Evidence based management of ipf

Introduction
Pharmacological therapies
Non pharmacological therapies
Treatment of selected complications &
comorbid conditions.
Palliative care
Newer Agents
Conclusion

 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.

 Unknown
Potential risk factors
 Cigarette smoking
 Environmental exposures
 Microbial agents (EBV, HCV, CMV, HHV-7, HHV-8)
 Gastroesophageal reflux
 Genetic Factors (ELMOD2, on chromosome 4q31)

 Unexplained chronic exertional dyspnea
 Cough
 Bibasilar inspiratory crackles (Velcro crackles)
 Clubbing
 Weight loss
 Fever
 Fatigue
 Myalgias
 Arthralgia
 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.

 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.

 No 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;35:593–599.
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;157:1063–1072.
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;110:278–282.
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;16:209–214.

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

 Inhibits 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;175:41–51.
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;12:105–111.
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;28:496–504.
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;158:220–225.
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;161:1172–1178.

colchicine (strong recommendation, very low-
quality evidence).

 Limited 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 post–lung 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;83:277–279.
2. Moolman JA, Bardin PG, Rossouw DJ, Joubert JR. Cyclosporin as a treatment for interstitial lung disease of unknown aetiology.
Thorax 1991;46:592–595.
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;44:1144–1150.
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;76:139–145.
5. Wahidi MM, Ravenel J, Palmer SM, McAdams HP. Progression of idiopathic pulmonary fibrosis in native lungs after single lung transplantation. Chest 2002;121:2072–2076.

cyclosporine A (strong recommendation, very low
quality evidence).

 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;144:291–296.
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;44:280–288.

 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;125:2169–2174.
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;100:340–347.

combination corticosteroid & immunomodulator
therapy (strong recommendation, low-quality
evidence).

 Antifibrotic and immunomodulatory properties.
 330 patients with IPF, randomized to receive IFN-γ 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-γ 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;350:125–133.

 Double blind RCT.
 826 patients were randomly assigned in a 2:1 ratio to
receive 200 µg 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-γ 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;374:222–228.

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

 Recombinant 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;151:1548–1561.
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;178:948–955.

etanercept (strong recommendation, moderate-
quality evidence).

 A procoagulant state may be involved in promoting
fibrosis via cell-surface receptor–mediated 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:S367–
S378.
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;69:207–215.
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;181:1085–1092.
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;39:125–132.

 The 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;128:1475–1482.

 One RCT published since the 2011 guideline randomized 145
patients with IPF to oral warfarin (target INR, 2.0–3.0) 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;186:88–95.

2011 2015
The 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).
Don’t 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.

 Potent inhibitor of lung fibroblast–myofibroblast
differentiation and proliferation.
 Inhibitor of extracellular matrix production
through inhibition of PDGF and TGF-β signaling.

 Placebo-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;181:604–610.

 Don’t use imatinib in patients with IPF (strong
recommendation, moderate confidence in

 Previously, 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;161:646–664.
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;10:449–455.

PANTHER Trial
 Multicentric 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,
1.16–74.1) 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;366:1968–1977.

2011 2015
combination corticosteroid,
azathioprine and acetylcysteine
therapy, but this therapy may
be a reasonable choice in a
minority (weak
recommendation, low quality
evidence).
Don’t use the combination
therapy of N-acetylcysteine,
azathioprine and prednisone in
patients with IPF. (strong
recommendation, low
confidence in estimates of
effect).

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;156:600–608.

 Ambrisentan 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: 641–649.

 Don’t 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).

 Previously 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.

 Nintedanib 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
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;370:2071–2082.

 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.

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;370:2071–2082.

 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.

 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, 1.06–1.25; moderate confidence).

 Use nintedanib in patients with IPF (conditional
recommendation, moderate confidence in

 Pirfenidone 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;446:177–185.
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;291:367–373.
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;289:211–218.
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;590:400–408.

 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.
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;171:1040–1047.
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;35:821–829.

 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).
1. 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

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;377:1760–1769.

 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.

The ASCEND trial
 A 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.

 Pirfenidone 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.

 Pooled results from these trials1-4 suggested improved
mortality with pirfenidone (RR, 0.70; 95% CI, 0.47–1.02;
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;171:1040–1047.
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;35:821–829.
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;377:1760–1769.
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: 2083–2092.

2011 2015
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
effect).

 Abnormal 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: 1804–1808.
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;1:369–376.
3. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J 2012;39:242–245.

 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;1:369–376.

2011 2015
Asymptomatic
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

 Sildenafil, 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-Mar´ın O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary
fibrosis. Lung 2010;188:115–123.
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;363:620–628.

 Primary 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;363:620–628.

 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, G´omez-Mar´ın O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung

 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.
1. Jackson RM, Glassberg MK, Ramos CF, Bejarano PA, Butrous G, G ´ omez-Mar´ın O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung
2010;188:115–123.
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;363:620–628.

 Don’t use sildenafil, a phosphodiesterase-5
inhibitor, for treatment of IPF (conditional
recommendation against, moderate confidence
in estimates of effect).

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;177:75–81.

BUILD-3 Study
 Randomized, 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

 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;42:1622–1632.

 Pooled for analysis1–3 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
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;177:75–81.
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;42:1622–1632.

2011 2015
Patients with IPF should not be
treated with bosentan (strong
recommendation, moderate-
quality evidence).
Don’t use bosentan or
macitentan, both dual ER-A
and ER-B endothelin receptor
antagonists, for the treatment
of IPF (conditional
recommendation against, low
effect).

 The 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.
Respirology 2005;10:449–455.

 Two 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;17:467–477.

 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;370:2093–2101.

 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.
Respirology 2005;10:449–455.
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

2011 2015
acetylcysteine monotherapy,
but this therapy may be a
reasonable choice in a minority
(weak recommendation, low-
quality evidence).
Don’t use N-acetylcysteine
monotherapy in patients with
IPF (conditional
recommendation, low
effect).

 Lung 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.

 Pooled 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;91:244–249.
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;84:1121–1128.
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;23:887–896.

 The 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.

 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;161:1172–1178.
2. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease:a clinical trial. Ann Intern Med 1980;93:391–398.
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.

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

 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;120:213–219.
2. Mallick S. Outcome of patients with idiopathic pulmonary fibrosis (IPF) ventilated in intensive care unit. Respir Med 2008;102:1355–1359.

 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 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;63:549–554.
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;13:394–399.

 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).

 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;128:1475–1482.
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;44:1144–1150.
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;49:109–115.

 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).

 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.

 There 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;160:600–607.
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;102:1015–1020.
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;44:372–376.
5. Collard HR, Anstrom KJ, Schwarz MI, Zisman DA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest 2007;131:897–899

 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.

 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;360:895–900.
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;143:1699–1708.

 Pulmonary 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.

 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
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;131:438–446.

 Asymptomatic 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).

 Focuses 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;168:995–1002.
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;19:128–130.

recommendation against the use of
the following agents for the treatment of
IPF
recommendation for the use of the
following agents for the treatment of
IPF
strong Weak/conditional strong Weak/conditional
 Anticoagulation
 Imatinib
 Combined
acetylcysteine &
azathioprine &
prednisone
 Selective
endothelin
receptor
antagonist
(ambrisentan)
 Corticosteroid
monotherapy
 Colchicine
 Cyclosporine A
Interferon ɣ 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.
 Nintedanib
Pirfenidone
Pulmonary
rehabilitation
 Corticosteroids
in patients with
acute
exacerbation of
IPF is weak
 Treatment of
asymptomatic
gastroesophageal
reflux

 Inhibition of transforming growth factor-β (TGF-β)
 Inhibition of connective tissue growth factor (CTGF)
 Somatostatin analogues
 Inhibitors of IL-13, IL-4 and CCL2
 Inhibition of LOXL2

 In animal models, TGF-β - increased prior to collagen
synthesis, and in lungs of individuals with pulmonary
fibrosis.
 3 isoforms in mammals, TGF-β1, is a key pro-fibrotic
agent.
 A Phase I trial of GC1008, an antibody targeting all TGF-
β isoforms, has recently been completed
(clinicaltrials.gov identifier NCT00125385)
 Study results yet to be available.

 Partial inhibition of αvβ6 integrin, a key activator or TGF-
β1, has been shown to prevent bleomycin-induced
pulmonary fibrosis without exacerbating inflammation in
mice1.
 A humanized monoclonal antibody against αvβ6 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.

 CTGF induced by TGF-β 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.

 Expression 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-β 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.

 CCL2 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-β1.
 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.
Dhimolea E, Reichert JM. World Bispecific Antibody Summit, September 27-28, 2011, Boston, MA. MAbs 2012;4:4-13.

 Inhibition of LOXL2 results in reduced levels of activated
fibroblasts and TGF-β 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.

 Reduces 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-β,
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.

 ANGII 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-β 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

Carbon monoxide
 Well-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-β-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).

 A 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

 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

 Pluripotent 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 1
Combined PEX, Rituximab and Steroids
Aerosol Interferon-gamma
IV mesenchymal stem cell therapy
SAR156597* (bispecific antibody targeting both IL-4 and IL-13)
IW001* (oral solution of Type V collagen)
Phase 2
BMS-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)*
Thalidomide
Phase 3 Thalidomide, cough in IPF patients.
* Study completed, results awaited.

 No 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.

Evidence based management of ipf

Evidence based management of ipf

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