| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Participants with Pulmonary Arterial Hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Participants with high blood pressure in the arteries of the lungs |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the effect of Treprostinil Palmitil Inhalation Powder (TPIP) compared with placebo on Pulmonary Vascular Resistance (PVR) |
|
| E.2.2 | Secondary objectives of the trial |
-To assess the effect of TPIP compared with placebo on exercise capacity
-To assess the safety and tolerability of TPIP compared with placebo
-To evaluate the PK of TP and TRE in plasma
-To evaluate the effect of TPIP compared with placebo on the concentration of NT-proBNP in blood |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
CT scan and Echo sub-studies:
2 substudies (1 each for transthoracic echocardiogram and pulmonary vascular volume assessment). These assessments are considered optional at the participant’s discretion (ie, a participant may choose to not have the assessment) and may not be performed at all study sites. Participants will be informed by the Investigator which substudies, if any, are available at their study site and a specific substudy ICF will be provided. |
|
| E.3 | Principal inclusion criteria |
1. Participants must be ≥ 18 to ≤ 75 years at the time of signing the ICF.
2. Participants must have a diagnosis of WHO Group 1 PH (PAH) in any of the following subtypes: • idiopathic; • heritable or • drug/toxin-induced or CTD-associated 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. New York Heart Association (NYHA)/WHO functional class II or III.
5. Medical history, physical examination, vital signs, ECG, and clinical laboratory results consistent with their degree of PAH and treatment.
6. Participants must be on stable 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)
7. No change in PH medications (eg, ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 30 days prior to Screening.
8. No change in long-term diuretic use dosage for at least 30 days prior to Screening (single or rescue doses allowed, per the Investigator).
9. Documented pre-bronchodilator predicted FEV1 ≥70% and FEV1/FVC ratio ≥ 70% within 1 year of Screening. If documented spirometry is not available, pulmonary function testing will be performed during Screening.
10. At least two 6MWTs during Screening with a 6MWT distance between 150 and 450 meters in length where both values are within 15% of each other.
11. Right heart catheterization at Screening (or within 30 days prior to Screening, if available) with all the following hemodynamic findings:
• Mean PAP ≥ 25 mmHg at rest
• PCWP ≤ 15 mmHg
• PVR of ≥ 5 WU
12. BMI within the range 18.0-37.0 kg/m2 (inclusive).
13. Male and female participants must use contraceptives that are consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male participants:
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. Such methods include true abstinence (refraining from heterosexual intercourse during the study), combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems.
• Female participants:
Women must be postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, (ie, hysterectomy and/or bilateral salpingo-oopherectomy), 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. Such methods include true abstinence (refraining from heterosexual intercourse during the study), combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation and supplemented with a double barrier (preferably male condom), intrauterine devices, intrauterine hormone-releasing systems, or vasectomized partner. For WOCBBP ≤45 years, an additional confirmatory testing of FSH level with a threshold of >40 mIU/mL should be performed to be considered infertile.
All WOCBP must have a negative urine pregnancy test prior to randomization.
14. Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline.
15. Male participants with pregnant or non-pregnant WOCBP partner must use a condom in order to avoid potential exposure to embryo/fetus.
16. Capable of giving signed informed consent
17. Able to understand and comply with protocol requirements |
|
| E.4 | Principal exclusion 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 TRE or mannitol (an excipient of the TPIP formulation).
3. Per the Investigator's discretion, previous intolerance to prostacyclin analogues or receptor agonists or previous chronic use (>30 days) of a prostacyclin analogue or receptor agonist within 30 days of the Screening Visit.
4. QTcF interval > 480 ms on resting ECG at Screening, not including participants with right bundle branch block (RBBB) leading to a prolongation of the QRS.
5. Any known ventricular or supraventricular tachyarrhythmia except for paroxysmal atrial fibrillation and any symptomatic bradycardia.
6. History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% or clinically significant valvular, constrictive, or symptomatic atherosclerotic heart disease.
7. Systolic BP < 90 mm Hg at Screening
8. Participation in a cardio-pulmonary rehabilitation program within 30 days of Screening Visit.
9. Evidence of thromboembolic disease as assessed by VQ scan, pulmonary angiography, or pulmonary CT scan.
10. Acutely decompensated heart failure within 30 days of Screening Visit.
11. Abnormal renal function (estimated glomerular filtration rate < 30 mL/min/1.73m2) at Screening.
12. Active liver disease or hepatic dysfunction manifested as: in
• Elevated liver function test results (ALT or AST > 2 × ULN)
• Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN; ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
• Known hepatic or biliary abnormalities, not including Gilbert's syndrome or asymptomatic gallstones
13. History of HIV infection
14. Established diagnosis of hepatitis B viral infection, or positive for HBsAg at the time of Screening.
• Participants who have gained immunity for hepatitis B virus infection after vaccination are eligible for the study.
• Participants with positive HBcAbs are eligible for the study only if the hepatitis B virus DNA level is undetectable.
15. Established diagnosis of hepatitis C viral infection at the time of screening. Participants positive for hepatitis C antibody are eligible for the study only if hepatitis C virus RNA is negative.
16. Active and current symptomatic COVID-19 or previous severe disease and/or hospitalization due to COVID-19
17. Use of live attenuated vaccines within 30 days of the Screening Visit.
18. Participants with Down’s Syndrome.
19. History of abnormal bleeding or bruising with a platelet count of <100,000/μL at Screening.
20. History of organ transplantation.
21. Known or suspected immunodeficiency disorder
22. Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant’s participation in the study.
23. Any clinically significant abnormal laboratory values at Screening or diseases or disorders (eg, cardiovascular, pulmonary, gastrointestinal, liver, kidney, neurological, musculoskeletal, endocrine, metabolic, psychiatric, physical impairment) that, in the opinion of the Investigator, may put the participant at risk by participating in the study, or interfere with the participant’s treatment, assessment, or influence the results of the study, or have compliance issues with the study or have a planned or anticipated major surgical procedure during the study.
24. History of alcohol or drug abuse within 6 months prior to Screening.
25. Any other medical or psychological condition including relevant laboratory abnormalities at Screening that, in the opinion of the Investigator, suggest a new and/or insufficiently understood disease.
26. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6MWT.
27. Participants with current or recent (past 30 days) lower respiratory tract infection
28. 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.
29. Change in PH medication (endothelin receptor agonists, phosphodiesterase type 5 inhibitors, and guanylate cyclase stimulators or diuretics) between Screening and Baseline.
30. Use of any investigational drug/device or participation in any investigational study within 30 days prior to the screening
31. Current use of cigarettes (as defined by CDC) or e-cigarettes: An adult who has smoked at least 100 cigarettes in his or her lifetime, and who currently smokes either every day or somedays.
32. Participants who currently inhale marijuana (recreational or medical).
33. Pregnant or breastfeeding.
34. Absolute neutrophil count ≤ 1000/μL at Screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent Change from Baseline in PVR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-Change from Baseline in 6MWT distance
-Percent change from Baseline in 6MWT distance
- Frequency of AEs and changes from Baseline in clinical laboratory evaluations, vital signs, ECG, and physical examination
- Plasma PK parameters of TP and TRE, including Cmax, tmax, AUC24,
AUC∞, AUClast, CL/F, Vd/F, and t½
- Change from Baseline in the concentration of NT-proBNP |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- at Week 5, Week 10, and Week 16
- at Week 5, Week 10, and Week 16
- over the 16-week treatment period
- on Day 1 and at Week 10
- at Week 5, Week 10 and Week 16
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Malaysia |
| Philippines |
| Switzerland |
| Australia |
| Brazil |
| Japan |
| Mexico |
| Serbia |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Denmark |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study is defined as the date of the last Follow-Up phone call or visit for the last participant in the study.
Participants who transition to the OLE study prior to the Week 20 follow-up telephone call or visit will be considered to have completed the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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