A Randomized, Double-Blind, Placebo-Controlled Study of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Arterial Hypertension

JRCT ID: jRCT2071220033

Registered date:02/08/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Pulmonary Arterial Hypertension
• Date of first enrollment: 02/08/2022
• Target sample size: 99
• Countries of recruitment: United States,Japan,Argentina,Japan,Australia,Japan,Mexico,Japan,Phillipines,Japan,Austria,Japan,Belgium,Japan,Brazil,Japan,Denmark,Japan,Germany,Japan,Italy,Japan,Malaysia,Japan,Spain,Japan,Switzerland,Japan,United Kingdom,Japan,Serbia,Japan
• Study type: Interventional

Intervention(s)

Experimental: Treprostinil Palmitil Inhalational Powder
Participants will be administered TPIP once per day at a starting dose of 80 micrograms. Participants will be titrated to the highest tolerated dose for each individual participant of between 80 micrograms and 640 micrograms during the initial 3 weeks of treatment. The overall treatment period will be 16 weeks.

Placebo Comparator: Placebo
Participants will be administered a placebo matching TPIP once per day for 16 weeks.

Outcome(s)

• Primary Outcome: Change from Baseline in Pulmonary Vascular Resistance at Week 16

Secondary Outcome

1. Change from Baseline in 6-Minute Walk Test Distance at Week 5, Week 10 and Week 16
2. Percent Change from Baseline in 6-Minute Walk Test Distance at Week 5, Week 10 and Week 16
3. Number of Participants Who Experience a Treatment-emergent Adverse Event (AE) from Day 1 up to Week 20
4. Number of Participants Who Experience a Clinically Significant Change from Baseline in Clinical Laboratory Evaluations, Vital Sign Measurements, Electrocardiogram (ECG) Measurements, Physical Examinations Over the 16-Week Treatment Period
5. Maximum Plasma Concentration (Cmax) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10, and 16: Predose and 0.5, 1, 2, 4 and 6 hours post-dose
6. Maximum Plasma Concentration (Cmax) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10, and 16: Predose and 0.5, 1, 2, 4 and 6 hours post-dose
7. Time to Maximum Plasma Concentration (Tmax) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
8. Time to Maximum Plasma Concentration (Tmax) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
9. Area Under the Concentration-time Curve from Time 0 to 24 Hours Post-Dose (AUC24) of Treprostinil Palmitil on Day 1 at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
10. Area Under the Concentration-time Curve from Time 0 to 24 Hours Post-Dose (AUC24) of Treprostinil on Day 1 at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
11. Area Under the Concentration-time Curve from Time 0 to Infinity (AUC infinity) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
12. Area Under the Concentration-time Curve from Time 0 to Infinity (AUC infinity) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
13. Area Under the Concentration-time Curve from Time 0 to Last Measurable Concentration (AUClast) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
14. Area Under the Concentration-time Curve from Time 0 to Last Measurable Concentration (AUClast) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
15. Apparent Total Clearance (CL/F) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5,10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
16. Apparent Total Clearance (CL/F) of Treprostinil on Day 1, at Weeks 2, 3, 5,10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
17. Apparent Volume of Distribution After Non-Intravenous Administration (Vd/F) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
18. Apparent Volume of Distribution After Non-Intravenous Administration (Vd/F) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
19. Elimination Half-Life (t1/2) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
20. Elimination Half-Life (t1/2) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
21. 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 or end of study.

Key inclusion & exclusion criteria

• Age minimum: > 18age old
• Age maximum: < 75age old
• Gender: Both

Include criteria

1. Participants must be greater than or equal to 18 to less than or equal to 75 years at the time of signing the informed consent form (ICF).
2. Participants must have a diagnosis of World Health Organization (WHO) Group 1 Pulmonary Hypertension (PH) [pulmonary arterial hypertension (PAH)] in any of the following subtypes idiopathic, heritable, drug or toxin-induced or connective tissue disease (CTD) associated pulmonary arterial hypertension (PAH), Congenital heart disease-related with simple systemic-to-pulmonary shunt at least 1 year following repair.
3. PAH diagnosis for at least 3 months.
4. Participants must be on stable pulmonary hypertension (PH) therapy consisting of up to 2 medications from the following classes
- Endothelin receptor antagonists (eg. ambrisentan, bosentan, macitentan)
- Phosphodiesterase type 5 inhibitors (eg. sildenafil, tadalafil)
- Guanylate cyclase stimulator (eg. riociguat)
5. No change in PH medications (eg. ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 30 days prior to Screening.
6. No change in long-term diuretic use or dosage for at least 30 days prior to Screening.
7. Body mass index (BMI) within the range of 18.0-37.0 kg per meter square (inclusive).
8. Male participants who are not sterile, and have 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.
9. 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 less than 1 percent 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.
10. Male participants: Male participants with pregnant or non-pregnant woman of childbearing potential partner must use a condom in order to avoid potential exposure to embryo or fetus.
11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.

Exclude criteria

1. History of PH other than idiopathic, hereditary, drug/toxin-induced, repaired simple congenital heart disease, or CTD-associated PAH (eg, complex, congenital heart disease-associated PAH, portal hypertension-associated PAH, PH belonging to Groups 2 through 5).
2. Allergy, or documented hypersensitivity or contraindication, to TPIP or Treprostinil (TRE) or mannitol (an excipient of the TPIP formulation).
3. Any known ventricular or supraventricular tachyarrhythmia except for paroxysmal atrial fibrillation and any symptomatic bradycardia.
4. History of heart disease including left ventricular ejection fraction (LVEF) less than or equal to 40% or clinically significant valvular, constrictive, or symptomatic atherosclerotic heart disease (eg, stable angina, myocardial infarction, etc).
5. Participation in a cardio-pulmonary rehabilitation program within 1 month of Screening Visit.
6. Evidence of thromboembolic disease as assessed by ventilation-perfusion (VQ) scan, pulmonary angiography, or pulmonary computerized tomography (CT) scan.
7. Active liver disease or hepatic dysfunction.
8. History of HIV infection.
9. Established diagnosis of hepatitis B viral infection, or positive for hepatitis B surface antigen (HBsAg) at the time of Screening.
10. Established diagnosis of hepatitis C viral infection at the time of screening.
11. Active and current symptomatic coronavirus disease 2019 (COVID-19) or previous severe disease and/or hospitalization due to COVID-19.
12. Use of live attenuated vaccines within 30 days of the Screening Visit.
13. Participants with Down Syndrome.
14. History of abnormal bleeding or bruising.
15. History of solid organ transplantation.
16. 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.
17. History of alcohol or drug abuse within 6 months prior to Screening.
18. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6-mintute walk test (eg, angina pectoris, claudication, musculoskeletal disorder, need for walking aids).
19. Participants with current or recent (past 30 days) lower respiratory tract infection.
20. 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.
21. Change in PH medication (endothelin receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase stimulators or diuretics) between Screening and Baseline.
22. Have participated in any other interventional clinical studies within 30 days prior to Screening.
23. Current use of cigarettes (as defined by Centers for Disease Control [CDC]) or e-cigarettes.
24. Participants who currently inhale marijuana (recreational or medical).
25. Pregnant or breastfeeding.

Related Information

• Primary Sponsor: F Ismat
• Secondary ID(s): 2021-001528-16,NCT05147805,2023-505541-99-00