Study Design and Rationale for the TETON-PPF Phase 3, Randomized, Controlled Clinical Trial of Inhaled Treprostinil in the Treatment of Progressive Pulmonary Fibrosis.

Background: Progressive pulmonary fibrosis (PPF) affects a group of patients with various underlying interstitial lung diseases (ILDs) who develop progressive fibrosis and exhibit a similar disease course to patients with idiopathic pulmonary fibrosis (IPF). In PPF, fibrosis becomes self-sustaining and behaves similarly across ILDs, irrespective of the initial trigger, with patients developing worsening respiratory symptoms, lung function, and quality of life and increased mortality despite usual treatments for the underlying ILD. Inhaled treprostinil has demonstrated improvements in FVC and reduced exacerbations of underlying lung disease in patients with pulmonary hypertension associated with ILD in post hoc analyses of a phase 3 study (Safety and Efficacy of Inhaled Treprostinil in Adult PH With ILD Including CPFE [INCREASE]) and its open-label extension. These results and preclinical evidence of treprostinil's antifibrotic activity support its investigation in the treatment of PPF. Inhaled treprostinil is also being investigated for the treatment of IPF in the Study of Efficacy and Safety of Inhaled Treprostinil in Subjects with Idiopathic Pulmonary Fibrosis (TETON) and the Multinational Study of Efficacy and Safety of Inhaled Treprostinil in Subjects With Idiopathic Pulmonary Fibrosis (TETON-2). Research Question: Does inhaled treprostinil improve absolute FVC over 52 weeks in patients with PPF? Study Design and Methods: The Study of the Efficacy and Safety of Inhaled Treprostinil in Subjects With Progressive Pulmonary Fibrosis (TETON-PPF) is a 52-week, randomized, double-blind, placebo-controlled, phase 3 study enrolling 698 patients. Eligible patients must have a diagnosis of PPF (other than IPF) with radiographic fibrosis of > 10% extent and FVC ≥ 45%. Background use of pirfenidone or nintedanib is allowed. The primary end point is change in absolute FVC at week 52. Secondary end points include time to first clinical worsening, time to first acute exacerbation of ILD, overall survival, change in % predicted FVC, change in the King's Brief Interstitial Lung Disease Questionnaire, and change in lung diffusion capacity. Safety parameters include adverse events, hospitalizations, oxygenation, and laboratory parameters. Results: The study was initiated in October 2023 and will continue until 698 patients enroll. Interpretation: When completed, TETON-PPF will confirm whether inhaled treprostinil is safe and effective for the treatment of PPF. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT05943535; URL: www.clinicaltrials.gov.