Evaluation of Long-Term Safety, Tolerability, and Efficacy of Treprostinil Palmitil Inhalation Powder in Pulmonary Arterial Hypertension Patients

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 Arterial Hypertension (PAH) who have previously participated in studies INS1009 201, INS1009 202, and other lead-in studies of TPIP. Assessing safety and tolerability is clinically relevant as it ensures that the treatment does not pose undue risks to patients and that it can be tolerated over extended periods, which is crucial for chronic conditions like PAH.

Secondary objectives include evaluating the effect of long-term TPIP use on exercise capacity, clinical status, clinical worsening rate, and mortality risk in participants with PAH. These factors are important as they directly impact the quality of life and survival of patients, providing a comprehensive understanding of the treatment's efficacy beyond safety and tolerability.

The clinical trial involves a total of **70 participants** diagnosed with **Pulmonary Arterial Hypertension** (PAH). The study population includes both male and female subjects, encompassing a broad **age range** from adolescents to adults. Participants were selected based on their completion of prior studies, specifically INS1009 201, INS1009 202, or other lead-in studies related to TPIP in PAH. The trial includes individuals who are capable of providing informed consent and have completed baseline screening assessments if necessary. The study population is characterized by a diverse health status, with a focus on those who have not experienced significant adverse reactions to TPIP in previous studies. Lifestyle factors such as diet and physical activity are not specified, but the inclusion of a **vulnerable population** is noted, indicating a careful consideration of participant safety and ethical standards in the trial design.

The clinical trial is designed to evaluate the **safety** and tolerability of long-term use of **treprostinil palmitil** inhalation powder in participants with **pulmonary arterial hypertension** (PAH). This is an open-label extension study, which follows participants who have completed previous studies involving treprostinil palmitil. The trial employs a randomized, controlled design, with participants receiving either the active drug or a placebo in the form of inhalation powder capsules containing one of three dosage strengths of TPIP (80 µg, 160 µg, or 320 µg). The trial is expected to run until December 18, 2026, with recruitment having started on December 12, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility. This is necessary if more than 30 days have elapsed since the end of their previous study visit. The primary endpoint of the study is the frequency and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints include changes in the six-minute walk distance (6MWD), concentration of NT proBNP in blood, REVEAL Lite 2.0 score, and NYHA/WHO functional capacity class at various intervals (Month 6, Month 12, Month 18, and Month 24). The study also monitors the annualized rate of clinical worsening events, which include all-cause death, hospitalization for right heart failure, and other specified events.

The expected length of participant involvement is up to 24 months, with regular follow-up visits to assess the primary and secondary endpoints. Participants may be terminated early from the study if they experience hypersensitivity or adverse drug reactions that, in the opinion of the investigator, present an unreasonable risk. Additionally, participants who were withdrawn early or discontinued in a previous PAH TPIP study due to similar concerns may also be excluded. The study aims to provide comprehensive data on the long-term effects of treprostinil palmitil in managing pulmonary arterial hypertension.

The clinical trial involves the administration of **Treprostinil Palmitil Inhalation Powder**, an experimental medication designed for the treatment of **Pulmonary Arterial Hypertension** (PAH). This medication is provided in the form of an inhalation powder, which is administered via inhalation. The active substance, **Treprostinil Palmitil**, is of chemical origin and is supplied by Insmed Incorporated. The maximum daily dose is 640 micrograms, with a total maximum dose of 71.68 milligrams over a treatment period of up to 16 weeks. The inhalation route is utilized to ensure direct delivery to the lungs, optimizing the therapeutic effects for participants with PAH.

In addition to the experimental treatment, a **placebo** is used as a comparator in the study. The placebo consists of inhalation powder capsules that mimic the experimental medication but contain no active substance. These capsules are available in three dosage strengths corresponding to the experimental treatment: 80 micrograms, 160 micrograms, or 320 micrograms. The placebo is employed to maintain the study's integrity by providing a control for evaluating the safety and effectiveness of the experimental medication.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed treatment regimen. The study aims to assess the long-term safety, tolerability, and effectiveness of Treprostinil Palmitil Inhalation Powder in individuals with PAH, building on previous studies and providing valuable data for future therapeutic applications.

The efficacy of **Treprostinil Palmitil Inhalation Powder** in the treatment of Pulmonary Arterial Hypertension (PAH) will be assessed through a series of predefined endpoints. Primary efficacy will be evaluated by monitoring the frequency and severity of treatment-emergent adverse events (TEAEs) throughout the study. Secondary efficacy endpoints include changes from pre-open-label extension (OLE) baseline to Month 6, Month 12, Month 18, and Month 24 in the 6-minute walk distance (6MWD), both absolute and relative, as well as changes in the concentration of NT-proBNP in blood, the REVEAL Lite 2.0 score, and the NYHA/WHO functional capacity class.

Additional secondary endpoints involve the annualized rate of clinical worsening events, which are defined as all-cause death or the onset of a TEAE with a fatal outcome occurring within 14 days after study drug discontinuation. Other criteria include hospitalization for right heart failure lasting more than 48 hours, heart-lung or lung transplant, or atrial septostomy. The study will also track the addition or increase in dose of specified PAH-specific medications, and the combined occurrence of events such as a 20% decrease in 6MWD, worsening WHO/NYHA functional capacity class, and the appearance or worsening of signs/symptoms of right heart failure. Plasma concentration levels of TP and TRE will also be measured as part of the efficacy assessment.