| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (WHO Group 1) |
Pulmonalarterielle Hypertonie (WHO-Gruppe 1)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Increased blood pressure within the arteries of the lungs |
| Bluthochdruck in den Lungenarterien |
|
| 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 the 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 |
Subjects with WHO Group 1 PAH who are
• Taking no more than 2 approved, non-prostacyclin PAH therapies and are on stable doses of pharmacologic therapies for ≥ 3 months
INCLUSION CRITERIA:
A subject will be eligible for inclusion in this study only if all of the following criteria are met:
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 (tests performed within 2 days before Day 1 are accepted) and agrees to practice a highly effective (failure rate of less than 1% per year when used consistently and correctly) method of birth control until 24 hours after completion of all study assessments defined in Appendix 1. 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 hasadequate birth control for study participation.
4. The subject has been diagnosed with 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 nonprostacyclin PAH-disease specific therapies for at least
3 months prior to Screening, is willing and able to add LIQ861 to their treatment regimen and is willing to hold the dosing of these therapies for at least 12 hours prior to study-mandated right heart catheterization
procedures.
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) and Forced Vital Capacity (FVC) ≥60% of predicted values and FEV1/FVC ratio ≥60% during the 6-month period prior to consent. |
|
| E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA:
A subject is not eligible for inclusion in the study if any of the following criteria apply:
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 PAH Group 1 subgroups not covered by the inclusion criteria (e.g., associated with portal hypertension [1.4.3] or with schistosomiasis [1.4.5]).
3. The subject is currently taking prostacyclin analogues or agonists, including treprostinil, iloprost, epoprostenol or selexipag.
4. The subject has discontinued any medication (except for anticoagulants, but otherwise including and not limited to oxygen, a different class of vasodilator, diuretic, digoxin, and digitalis) for pulmonary hypertension within 14 days prior to Day 1.
5. The subject has had a new type of 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 systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg at the time of screening or Day 1.
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 symptomatic coronary artery disease (CAD).
8. The subject has had an atrial septostomy.
9. The subject has a history of prolongation of QT interval on ECG as follows: Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec.
10. The subject has any serious or life-threatening disease other than conditions associated with PAH.
11. The subject is taking any excluded medications listed in the Investigator’s Brochure, namely inhibitors and inducers of CYP2C8.
12. 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).
13. The subject has had an acute pulmonary embolus within 6 months prior to Baseline.
14. The subject has had a stroke or transient ischemic attack within 6 months prior to Baseline.
15. The subject has evidence of an active uncontrolled sepsis or systemic infection in the period after informed consent up to Baseline.
16. The subject is pregnant or lactating.
17. The subject has any musculoskeletal disease or any other disease that limits evaluation of 6MWD.
18. The subject has participated in an investigational product or device study within the 30 days prior to Baseline.
19. The subject has current evidence of drug abuse in the opinion of the Investigator.
20. The subject has severe hepatic impairment as evidenced by any history of ascites AND encephalopathy.
21. The subject has severe renal impairment (estimated glomerular filtration rate [eGFR] <35 mL/min utilizing the Modification of Diet in Renal Disease (MDRD) study equation at Screening or requires dialytic support).
22. The subject is an employee or an immediate family member to an employee of the Sponsor or the Investigator.
23. The subject is not a member or beneficiary of a social security scheme.
24. The subject lacks a legal protection measure.
25. The subject has been deprived of their liberty by a judicial or administrative decision.
26. The subject has a known Hepatitis B or Hepatitis C infection with active viral replication.
27. The subject has a known HIV infection with CD4 count less than 200 and more than undetectable viral load, defined as less than 50 copies/mL.
28. The subject required use of intravenous inotropes including, but not limited to, Levosimendan, Dopamine, Dobutamine, Dopexamine, Epinephrine, Isoprenaline (isoproterenol), Norepinephrine (noradrenaline), Milrinone, or Amrinone, within 30 days prior to Baseline.
29. The subject has been administered intravenous diuretic within 30 days prior to Baseline.
30. Subjects taking vitamin K antagonist therapy with a known INR ≥3.5 (assessed per local care standards) at the time of screening assessments or at Baseline. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Hemodynamic Endpoints:
For Part A of the study, the change in Pulmonary Vascular Resistance (PVR) measured from Baseline (pre-dose) to maximal response (eMAX) at Day 1 will be considered the primary efficacy endpoint.
For Part B of the study, the change in PVR measured from Baseline (predose) to post dose at Week 16 will be considered the primary efficacy endpoint.
During the open-label extension period, change in PVR and other hemodynamic endpoints will not be assessed.
-----
Safety Endpoints:
The primary safety endpoint in Part A, Part B and the open-label extension period will be the incidence and severity of 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the whole study |
|
| E.5.2 | Secondary end point(s) |
Hemodynamic Endpoints:
For part A:
• PVRI, Mean SBP, Mean PAP, PCWP, RAP, CO, CI, SVR, SVRI, PAO2%, SvO2, SaO2 and HR.
For part B:
• PVRI, Mean SBP, Mean PAP, PCWP, RAP, CO, CI, SVR, SVRI, PAO2%, SvO2, SaO2 and HR.
During the open-label extension period, change in PVR and other hemodynamic endpoints will not be assessed.
-----
Secondary Acute Safety endpoints are as follows:
• Incidence of drug-related AEs within 4 hours of dosing.
• Change from baseline measurements to 240 minutes in vital signs.
• Change from baseline measurements to 120 minutes in ECG/heart monitor assessments.
Secondary Chronic Safety endpoints are as follows:
• Incidence of drug-related AEs.
• Changes from Day 1 (Baseline) measurements to Week 16/Early Termination/Week 126 in vital signs, clinical laboratory, and physical exam findings.
-----
Pharmacokinetic Endpoints:
Individual PK parameters for treprostinil will be summarized by treatment using descriptive statistics. PK 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 (pre-dose) 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.
-----
Exploratory Endpoints:
For all subjects in Part B:
• Change from Day 1 (Baseline) to Weeks 4, 8, and 16 in 6MWD.
• Time to first significant change in 6MWD.
• Change from Day 1 (Baseline) to Weeks 4, 8, and 16 in NYHA Functional Class status.
• Change from Day 1 (Baseline) to Weeks 4, 8, and 16 in NT-proBNP levels.
• Change from Day 1 (Baseline) to Week 16 in the REVEAL registry risk score version 2.0.
• Change from Day 1 to Week 16 in the number and percentage of subjects to attain or maintain four, versus three, two, or one, low risk characteristics defined as:
o NYHA Functional Class I or II
o 6MWD >440 m
o RAP <8 mmHg and CI ≥2.5 L/min/m²
o NT-proBNP less than 300 ng/L.
• Time to and reason for discontinuation of LIQ861. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the whole study |
|
| 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
| 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 | 6 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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