A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder in Participants With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The main objective of the study is to assess the effect of treprostinil palmitil inhalation powder (TPIP) compared with placebo on pulmonary vascular resistance.

Official Title
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A Phase 2b, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder in Participants With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Treprostinil Palmitil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be ≥ 18 to ≤ 75 years at the time of signing the informed consent form (ICF). Participants must have a diagnosis of World Health Organization (WHO) Group 1 Pulmonary Hypertension (PH) (PAH) in any of the following subtypes: Idiopathic Heritable Drug/toxin-induced or connective tissue disease (CTD)-associated PAH PAH diagnosis for at least 3 months. Participants must be on stable PH therapy consisting of up to 2 medications from the following classes: Endothelin receptor antagonists (eg, ambrisentan, bosentan, macitentan) Phosphoesterase type 5 inhibitors (eg, sildenafil, tadalafil) Guanylate cyclase stimulator (eg, riociguat) No change in PH medications (eg, ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 30 days prior to Screening. No change in long-term diuretic use or dosage for at least 30 days prior to Screening. Body Mass Index (BMI) within the range 18.0-37.0 kg/m^2 (inclusive). Male participants: Male participants who are not sterile, with female partners of childbearing potential, must be using effective contraception from Day 1 to at least 90 days after the last dose of study drug. Female participants: Women must be postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, (ie, post-tubal ligation for at least 12 months) or using highly effective contraception methods (ie, methods that alone or in combination achieve <1% unintended pregnancy rates per year when used consistently and correctly) from Day 1 to at least 90 days after the last dose of study drug. Male participants with pregnant or non-pregnant woman of childbearing potential partner must use a condom in order to avoid potential exposure to embryo/fetus. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol. Exclusion Criteria: History of PH other than idiopathic, hereditary, drug/toxin-induced, or CTD-associated PAH (eg, congenital heart disease-associated PAH, portal hypertension-associated PAH, PH belonging to Groups 2 through 5). Allergy, or documented hypersensitivity or contraindication, to TPIP or Treprostinil or mannitol (an excipient of the TPIP formulation). Any known ventricular or supraventricular tachyarrhythmia except for paroxysmal atrial fibrillation and any symptomatic bradycardia. History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% or clinically significant valvular, constrictive, or symptomatic atherosclerotic heart disease (eg, stable angina, myocardial infarction, etc). Participation in a cardio-pulmonary rehabilitation program within 1 month of Screening Visit. Evidence of thromboembolic disease as assessed by ventilation-perfusion (VQ) scan, pulmonary angiography, or pulmonary computed tomography (CT) scan. Active liver disease or hepatic dysfunction. History of HIV infection. Established diagnosis of hepatitis B viral infection, or positive for hepatitis B surface antigen (HBsAg) at the time of Screening. Established diagnosis of hepatitis C viral infection at the time of screening. Active and current symptomatic coronavirus disease 2019 (COVID-19) or previous severe disease and/or hospitalization due to COVID-19. Use of live attenuated vaccines within 30 days of the Screening Visit. Participants with Down's Syndrome. History of abnormal bleeding or bruising. History of solid organ transplantation. Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged infections suggesting an immune compromised status, as judged by the Investigator. History of alcohol or drug abuse within 6 months prior to Screening. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6-minute walk test (eg, angina pectoris, claudication, musculoskeletal disorder, need for walking aids). Participants with current or recent (past 30 days) lower respiratory tract infection. History of malignancy in the past 5 years, with exception of completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell carcinoma of the skin. Change in PH medication (endothelin receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase stimulators or diuretics) between Screening and Baseline. Have participated in any other interventional clinical studies within 30 days prior to Screening. Current use of cigarettes (as defined by Centers for Disease Control and Prevention) or e-cigarettes. Participants who currently inhale marijuana (recreational or medical). Pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treprostinil Palmitil Inhalation Powder<br>Participants will be administered TPIP once per day at a starting dose of 80 micrograms (μg). Participants will be up-titrated to the highest tolerated dose for each individual participant of between 80 μg and 640 μg during the initial 3 weeks of treatment. The overall treatment period will be 16 weeks. | Drug: Treprostinil Palmitil<br>* Administered by oral inhalation using a Plastiape capsule-based dry powder inhaler.<br>* Other names: INS1009;|
| Placebo Comparator: Placebo<br>Participants will be administered a placebo matching TPIP once per day for 16 weeks. | Drug: Placebo<br>* Administered by oral inhalation using a Plastiape capsule-based dry powder inhaler.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Pulmonary Vascular Resistance at Week 16 |  | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in 6-Minute Walk Test Distance at Week 5, Week 10 and Week 16 |  | Baseline and Week 5, Week 10 and Week 16 | 
| Percent Change from Baseline in 6-Minute Walk Test Distance at Week 5, Week 10 and Week 16 |  | Baseline and Week 5, Week 10 and Week 16 | 
| Number of Participants Who Experience a Treatment-emergent Adverse Event (AE) |  | Day 1 up to Week 20 | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Clinical Laboratory Evaluations |  | Baseline to Week 16 | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Sign Measurements |  | Baseline to Week 16 | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Electrocardiogram (ECG) Measurements |  | Baseline to Week 16 | 
| Number of Participants Who Experience a Clinically Significant Change from Baseline in Physical Examinations |  | Baseline to Week 16 | 
| Maximum Plasma Concentration (Cmax) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Maximum Plasma Concentration (Cmax) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Time to Maximum Plasma Concentration (Tmax) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Time to Maximum Plasma Concentration (Tmax) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Area Under the Concentration-time Curve from Time 0 to 24 Hours Post-Dose (AUC24) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Area Under the Concentration-time Curve from Time 0 to 24 Hours Post-Dose (AUC24) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Area Under the Concentration-time Curve from Time 0 to Infinity (AUC∞) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Area Under the Concentration-time Curve from Time 0 to Infinity (AUC∞) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Area Under the Concentration-time Curve from Time 0 to Last Measurable Concentration (AUClast) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Area Under the Concentration-time Curve from Time 0 to Last Measurable Concentration (AUClast) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Apparent Total Clearance (CL/F) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Apparent Total Clearance (CL/F) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Apparent Volume of Distribution After Non-Intravenous Administration (Vd/F) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Apparent Volume of Distribution After Non-Intravenous Administration (Vd/F) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Elimination Half-Life (t1/2) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Elimination Half-Life (t1/2) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Accumulation Ratio Based on Maximum Plasma Concentration (Rac[Cmax]) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Accumulation Ratio Based on Maximum Plasma Concentration (Rac[Cmax]) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Accumulation Ratio Based on Area Under the Concentration-Time Curve at 24 Hours Post-Dose (Rac[AUC24]) of Treprostinil Palmitil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Accumulation Ratio Based on Area Under the Concentration-Time Curve at 24 Hours Post-Dose (Rac[AUC24]) of Treprostinil |  | Day 1, Weeks 5, 10 and 16: 24 hours pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose | 
| Change from Baseline in the Concentration of N-Terminal-Pro Hormone Brain Natriuretic Peptide (NT-proBNP) Levels at Week 5, Week 10 and Week 16 |  | Baseline and Week 5, Week 10 and Week 16 or end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treprostinil Palmitil, Pulmonary Arterial Hypertension