BACKGROUND: Preclinical data indicate that inhaled treprostinil may be useful for the treatment of idiopathic pulmonary fibrosis (IPF) through an antifibrotic mechanism, a premise that is supported by clinical observation. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with IPF to receive inhaled treprostinil or placebo (12 breaths four times daily) over a period of 52 weeks. The primary end point was the change from baseline in the absolute forced vital capacity (FVC) at week 52. Secondary end points, which were analyzed in a prespecified order to control for multiplicity, were clinical worsening and acute exacerbation of IPF (each assessed in a time-to-event analysis), death by week 52, and the change from baseline in the percentage of predicted FVC, quality of life, and the diffusing capacity of the lungs for carbon monoxide by week 52. Safety was also assessed. RESULTS: A total of 593 patients underwent randomization and received at least one dose of treprostinil (298 patients) or placebo (295 patients). Of these, 463 patients (224 in the treprostinil group and 239 in the placebo group) completed the trial assessments through week 52. The mean age of the patients was 71.7 years, 80.1% were men, the mean FVC at baseline was 76.8%, and 75.4% of the patients were receiving background antifibrotic therapy. The median change in FVC at week 52 was -49.9 ml (95% confidence interval [CI], -79.2 to -19.5) in the treprostinil group and -136.4 ml (95% CI, -172.5 to -104.0) in the placebo group; the between-group difference in the change in FVC was 95.6 ml (95% CI, 52.2 to 139.0; P<0.001). Clinical worsening occurred in 81 patients (27.2%) in the treprostinil group and 115 patients (39.0%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; P = 0.02). No substantial between-group difference in the time to IPF exacerbation was observed, and so no further inferences with regard to subsequent secondary end points were made. The most common adverse event was cough, reported in 48.3% of the patients in the treprostinil group and 24.1% of those in the placebo group. Discontinuation of treprostinil or placebo occurred in 33.6% and 24.7%, respectively, with approximately half these patients citing adverse events as the primary reason for discontinuation. CONCLUSIONS: In patients with IPF, inhaled treprostinil was associated with a smaller decline in FVC and fewer clinical-worsening events than placebo over a period of 52 weeks. (Funded by United Therapeutics; TETON-2 ClinicalTrials.gov number, NCT05255991.).
