| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (WHO Group 1) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Increased blood pressure within the arteries of the lungs |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077739 |
| E.1.2 | Term | Pulmonary arterial hypertension WHO functional class I |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to characterize hemodynamic dose-response relationships for LIQ861. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to evaluate the acute and chronic safety and tolerability of LIQ861 in subjects with Pulmonary Arterial Hypertension. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. An Institutional Review Board (IRB) approved informed consent is signed and dated by the subject prior to any study-related activities.
2. The subject is 18 years of age or older.
3. If the subject is a female of childbearing potential, then the subject has a negative pregnancy test at the Day 1 Visit and agrees to practice a highly effective (failure rate of less than 1% per year when used consistently and correctly) method of birth control throughout the duration of the study. If the subject is postmenopausal or has documented surgical sterilization, a pregnancy test and birth control is not necessary. It is the Investigator’s responsibility for determining whether the subject has adequate birth control for study participation.
4. The subject has been diagnosed with Pulmonary Arterial Hypertension (PAH) belonging to one of the following subgroups of the updated Nice Clinical Classification Group 1, which includes:
a. Idiopathic PAH (1.1), or
b. Heritable PAH (1.2), or
c. Drug and toxin induced PAH (1.3), or
d. PAH associated with connective tissue disease (1.4.1), HIV infection (1.4.2), or congenital heart disease (1.4.4) with simple systemic-to-pulmonary shunt at least 1 year after surgical repair
5. The subject is NYHA Functional Class II - IV at Screening and:
a. has not previously been treated for PAH, or
b. has documented stable doses of no more than 2 approved non-prostacyclin therapies for at least 3 months prior to screening and is willing and able to add LIQ861 to their treatment regimen.
6. The subject can complete a baseline six-minute walk distance (6MWD) ≥ 150 m.
7. The subject has had evidence of Forced Expiratory Volume in 1 Second (FEV1) ≥ 60% and FEV1/ Forced Vital Capacity (FVC) ratio ≥ 60% during the 6-month period prior to consent. |
|
| E.4 | Principal exclusion criteria |
1. The subject's clinical condition is such that, in the opinion of the Investigator, they are not expected to remain clinically stable for the duration of the study.
2. Subjects with pulmonary hypertension (PH) in the Updated Nice Classification Groups 2-5, or Pulmonary Arterial Hypertension (PAH) Group 1 subgroups not covered by the inclusion criteria (e.g., associated with portal hypertension or with schistosomiasis)
3. The subject is currently taking prostacyclin analogues or agonists, including treprostinil, iloprost, and selexipag
4. The subject has had any PAH medication (except for anticoagulants) discontinued within 14 days prior to Day 1.
5. The subject has had a new type of chronic therapy (including but not limited to oxygen, a different class of vasodilator, diuretic, digoxin, and digitalis) for pulmonary hypertension added within 30 days prior to Day 1.
6. The subject has uncontrolled systemic hypertension as evidenced by persistent systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.
7. The subject has a history of hemodynamically significant left-sided heart disease including, but not limited to: aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, or coronary artery disease (CAD).
8. The subject has had an atrial septostomy.
9. The subject has any serious or life-threatening disease other than conditions associated with PAH.
10. The subject is taking any excluded medications listed in the Investigator’s Brochure, namely inhibitors and inducers of CYP2C8 (See Appendix 3 in the Protocol).
11. The subject has a hypersensitivity or allergy to any of the ingredients of LIQ861, NO, or other clinically relevant allergies (clinical relevance per Investigator judgment).
12. The subject has had a pulmonary infarction (defined as infarction in more than one lung segment documented by V/Q scan or pulmonary angiography) within two weeks of Screening.
13. The subject has had a stroke or transient ischemic attack (TIA) within six months of Screening.
14. The subject has evidence of an active uncontrolled sepsis or systemic infection during Screening.
15. The subject is pregnant or lactating.
16. The subject has any musculoskeletal disease or any other disease that would limit ambulation.
17. The subject has participated in an investigational product or device study within the 30 days prior to Screening.
18. The subject has current evidence of drug abuse in the opinion of the Investigator.
19. The subject has severe hepatic impairment as evidenced by any history of ascites AND encephalopathy.
20. The subject has severe renal impairment (estimated glomerular filtration rate [eGFR] < 35).
21. The subject is an employee or an immediate family member to an employee of the sponsor or the Investigator.
22. The subject is not a member or beneficiary of a social security scheme.
23. The subject is not subject to a legal protection measure.
24. The subject has not been deprived of their liberty by a judicial or administrative decision.
25. The subject has a known Hepatitis B, Hepatitis C, or HIV infection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Hemodynamic Endpoints:
Hemodynamic measurements will include Heart Rate (HR), Systemic Arterial Pressure (SAP, systolic, diastolic, and mean), Pulmonary Artery Pressure (PAP, systolic, diastolic, and mean), Pulmonary Capillary Wedge Pressure (PCWP), Right Atrial Pressure (RAP), Cardiac Output (CO), Pulmonary Artery Saturation (PaO2%), and Systemic Arterial Oxygen Saturation measured by pulse oximetry (SaO2%). Pulmonary Vascular Resistance (PVR) and Systemic Vascular Resistance (SVR) will be calculated.
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Safety Endpoints:
The primary safety endpoint in Parts A and B will be the incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class, dose level, time on drug, and relationship to dose.
Acute Safety endpoints are as follows:
• Incidence of drug-related adverse events within 4 hours of dosing.
• Change from baseline measurements to 240 minutes in vital signs and ECG assessments.
Chronic Safety endpoints are as follows:
• Incidence of drug-related adverse events.
• Changes from baseline measurements to Week 16/Early Termination in clinical laboratory, physical exam findings, and vital signs.
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Pharmacokinetic Endpoints:
Individual pharmacokinetic parameters for treprostinil will be summarized by treatment using descriptive statistics. Pharmacokinetic parameters such as the maximum observed plasma concentration (Cmax), time to Cmax (tmax), the area under the plasma concentration versus time curve from time 0 (predose) to time infinity (AUCinf), AUC from time 0 to time of last measurable plasma concentration (AUClast), the percentage of AUC that is extrapolated beyond the last measurable concentration (AUCext), the terminal phase rate constant (λz), the apparent systemic clearance (CL/F), the apparent volume of distribution in the terminal phase (Vz/F), mean residence time (MRT), and the terminal phase half-life (t½) will be calculated using non-compartmental analyses. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the whole study |
|
| E.5.2 | Secondary end point(s) |
For all subjects in Part B:
• Change from Day 1 to Weeks 2, 8, and 16 in six-minute walk distance (6MWD).
• Change from Day 1 to Weeks 2, 8, and 16 in NYHA Functional Class status.
• Change from Day 1 to Weeks 2, 8, and 16 in NT-proBNP levels.
• Change from Day 1 to Week 8 and Week 16 in the French Registry Risk Equation.
• Change from Day 1 to Week 16 in the REVEAL registry risk score.
• Time to and reason for discontinuation of LIQ861. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout part B: week 2 (+/- 2 days ) until week 16 (+/- 7 days). |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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