epoprostenol in 8 patients with ILD and pulmonary HTN (one had IPF) demonstrated improved pulmonary hemodynamics but worsened shunt flow and oxygenation1.

A retrospective study of long-term therapy with intravenous epoprostenol or oral bosentan in 19 patients with ILD and pulmonary hypertension (eight with IPF) suggested improvement in 6-minute-walk distance and quality of life over 6 months2. 1. Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld- Wollbruck B, Grimminger F, Seeger W. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 1999;160:600607.2. Minai OA, Sahoo D, Chapman JT, Mehta AC. Vaso-active therapy can improve 6-min walk distance in patients with pulmonary hypertension and fibrotic interstitial lung disease. Respir Med 2008;102:10151020.4. Madden BP, Allenby M, Loke T, Sheth A. A potential role for sildenafil in the management of pulmonary hypertension in patients with parenchymal lung disease. Vascul Pharmacol 2006;44:372376.5. Collard HR, Anstrom KJ, Schwarz MI, Zisman DA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest 2007;131:897899

SUMMARY OF EVIDENCE Contd.Ambrisentan treatment, stratified in the ARTEMIS-IPF trial based on PH status, as assessed by right-sided heart catheterization, showed no significant subgroup effect in patients with documented mean pulmonary artery pressures higher than 25 mm Hg.

An increase in disease progression and hospitalization found in patients treated with ambrisentan.

SUMMARY OF EVIDENCE Contd.A single dose of sildenafil has been shown to improve pulmonary hemodynamics without increasing shunt flow or worsening oxygenation1.

Within the STEP-IPF trial, investigators examined the effect of sildenafil treatment on the subgroup of patients with ECHO documented right ventricular hypertrophy or RVSD2.

Patients with RVSD was found to have a significant improvement on the primary outcome of 6-minute-walk distance. 1. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension:a randomised controlled trial. Lancet 2002;360:895900.2. Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez FJ; IPFnet Investigators. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and rightsided ventricular dysfunction. Chest 2013;143:16991708.

RECOMMENDATIONPulmonary hypertension should not be treated in the majority of patients with IPF, but treatment may be a reasonable choice in a minority (weak recommendation, very low-quality evidence) 2011 guidelines.

2015 committee did not make a recommendation regarding treatment of PH in patients with IPF.

The committee acknowledged that further evidence is needed and should be evaluated to guide this clinical decision.

Should asymptomatic gastroesophageal reflux disease be medically treated in patients with IPF?Abnormal GER is a risk factor for aspiration, which is a known cause of pneumonitis, and may contribute to chronic airways inflammation and fibrosis.

Two retrospective case series describe stabilization of pulmonary function and oxygen requirements with medical and surgical management of gastroesophageal reflux1,2.1. Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE II, Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006;27:136142.2. Linden PA, Gilbert RJ, Yeap BY, Boyle K, Deykin A, Jaklitsch MT, Sugarbaker DJ, Bueno R. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg 2006;131:438446.

RECOMMENDATIONAsymptomatic gastroesophageal reflux disease should be medically treated in the majority of patients with IPF, but treatment may not be reasonable in a minority (weak recommendation, very low-quality evidence).

PALLIATIVE CARE

Palliative careFocuses on reducing symptoms and providing comfort to patients, rather than treating patients disease.

Worsening of symptoms such as cough and dyspnea are common and difficult to treat.

Limited data suggest that corticosteroids and thalidomide may be beneficial for chronic cough in IPF1,2.

Chronic opioids may be used for severe dyspnea and cough3.1. Hope-Gill BDM, Hilldrup S, Davies C, Newton RP, Harrison NK. A study of the cough reflex in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:9951002.2. Horton MR, Danoff SK, Lechtzin N. Thalidomide inhibits the intractable cough of idiopathic pulmonary fibrosis. Thorax 2008;63:749.3. Allen S, Raut S, Woollard J, Vassallo M. Low dose diamorphine reduces breathlessness without causing a fall in oxygen saturation in elderly patients with end-stage idiopathic pulmonary fibrosis. Palliat Med 2005;19:128130.

recommendation against the use of the following agents for the treatment of IPFrecommendation for the use of the following agents for the treatment of IPFstrongWeak/conditionalstrongWeak/conditional Anticoagulation Imatinib Combined acetylcysteine & azathioprine & prednisone Selective endothelin receptorantagonist (ambrisentan) Corticosteroid monotherapy Colchicine Cyclosporine AInterferon 1b Etanercept Sildenafil Dual endothelin receptor antagonists(macitentan, bosentan)Acetylcysteine monotherapy Mechanical ventilation in patients with respiratory failure due to IPF Treatment of pulmonary hypertension associated with IPF Long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia. Lung transplantation in appropriate patients. NintedanibPirfenidone Pulmonary rehabilitation Corticosteroids in patients with acute exacerbation of IPF is weak Treatment of asymptomaticgastroesophageal reflux

Newer Agents

Targeting cytokine networks involved in immune and structural cell activationInhibition of transforming growth factor- (TGF-)Inhibition of connective tissue growth factor (CTGF)Somatostatin analoguesInhibitors of IL-13, IL-4 and CCL2Inhibition of LOXL2

Targeting angiogenesis & ECMcollagen depositionTargeting renin-angiotensin system

TGF- InhibitorsIn animal models, TGF- - increased prior to collagen synthesis, and in lungs of individuals with pulmonary fibrosis.

3 isoforms in mammals, TGF-1, is a key pro-fibrotic agent.

A Phase I trial of GC1008, an antibody targeting all TGF- isoforms, has recently been completed (clinicaltrials.gov identifier NCT00125385)

Study results yet to be available.

Partial inhibition of v6 integrin, a key activator or TGF-1, has been shown to prevent bleomycin-induced pulmonary fibrosis without exacerbating inflammation in mice1.

A humanized monoclonal antibody against v6 integrin, STX-100 is currently under evaluation in a randomized, placebo-controlled phase II IPF trial (clinicaltrials. gov identifier NCT01371305).

1. Horan GS, Wood S, Ona V, et al. Partial inhibition of integrin alpha(v) beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med 2008;177:56-65.

Connective tissue growth factor (CTGF) InhibitorsCTGF induced by TGF- mediates some of the profibrotic effects & also activates type-1 collagen expression.

Human CTGF antibody, FG-3019, showed reduced histological signs of fibrosis in animal models.

Preliminary safety and efficacy data from an open-label, phase II trial of FG-3019 (clinicaltrials.gov identifier NCT01262001) shows improvement or stability of fibrosis as determined by HRCT scan quantification was apparent in 14 of 25 IPF patients after 24 weeks and this improvement was positively associated with changes in FVC.Raghu G, Scholand MB, De Andrade J, et al. LATE-BREAKING ABSTRACT: Phase 2 trial of FG-3019, anti-CTGF monoclonal antibody, in idiopathic pulmonary fibrosis (IPF): Preliminary safety and efficacy results ERS Annual Congress, Vienna 2012.

Somatostatin analoguesExpression of somatostatin receptors is increased in human IPF lungs.

SOM230, somatostatin analog showed antifibrotic effect in bleomycin-model, resulting in a decreased expression of TGF- and CTGF.

Treatment with octreotide, showed decrease in parenchymal fibrosis & structural deformities in the bleomycin model.

A small non-randomized, open-label study of 25 IPF patients received octreotide over a 48-week period &17 completed the study. (clinicaltrials.gov identifier NCT00463983).

Compared to historical controls (subjects from other published IPF trials), the rate of decline in pulmonary function (FVC and DLCO) was lower in subjects treated with octreotide.Crestani B, Chapron J, Wallaert B, et al. Octreotide treatment of idiopathic pulmonary fibrosis: a proof-of-concept study. Eur Respir J 2012;39:772-5.

Inhibitors of IL-13, IL-4 and CCL2CCL2 is a known fibrocyte chemo-attractant , further, high CCL2 levels may be correlated with progression of IPF.

IL-13 has also been observed to stimulate collagen deposition and myofibroblast differentiation both independently and with the help of TGF-1.

Phase II trials of CNTO888 and QAX576, CCL2 and IL-13 antibodies, respectively, have recently been completed. The results of both trials are awaited (clinicaltrials.gov identifier NCT00786201 and NCT00532233).

Tralokinumab, a human recombinant monoclonal antibody for IL-13 is currently being tested for IPF in a phase II randomized, placebo-controlled trial (clinicaltrials. gov identifier NCT01629667).

Interleukin 4, a cytokine structurally related to IL-13, has also been implicated in the abnormal proliferation of fibroblasts that characterizes IPF.

Both IL-13 and IL-4 are elevated in the BAL fluid of IPF patients. A randomized, double-blind, placebo-controlled study of an engineered bispecific antibody targeting both IL-4 and IL-13, SAR156597, has been completed, results awaited. (clinicaltrials.gov identifier NCT01529853).Dhimolea E, Reichert JM. World Bispecific Antibody Summit, September 27-28, 2011, Boston, MA. MAbs 2012;4:4-13.

Inhibition of LOXL2Inhibition of LOXL2 results in reduced levels of activated fibroblasts and TGF- pathway signaling in human fibroblasts and bleomycin-treated mice.

An allosteric inhibitor of LOXL2, the humanized monoclonal antibody GS-6624 (formerly AB0024), was evaluated in a phase I trial for the treatment of IPF (clinicaltrials.gov identifier NCT01362231), and a phase II trial is planned.

Targeting angiogenesis and ECM collagen depositionReduces both angiogenesis & fibrosis in the bleomycin model.

Minocycline hydrochloride, a broad-spectrum tetracycline antibiotic with anti-inflammatory and anti-angiogenic properties, was evaluated in a phase III clinical study of IPF patients (clinicaltrials.gov identifier NCT00203697).

The safety of tetrahiomolybdate, was also evaluated in IPF in a phase I trial (clinicaltrials.gov identifier NCT00189176).

Although both studies have concluded, their results are yet unknown.

A key feature of IPF is the excessive deposition of extracellular matrix & basement membrane disruption that may be at least in part due to an imbalance between secreted matrix metalloproteinases (MMPs) and their inhibitors (TIMPs).

Doxycyline, an MMP inhibitor, has been observed to attenuate fibrosis, inhibiting MMPs, collagen-1, TGF-, and CTGF human and bleomycin-exposed mice.

Doxycycline was tested in two open-label studies performed in India, and a non-statistically significant trend toward improved 6MWT and FVC was observed1,2.1. Mishra A, Bhattacharya P, Paul S, et al. An alternative therapy for idiopathic pulmonary fibrosis by doxycycline through matrix metalloproteinase inhibition. Lung India 2011;28:174-9. 2. Bhattacharyya P, Nag S, Bardhan S, et al. The role of long-term doxycycline in patients of idiopathic pulmonaryfibrosis: The results of an open prospective trial. Lung India 2009;26:81-5.

Targeting the renin-angiotensin systemANGII induces apoptosis in alveolar epithelial cells & the proliferation, activation, and migration of fibroblasts, resulting in abnormal deposition of ECM components.

Myofibroblasts from IPF lungs synthesize more ANGII and active TGF- than fibroblasts from normal lungs.

Bleomycin-induced lung injury is attenuated by administration of ACE inhibitors (ramipril or captopril), or an AT1 inhibitor (Losartan) or deletion of the AT1 gene.

the safety and efficacy of losartan are currently being investigated in a phase II open-label clinical trial of IPF (clinicaltrials.gov identifier NCT00879879).

Other potential therapies for IPFCarbon monoxideWell-described anti-proliferative properties.Transient exposure to CO has also demonstrated to reduce fibrosis in the bleomycin model. Antifibrotic effects of CO may be due to its inhibition of TGF--induced ECM constituents fibronectin and type I collagen production in fibroblasts.

Low-dose inhaled CO is currently being tested as a potential IPF therapy in a phase II trial (clinicaltrials.gov identifier NCT01214187).

CotrimoxazoleA phase III interventional, double-blind, RCT to evaluate the efficacy and safety of Trimethoprim-sulfamethoxazole in the Treatment of IPF.

Cotrimoxazole may improve the clinical course of the disease through eradication of Pneumocystis jiroveci colonization and other mechanisms such as inhibiting the activation of alveolar macrophages and producing alterations in the surfactant system.https://clinicaltrials.gov/ct2/show/NCT01777737?term=pulmonary+fibrosis&rank=6

Sirolimus (Rapamycin)The investigators propose to test the hypothesis that therapy with the mTOR inhibitor, sirolimus, reduces the number of circulating fibrocytes in patients with IPF.

Short-term pilot trial of sirolimus in patients with IPF to determine its effect on the number and phenotype of circulating fibrocytes is currently recruiting.https://clinicaltrials.gov/ct2/show/NCT01462006

Stem cell therapyPluripotent stem cells derived from embryonic or adult tissues can differentiate into lung epithelial and endothelial cells, ameliorating lung injury and fibrosis.

A Phase I, open-label safety and feasibility study of mesenchymal stem cell treatment for IPF in up to 8 subjects was started in Australia (clinicaltrials. gov identifier NCT01385644). Results awaited.

US FDA very recently approved the first clinical trial of intravenous mesenchymal stem cell therapy for IPF, a phase I study is currently recruiting patients. (clinicaltrials.gov identifier NCT02135380).

Phase 1Combined PEX, Rituximab and SteroidsAerosol Interferon-gammaIV mesenchymal stem cell therapySAR156597* (bispecific antibody targeting both IL-4 and IL-13)IW001* (oral solution of Type V collagen)Phase 2BMS-986020 (Lysophosphatidic Acid Receptor Antagonist)Tralokinumab (monoclonal antibody the blocks the action of a protein IL-13)Lebrikizumab (humanized monoclonal antibody targeting the protein IL-13)Simtuzumab (humanized monoclonal antibody targeting the human LOXL2 protein)Riociguat (stimulator of soluble guanylate cyclase)FG-3019 (human monoclonal antibody acting upon connective tissue growth factor)*STX-100 (monoclonal antibody)Carlumab ( aka CNTO888 - CCL2 antibody)*QAX576 (IL-13 antibody)*ThalidomidePhase 3Thalidomide, cough in IPF patients.

* Study completed, results awaited.

ConclusionsNo pharmacologic interventions received strong recommendations for treatment in 2015 update.

Conditional recommendations have been made for treatment with novel agents such as pirfenidone, nintedanib & anti-acid treatment for patients with IPF.

Clinicians confronted with treating patients with IPF should individualize decisions with their patients.

Some treatment options with potential clinical benefit (e.g., clotrimazole) in IPF were not addressed in 2015 update.

This and other treatment interventions such as treatment for acute exacerbation, pulmonary rehabilitation, oxygen supplementation, mechanical ventilation, palliative care, and so on, as well other pertinent new evidence that may become available, will be addressed in another update focused on treatment in the near future by the committee.

Although it is clear that treatment with warfarin for IPF is not beneficial, studies using new oral agents may be worthwhile.

Triple therapy with prednisone, azathioprine, and N-acetylcysteine is harmful, although it is unknown which specific component or combination and what doses of the individual components cause harm.

Treatment with different formulation of N-acetylcysteine or other antioxidants, stratified on the basis of the burden of oxidant stress, are worthwhile considerations.

The safety profile of dual ERAs in patients with IPF and their known therapeutic benefits for treatment of PH, especially macitentan, are worthwhile considerations and should dictate future studies looking at their role in patients with IPF with documented PH.

Pursuing treatment with ambrisentan, a selective ERA, is not appropriate, given the documented decline in respiratory status seen in the context of a large clinical trial.

It is less clear whether the abnormal acid GER is the cause or the effect of IPF.

Further studies are warranted to determine the safety and efficacy of antiacid treatment, the adherence of conservative measures to prevent or decrease the risks of insults to the lung by microaspiration, and the role for surgical correction to eliminate or decrease GER.

Co-morbidities should be addressed.

Vast majority of patients with IPF are older than 60 years and manifest an increasing number of co-morbidities that warrant prompt detection and treatment strategies.

This includes conditions such as PH, emphysema, airflow obstruction, GERD, sleep apnea, coronary artery diseases, obesity, etc.

Lung transplantation is indicated for a subgroup of patients with IPF who meet criteria; however, it is unclear whether single or bilateral lung transplantation is preferential for long-term outcomes.

Palliative care for symptoms, such as shortness of breath, cough, and fatigue, as well as comfort care for the terminally ill, is essential for patients with IPF at the end of life.

Future studies need to address these as endpoints in assessing response to new treatment strategies.

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