TABLE 1.

Clinical trials in pulmonary fibrosis that target vascular permeability or coagulation

Clinical trial	Treatment	Study drug(s) mechanism of action	Duration	Primary endpoint	Study outcome
Palmer et al. [163] Randomized, double-blind, placebo-controlled, phase 2 trial of BMS-986020, a lysophosphatidic acid receptor antagonist for the treatment of idiopathic pulmonary fibrosis	BMS-986020 600 mg once or twice daily versus placebo	LPA antagonist	26 weeks	Rate of change in forced vital capacity FVC)	Reduction in rate of decline in FVC with twice daily BMS-986020 compared to placebo
Maher et al. [164] Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial	GLPG1690 600 mg once daily versus placebo	Autotaxin inhibition	12 weeks	Safety, tolerability, pharmacokinetics, and pharmacodynamics	One serious adverse event in GLPG1690 treatment group. Phase 3 study in process (ClinicalTrials.gov Identifier: NCT03711162)
A study to evaluate the safety, tolerability, and activity of KD025 in subjects with idiopathic pulmonary fibrosis (ClinicalTrials.gov Identifier: NCT02688647]	KD025 400 mg once daily versus best supportive care	ROCK inhibition	24 weeks	Change in FVC and safety and tolerability	Study ongoing
Richeldi et al. [76] Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis	Nintedanib150 mg twice daily versus placebo	Tyrosine kinase inhibitor including VEGF	52 weeks	Rate of decline in FVC	Reduction in rate of decline in FVC with nintedanib compared to placebo
Kolb et al. [165] Nintedanib plus sildenafil in patients with idiopathic pulmonary fibrosis	Nintedanib 150 mg twice daily+sildenafi 20 mg three times daily versus nintedanib 150 mg twice daily+placebo	Tyrosine kinase inhibitor including VEGF (nintedanib) and phosphodiesterase-5 inhibitor (sildenafil)	24 weeks	Change in St George’s Respiratory Questionnaire (SGRQ) score at 12 weeks	No change in SGRQ scores from baseline to 12 weeks between treatment groups
Distler et al. [166] Nintedanib for systemic sclerosis–associated interstitial lung disease	Nintedanib 150 mg twice daily versus placebo	Tyrosine kinase inhibitor including VEGF	52 weeks	Rate of decline in FVC	Reduction in rate of decline in FVC with nintedanib compared to placebo
Flaherty et al. [167] Nintedanib in progressive fibrosing interstitial lung diseases	Nintedanib 150 mg twice daily verusus placebo	Tyrosine kinase inhibitor including VEGF	52 weeks	Rate of decline in FVC	Reduction in rate of decline in FVC with nintedanib compared to placebo
Noth et al. [115] A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis	Warfarin dosed achieve an international normalised ratio of 2.0 to 3.0 versus placebo	Vitamin K antagonist	48 weeks	Composite outcome (time to death, hospitalisation or a 10% or greater absolute decline in FVC)	Trial stopped early due to increased mortality in warfarin treatment group
Silver et al. [168] Safety and tolerability of thrombin inhibition in scleroderma-associated interstitial lung disease	Dabigatran 75 mg twice daily	Direct thrombin inhibition	6 months	Safety and tolerability	No serious adverse events. Well tolerated.
Kondoh et al. [161] Thrombomodul in alfa for acute exacerbation of idiopathic pulmonary fibrosis: a randomized, double-blind, placebo-controlled trial	Thrombomodulin alfa 380 U·kg−1 daily versus placebo	Recombinant human soluble thrombomodulin	14 days	90-day survival	No difference in the 90-day survival between treatment groups.

Multiple clinical trials have been performed or are actively enrolling, with targets that affect permeability of the vascular endothelium. Some targets, such as nintedanib, have multiple targets, and it is not known how much of the anti-fibrotic effect they demonstrate is related to their effect on vascular permeability.