Long-term Safety and Tolerability Evaluation of Inhaled Treprostinil in Patients with Idiopathic Pulmonary Fibrosis or Progressive Pulmonary Fibrosis

The primary objective of this study is to evaluate the long-term **safety** and tolerability of inhaled **treprostinil** in subjects with idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This is clinically relevant as it aims to assess the sustained impact of treprostinil, a prostacyclin analogue, on patients with fibrotic lung disease, potentially offering insights into its viability as a long-term treatment option.

Secondary objectives include:

• To provide or continue to provide inhaled treprostinil for eligible subjects who participated in previous studies RIN-PF-301, RIN-PF-303, or RIN-PF-305.

The clinical trial involves a total of **1524 participants** diagnosed with **Fibrotic Lung Disease**, specifically focusing on individuals with Idiopathic Pulmonary Fibrosis (IPF) or Progressive Pulmonary Fibrosis (PPF). The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on their previous involvement in related studies (RIN-PF-301, RIN-PF-303, or RIN-PF-305) and their ability to comply with study requirements. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Lifestyle factors such as diet and physical activity are not specified, but participants are required to adhere to specific contraceptive measures if of childbearing potential. The study aims to evaluate the long-term safety and tolerability of inhaled treprostinil in this population.

The clinical trial is designed as a **Phase 3**, multicenter, multinational, open-label extension study to evaluate the long-term safety and tolerability of inhaled **Treprostinil** in subjects with **fibrotic lung disease**, specifically idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). The trial will involve participants who have previously completed studies RIN-PF-301, RIN-PF-303, or RIN-PF-305. The study is expected to commence recruitment on January 25, 2024, and conclude by May 31, 2027, with a maximum treatment period of 72 weeks.

Participants will be administered **Treprostinil** in the form of a nebuliser solution via an ultrasonic nebuliser, specifically the TD-300/A (TD-300) Tyvaso Inhalation System. The study will include several key visits: an inclusion (screening) visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The primary endpoints will focus on changes in absolute forced vital capacity (FVC), time to clinical worsening, time to acute exacerbation, overall survival, and changes in various clinical parameters such as the King's Brief Interstitial Lung Disease Questionnaire score and N-terminal pro-brain natriuretic peptide levels. Safety will be assessed through adverse events, clinical laboratory parameters, vital signs, and electrocardiograms.

Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or any safety concerns as determined by the investigator. The study will adhere to strict eligibility criteria, including informed consent, non-pregnancy for women of childbearing potential, and effective communication with study personnel. The trial aims to provide continued access to inhaled **Treprostinil** for eligible subjects, ensuring comprehensive monitoring and evaluation throughout the study period.

The clinical trial involves the administration of **Treprostinil**, a **nebuliser solution** formulated for **inhalation use**. Treprostinil is a chemically synthesized compound provided by United Therapeutics Corporation. The pharmaceutical form of the medication is a nebuliser solution, specifically designed for administration via an ultrasonic nebuliser. The maximum daily dose of Treprostinil is 360 micrograms, with a total maximum dose of 777.66 micrograms over the treatment period. The treatment duration is capped at 72 hours. The administration of Treprostinil is facilitated by the TD-300/A (TD-300) nebuliser, part of the Tyvaso Inhalation System, which includes two nebulisers, accessories, and an initial month of supplies such as disposable filters and plastic mouthpiece assemblies. The nebulisers are supplied in standard packaging separate from the study drug.

In this study, Treprostinil is the primary investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to evaluate the long-term safety and tolerability of inhaled Treprostinil in subjects with fibrotic lung disease, specifically idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed treatment regimen.

Efficacy in this clinical trial will be assessed by evaluating the effect of continued long-term therapy with inhaled **Treprostinil** on several key parameters. These include the change in absolute forced vital capacity (FVC), time to clinical worsening (including time to death, respiratory hospitalization, or a ≥10% relative decline in % predicted FVC), time to acute exacerbation of idiopathic pulmonary fibrosis (IPF) or interstitial lung disease (ILD), overall survival, change in % predicted FVC, change in King's Brief Interstitial Lung Disease Questionnaire score, change in N-terminal pro-brain natriuretic peptide, change in diffusion capacity of lungs for carbon monoxide, and change in resting supplemental oxygen use.