Table 2. An overview of select clinical trials of in IPF - Unsuccessful Treatments to Date. (Modified from Datta et al., 2011).

Agent/treatment	Potential mechanism of action	Select clinical trial or retrospective series	Clinical trials registry number	Study design where appropriate	End points and duration of trial where appropriate/available	Outcome/comments
Corticosteroids	Suppression of cellular and humoral immunity; reduction of proinflammtory molecules	Significant lack of studies evaluating prednisolone against placebo Flaherty et al. (2001)	None available	Open label study; (n=41)	Primary end point: CRP score at 3 months	27% responders/ 46% stable/ 27% non-responders. Adverse effects noted in all patients Cochrane Review of 2003 found no evidence for an effect of corticosteroids in IPF; no high quality prospective studies were identified as suitable for meta-analysis (Richeldi et al., 2003)
Azathioprine as adjunctive to prednisolone	Inhibits adenine deaminase and impairs cell proliferation (particularly leukocytes); anti-inflammatory	Raghu et al. (1991)	None available	Prospective, double-blinded, randomized placebo-controlled trial; prednisolone + azathioprine (n=14) vs. prednisolone + placebo (n=13)	Primary end points: ΔFVC/DLco/A-a gradient at 1 year; survival at 9 years	Marginally significant survival benefit in azathioprine + prednisolone group only after age-adjustment No significant improvement in remaining parameters
Azathioprine + prednisolone	As above	Thorax National Institute, Chile	NCT00518310	Prospective, double-blinded, randomized trial; Azathioprine + prednisolone vs. placebo; planned enrollment (n=100)	Primary end point: progression free survival at 2 years	Trial status unknown; results awaited
Cyclophosphamide	Alkylating agent with anti-inflammatory properties	Collard et al. (2004)	None available	Retrospective case series; cyclophosphamide + prednisolone vs. no treatment; (n=82) in each group	Primary end point: Survival at 6–12 months	No evidence for a therapeutic benefit. Significant potential adverse effects
Everolimus	Immunosuppressant-macrocyclic proliferation cyclic inhibitor	Malouf (2011)	ANZCTR 12605000599673	Prospective, double-blinded, randomized placebo-controlled trial; everolimus (n=44) vs. placebo (n=45)	Primary end point: Δ6MWD, arterial oxygen saturation, quality of life, and dysnpea score up to 36 months	Trial completed; increased time to disease progression in treatment group. 180 days vs. 450 days for placebo group. 48% of patients in treatment arm did not tolerate an 8mg dose. 23% of these patients discontinued for this reason
Warfarin	Anticoagulation via inhibition of Vitamin K reduction	Kubo et al. (2005)	None available	Randomized open label trial; prednisolone + warfarin/low molecular weight heparin(n=31) vs. prednisolone + placebo (n=33)	Primary end points: time to death and hospitalization-free time over 1 year	Anti-coagulant therapy resulted in a significant increase in survival of patients with IPF and a significant improvement in survival associated with acute exacerbations of IPF
Warfarin	As above	ACE-IPF trial NHLBI – Duke University, USA Noth et al. (2012)	NCT00957242	Prospective, double-blinded, randomized placebo-controlled trial; warfarin vs. placebo; currently recruiting, planned enrollment (n=256)	Primary end points: time to death or disease progression over 48 weeks	Trial terminated; excess mortality in warfarin arm (14 warfarin vs. 3 placebo deaths). Low probablity of treatment benefit. Higher rates of hospitalization and acute exacerbation.
Heparin	Anticoagulation via inhibition of thrombin and other proteases.	Markart et al. (2010)	None available	Open label exploratory study evaluating safety of nebulized heparin in IPF; (n=21)	Study designed to assess safety and tolerability	Trial completed; adequate local anticoagulation achieved with no significant adverse effects. Future trials planned to evaluate efficacy.
Bosentan	Endothelin-1 (ET) receptor antagonist; ET promotes fibroblast proliferation, differentation, collagen synthesis, and endothelial cell mitosis	BUILD-1 trial King et al. (2008)	NCT00071461	Prospective, double-blinded, randomized placebo-controlled trial; bosentan (n=74) vs. placebo (n=84)	Primary end point: 6MWD at 12 months	Trial completed; no effect on primary outcome between treatments arms; post hocanalysis demonstrated trend in delayed time to disease progression or death in the bosentan arm of IPF patients who had undergone lung biopsy
Bosentan	As above	BUILD-3 trial (Actelion, Switzerland)	NCT00631475	Prospective, double-blinded, randomized placebo-controlled trial; total (n=616), bosentan: placebo 2:1 recruitment complete	Primary end points: time to disease progression or death over 8-32 months	Trial terminated at interim analysis stage due to lack of efficacy
Ambrisentan	As above	ARTEMIS-IPF trial (Gilead, USA)	NCT00768300	Prospective, double-blinded randomized placebo-controlled trial; ambrisentan vs. placebo, currently recruiting, planned enrollment (n=600)	Primary end points: time to disease progression or death, event driven over 4 years	Trial terminated at interim analysis stage due to lack of efficacy
Macitentan	As above	MUSIC trial (Actelion, Switzerland)	NCT00903331	Prospective, double-blinded randomized placebo-controlled trial; total n=178; macicentan vs. placebo, recruitment complete	Primary end point: ΔFVC over 12 months	Trial terminated; did not meet primary endpoint between treatment arms of FVC
Sildenafil	Phosphodiesterase 5 inhibitor. Causes vasorelaxation by stabilizing cGMP	Step-IPF Clinical Research Network, USA (Zisman et al., 2010)	NCT00359736	Prospective, double-blinded, randomized placebo-controlled trial:sildenafil (n=89) vs. placebo (n=91). Double-blind study over initial 12 weeks, followed by open label extension for 12 weeks with all patients receiving sildenafil	Primary end points: Δ 6MWD over 12 weeks Secondary end point: dyspnea score at 6 months	Trial completed; No significant improvement in primary end point in treatment arm, but significant improvement in secondary end points in sildenafil arm, including DLco and quality of life score
Interferon (IFNγ1b)	Immunoregulatory cytokine limiting fibroblast proliferation and collagen synthesis	INSPIRE trial King et al. (2009)	NCT00075998	Prospective, double-blinded, randomized placebo-controlled trial; interferon (n=551) vs. placebo (n=275)	Primary end point: survival from time of randomization	Trial ended prematurely; overall survival had crossed predefined boundary at planned interim stage analysis (64 weeks); however, no difference between treatment and placebo arms
Inhaled IFNγ1b	As above	National Centre for Research Resources, USA Diaz et al. (2012)	NCT00563212	Non-randomized, open-label, single interventional study with nebulized interferon-γ Recruiting patients; planned enrollment n=10	Primary end point: safety and tolerability Secondary end points: lung function trends and BALF [IFN-γ] at 1 year	Trial completed; aerosolized IFNγ1b was well tolerated and associated with minimal change in FVC over 80 weeks and a decreased slope of decline in TLC and DlCO
Etanercept	TNFα inhibitor -anti-inflammatory, anti-fibrogenic	Raghu et al. (2008)	NCT00063869	Prospective, double-blinded, randomized placebo-controlled trial; etanercept (n=34) vs. placebo (n=31)	Primary end points: Δ FVC, DLco/ΔA-a gradient over 48 weeks	Trial completed; no significant difference observed between treatment groups. Etanercept therapy resulted in a non-significant reduction in disease progression in several physiological, functional and QoL end points
Imatinib mesylate	Inhibitor of PDFG and TGFβ signaling, which promote fibroblast to myofibroblast transformation and proliferation and ECM production	Daniels et al. (2010)	NCT00131274	Prospective, double-blinded, randomized placebo-controlled trial; imatinib (n=59) vs. placebo (n=60)	Primary end point: time to disease progression (>10% decline in predicted FVC) or death over 92 weeks	Trial completed; no change in primary end point between treatment and placebo
CC-930	JNK inhibitor-JNK induces tissue factor expression and thrombin and fibren generation	Celgene Corporation	NCT01203943	Prospective, double-blinded, randomized placebo-controlled trial; planned enrollment n=28	Primary end point: safety up to 4 weeks of treatment Secondary end point: pharmacokinetics and long-term safety	Trial terminated at interim analysis stage due to unfavorable risk benefit profile.

6MWD, 6 min walk test distance; A-a, alveolar:arterial ANZCTR, Australian New Zeland clinical trials registry; BALF, bronchoalveolar lavage fluid; CCL-2, Chemokine (C-C motif) ligand 2; cGMP, cyclic guanosine monophosphate; CRP, clinical-radiographic-physiological; DLco, carbon monoxide dilution; FGFR, fibroblast growth factor receptor; FVC, forced vital capacity; H2, histamine H2 receptor blocker; HRCT, high resolution computer tomography; IFN-γ, interferon-gamma; IL-13, interleukin 13; IL-4, interleukin 4; LOXL-2, lysyl oxidase-like enzyme 2; MMP, matrix metalloproteinase; NCT, clinicaltrials.gov identifier; PDGFR, platelet-derived growth factor receptor; PPI, proton pump inhibitor; pred, predicted QoL, quality of life; TGFβ, transforming growth factor-beta; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. Permission has been obtained from John Wiley and Sons for reuse of figure Table 2.