Table 1. A summary overview of negative randomized placebo-controlled trials undertaken in idiopathic pulmonary fibrosis.

Compound	Study	Study design	Patients	Primary end-point	Results
Warfarin (anticoagulant)	ACE-IPF [45] 2012	Phase III Warfarin vs. placebo for 48 weeks	n = 256 terminated at 145	Composite of all-cause mortality, hospitalization and ≥10% absolute FVC decline	Increased mortality in warfarin arm (14 vs. 3 deaths in placebo arm P = 0.005). Study terminated at unscheduled interim analysis by the DSMB.
Everolimus (mTOR inhibitor)	Malouf et al. [46] 2011	Phase II 4 mg bd Everolimus vs. placebo for 3 years	n = 89	Time to disease progression defined by the time to the second of any two of a 10% change in FVC or TLC; 15% change in DLCO; a 4% point change in resting room air SaO2	Increased disease progression in everolimus arm (180 days vs. 450 days in placebo arm P <0.01). Higher frequency of AEs in patients in everolimus arm.
Bosentan (dual endothelin receptor antagonist)	BUILD1 [47] 2008	Phase III Bosentan 125 mg bd vs. placebo for 1 year	n = 158	BUILD1: change in 6MWT at 12 months	No significant change in 6MWT between treatment groups but post hoc analysis showed a trend towards reduced mortality in patients in the bosentan arm who had undergone a surgical lung biopsy.
	BUILD3 [48] 2011	Phase III Bosentan 125 mg bd vs. placebo for 3 years	n = 616	BUILD3: time to disease progression (≥10% absolute FVC decline or ≥15% decline in DLCO or acute exacerbation)	No significant difference in time to disease progression in patients diagnosed with a surgical lung biopsy.
Ambrisentan (type A endothelin receptor antagonist)	ARTEMIS [49] IPF 2013	Phase III Ambrisentan 10 mg vs. placebo for 18 months.	n = 660 terminated at 492	Time to disease progression defined by death or respiratory hospitalization, ≥10% absolute FVC decline or ≥15% decline in DLCO or acute exacerbation	Terminated at interim analysis due to lack of efficacy. Increased disease progression in ambrisentan arm (n = 90 (27.4%) vs. n = 28 (17.2%) in placebo arm P = 0.01). Increased respiratory hospitalizations in ambrisentan arm (n = 44 (13.4%) vs. n = 9 (5.5%) in placebo arm P = 0.007).
Macitentan (dual endothelin receptor antagonist)	MUSIC trial [50] 2013	Phase II Macitentan 10 mg vs. placebo for 1 year	n = 178	Change in FVC at 12 months	No significant difference in change in absolute FVC between treatment groups.
Sildenafil (phosphodiesterase-5 inhibitor)	STEP-IPF [51] 2010	Phase III Sildenafil 20 mg tds vs. placebo for 12 weeks, followed by 12-week open-label extension with all patients receiving sildenafil	n = 180	≥20% increase in the 6MWT at 12 weeks	No significant difference in the number of patients with ≥20% increase in 6MWT distance, but significant improvement in secondary outcomes DLCO and QOL scores.
Interferon γ -1b (Th1 cytokine)	Raghu et al. [5] 2004	Phase III 200 µg subcutaneous IFNγ-1b vs. placebo 3 times weekly for 48 weeks	n = 330	Progression-free survival	No significant difference in progression-free survival.
	INSPIRE [52] 2009	Phase III 200 µg subcutaneous IFNγ-1b vs. placebo 3 times weekly for 96 weeks	n = 826	Overall survival time from randomization	No significant survival benefit with IFNγ-1b at second interim analysis hence study terminated at this point.
Etanercept (recombinant soluble human TNF-α receptor)	Raghu et al. [53] 2008	Phase II Etanercept 25 mg vs. placebo twice weekly for 48 weeks	n = 88	Changes from baseline in FVC% predicted, DLCO% predicted and P(a–a)O2 at rest.	No significant difference in primary end-points between etanercept and placebo groups.
Imatinib (tyrosine kinase inhibitor with activity against PDGF receptors, c-kit and c-abl)	Daniels et al. [54] 2010	Phase II Imatinib 600 mg vs. placebo for 96 weeks	n = 119	Time to disease progression (10% decline in percent predicted FVC from baseline) or time to death.	No significant difference in survival or lung function between treatment groups.
Co-trimoxazole (antibiotic)	Shulgina et al. [55] 2013	Phase II Co-trimoxazole 960 mg twice daily vs. placebo for 52 weeks	n = 181	12 month change in FVC	No significant difference between groups in FVC but improved survival in treatment adherent subjects

6MWT, 6-minute walk distance; AE, adverse effect; ARTEMIS; Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF; bd, bis in die (twice daily); BUILD, Bosentan Use in Interstitial Lung Disease; DL_CO, carbon monoxide diffusing capacity; DSMB, Data and Safety Monitoring Board; FVC, forced vital capacity; IFN, interferon; INSPIRE, interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis; IPF, idiopathic pulmonary fibrosis; mTOR, mammalian target of rapamycin; MUSIC, Macitentan for the treatment of idiopathic pulmonary fibrosis; PDGF, platelet-derived growth factor; QOL, quality of life; SaO₂, oxygen saturation; STEP-IPF, Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis; TLC, total lung capacity; TNF, tumor necrosis factor.