Evaluation of Long-Term Safety and Efficacy of Treprostinil Palmitil Inhalation Powder in Pulmonary Hypertension Associated with Interstitial Lung Disease

The primary objective of this study is to evaluate the **safety** and **tolerability** of the long-term use of Treprostinil Palmitil Inhalation Powder (TPIP) in participants with Pulmonary Hypertension Associated with Interstitial Lung Disease (PH-ILD). This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use in this patient population, which is crucial for managing a chronic condition like PH-ILD.

Secondary objectives include: - Evaluating the effect of long-term TPIP use on exercise capacity, lung function, and blood biomarkers of disease severity in participants with PH-ILD. - Assessing the impact on clinical worsening rate and exacerbations of underlying lung disease. - Evaluating the effect on quality of life (QOL) through patient-reported outcome (PRO) measures. - Further evaluating the pharmacokinetic (PK) profile of TPIP in this population. These objectives are important for understanding the broader therapeutic benefits and physiological impacts of TPIP, beyond its safety and tolerability.

The clinical trial involves a total of **12 participants** diagnosed with **Pulmonary Hypertension Associated with Interstitial Lung Disease** (PH-ILD). The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on their completion of the end of treatment visit in Study INS1009-211 or any other lead-in PH-ILD TPIP study. The trial includes individuals who are capable of providing informed consent and who meet specific baseline screening assessments if more than 30 days have elapsed since their last study visit. The trial population is characterized by a vulnerable group, indicating that special considerations are taken into account for their participation. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and tolerability of long-term use of **Treprostinil Palmitil Inhalation Powder** in participants with **Pulmonary Hypertension Associated with Interstitial Lung Disease**. This is an open-label extension study, following participants who have completed prior studies such as Study INS1009-211. The trial employs a non-randomized, open-label design, allowing all eligible participants to receive the investigational product. The trial is expected to last until April 15, 2026, with recruitment having commenced on May 11, 2023.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility, especially if more than 30 days have elapsed since the end of their previous study visit. The inclusion criteria require participants to have completed the end of treatment visit in a lead-in study and to be capable of providing informed consent. The primary endpoint focuses on the frequency and severity of treatment-emergent adverse events (TEAEs) during the study. Secondary endpoints include changes in six-minute walk distance (6MWD), forced vital capacity (FVC), forced expiratory volume (FEV1), and other pulmonary function tests at specified intervals up to 24 months.

Study visits are scheduled at baseline, and then at months 6, 12, 18, and 24, to assess changes from the pre-open-label extension baseline in various clinical parameters. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 24 months. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or the participant's decision to withdraw consent. The investigational product, **Treprostinil Palmitil Inhalation Powder**, is administered via a Plastiape capsule-based dry powder inhaler device, with a maximum daily dose of 640 micrograms and a total dose not exceeding 467,840 micrograms over the treatment period.

The clinical trial involves the administration of **Treprostinil Palmitil Inhalation Powder**, an experimental medication designed for the treatment of **pulmonary hypertension associated with interstitial lung disease**. The pharmaceutical form of this medication is an inhalation powder, and it is administered via inhalation using a Plastiape capsule-based dry powder inhaler device (RS01 Mod 7). The active substance, **Treprostinil Palmitil**, is of chemical origin and is provided by INSMED INC. The maximum daily dose is 640 micrograms, with a total maximum dose of 467,840 micrograms over a treatment period of 24 weeks. The inhalation powder is not a pediatric formulation and is intended for adult use only. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group, which receives inhalation powder capsules containing one of three dosage strengths of TPIP: 80 micrograms, 160 micrograms, or 320 micrograms. The placebo is designed to match the experimental medication in appearance and administration method but does not contain the active substance. The placebo serves as a comparator treatment to evaluate the safety, tolerability, and effectiveness of the Treprostinil Palmitil Inhalation Powder. Participants in the placebo group follow the same administration schedule and compliance monitoring as those receiving the active treatment.

The efficacy of **Treprostinil Palmitil Inhalation Powder** in the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD) will be assessed through a series of secondary endpoints. These include changes from the pre-open-label extension (OLE) baseline to various timepoints—Month 6, Month 12, Month 18, and Month 24—in several parameters. The parameters include the 6-minute walk distance (6MWD), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and forced expiratory flow at 25-75% (FEF25-75%), both in absolute and relative terms. Additionally, changes in the concentration of NT-proBNP in blood and diffusing capacity of the lungs for carbon monoxide (DLCO) will be measured at specified intervals.

The study will also evaluate the annualized rate of clinical worsening events, defined by criteria such as hospitalization due to cardiopulmonary indications, lung transplantation, death from any cause, a significant decrease in 6MWD, or the need for additional pulmonary hypertension therapy. The annualized rate of adverse event-related interstitial lung diseases (AE-ILDs) and changes in quality of life scores, as measured by the K-BILD and EQ-5D-5L questionnaires, will also be assessed. Plasma concentration levels of treprostinil palmitil and treprostinil will be monitored to provide additional insights into the drug's efficacy.