| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (PAH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| PAH includes rare, chronic cardiopulmonary diseases involving common pathologic features of inappropriate cell growth resulting in increased resistance to blood flow through the pulmonary vasculature. |
|
| 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 | 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077729 |
| E.1.2 | Term | Pulmonary arterial hypertension WHO functional class III |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 | 10077730 |
| E.1.2 | Term | Pulmonary arterial hypertension WHO functional class IV |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 | 10077740 |
| E.1.2 | Term | Pulmonary arterial hypertension WHO functional class II |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 objective of the study is to establish an optimal dose of AV-101 based primarily upon the change in PVR (assessed by right heart catherization) and the safety and tolerability of AV-101 as evaluated in the Phase 2b Part of the study. The optimal dose will be taken into the Phase 3 Part of the study where the placebo-corrected change in 6MWD after 24 weeks of treatment will be used as the primary endpoint. |
|
| E.2.2 | Secondary objectives of the trial |
| Change from baseline in NT-proBNP levels, Time to Clinical Worsening's, Multicomponent Clinical Improvements, Maintenance or Improvement of Functional Class, Change in REVEAL Lite 2.0 score and Quality of Life will be evaluated. |
|
| 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 |
The sub-study is the Pharmacokinetic study conducted in Phase 2b part of the study.
At selected study sites in the Phase 2b Part of the study, steady state pharmacokinetics will be assessed at Week 4 pre-dose and at multiple timepoints post-administration of the study medication.
A pre-dose trough PK sample will be taken from all subjects in the study at the Week 24 visit prior to any other procedures (excluding HRQoL and vital signs). The purpose of the Week 24 PK sample is to allow for potential exposure-response analyses for efficacy and safety. |
|
| E.3 | Principal inclusion criteria |
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1. Male or female adults (between 18 and 75 years) at the Screening Visit within 28 days prior to Day 1
2. Subjects with a diagnosis of PAH belong to one of the subgroups of the NICE classification of Group 1:
- a. I/HPAH, PAH-CTD
- b. PAH due to drugs and toxins (having been in the care of the Investigator for at least one year with no relapses of drug or toxin/chemical abuse),
- c. HIV associated or
- d. PAH due to repaired congenital heart disease (at least 1 year since repair)
3. World Health Organization (WHO) Functional Class II, III or IV symptoms
4. Meets all of the following hemodynamic criteria by means of an RHC at Screening: mPAP ≥ 25 mmHg, PVR > 400 dynes.sec/cm5 and PCWP ≤ 15 mmHg. For the Intermediate and Phase 3 Parts, RHC procedures performed within 6-months of screening may be accepted provided the RHC was conducted as described in the Protocol
5. On a stable background of at least two PAH medications. Parenteral and oral prostacyclins (including prostanoids and prostacyclin receptor antagonists) are permitted. Subjects should have been stable on their PAH medications for at least 90 days. Stability of parenteral prostacyclins means a change of no more than 10% in the previous 12 weeks
6. A history of ventilation/perfusion (V/Q) scan, pulmonary arteriogram, or CT angiogram negative for chronic thromboembolic pulmonary hypertension (CTEPH) at the time of their Group 1 PAH diagnosis
7. Must meet all of the following criteria for pulmonary function (spirometry) tests completed no more than 24 weeks before the Screening Visit: FEV1 ≥ 60% of predicted normal and FEV1:FVC ratio ≥ 0.60
8. Must have a resting arterial oxygen saturation (SaO2) ≥ 90%, with or without supplemental oxygen, as measured by pulse oximetry at the Screening Visit
9. Must be able to walk a distance of at least 100 m but no more than 475 m during the screening 6-minute walk test. In addition, the subject must be able to demonstrate a stable baseline for the 6 minute walk tests between the Screening and Randomization Visits as described in the Protocol
10. Able to understand the study procedures and be willing to comply with the study restrictions Willing and able to sign a written informed consent prior to all study-related procedures
11. Female subjects of childbearing potential must agree to use an acceptable form of contraception for at least 28 days prior to when they will receive the first dose of study drug, and for at least 30 days after completing or discontinuing study treatment
12. Evidence of negative test for SARS-CoV-2, by PCR, at the Screening Visit; Subjects with a previous COVID-19 infection may be included provided the PCR test is negative for SARS-CoV-2 and they do not have chronic symptoms as a result of COVID-19. COVID-19 testing may be performed at local lab, per site/local guidelines, or via the study Central Lab. Subjects who have been fully vaccinated against SARS-CoV-2 may be enrolled without need for PCR testing
13. Has not enrolled in an exercise training program for pulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 24 weeks of the study
14. If currently enrolled in an exercise training program for pulmonary rehabilitation for more than 12 weeks at the time of the Screening Visit, must agree to maintain their current level of rehabilitation for the first 24 weeks of the study |
|
| E.4 | Principal exclusion criteria |
1. Taking warfarin (or any vitamin K antagonists), Direct Oral Anticoagulants (DOACs) or dual antiplatelet therapy within 2 weeks prior to Day 1/Randomization. (DSMB and Sponsor will decide whether to allow warfarin in Phase 3 Part of the study)
2. PH belonging to Groups 2 to 5 of the 2018 NICE classification
3. A history of LVEF ≤ 40% on echocardiogram within 6 months of screening, or clinically significant ischemic, mitral or aortic valve disease, or constrictive heart disease in the opinion of the Investigator
4. Evidence of ≥ 3 of the following left ventricular disease/dysfunction risk factors:
- a) Body mass index (BMI) ≥ 30 at the Screening Visit or
- b) History of essential hypertension
- c) Diabetes mellitus – any type
- d) Historical evidence of significant coronary artery disease (CAD) established by any one of the following:
- i. History of myocardial infarction
- ii. History of Percutaneous Coronary Intervention (PCI)
- iii. Angiographic evidence of Coronary Artery Disease (CAD) (> 50% stenosis in at least on vessel), by angiography
- iv. Positive stress test with imaging
- v. Previous coronary artery surgery
- vi. History of chronic stable angina or unstable angina
5. Taking inhaled prostacyclins within the past 3 months prior to the Screening Visit
6. History of chronic uncontrolled asthma (subjects taking corticosteroids will be allowed into the study)
7. History of any illness or condition that, in the opinion of the Investigator could confound the results of the study or pose an additional risk to the subject through their participation in the study
8. Inability to use or may have potential difficulties using an inhaler device during each dosing period
9. Participating in a clinical study (e.g., attending follow-up visits) or who have received an investigational drug (new chemical entity) in the past 30 days prior to the Screening Visit. Involvement in strictly observational studies (Registries) is allowed provided this is approved by the Contract Research Organization (CRO) Medical Monitor
10. Donated blood, plasma, or platelets in the month prior to screening or who have made donations on more than two occasions within the 12 months preceding the first dose administration of study drug or have had a loss of ≥ 400 mL of blood within 2 months prior to Day 1/Randomization
11. Deficient thrombocyte function, thrombocytopenia < 50 x10^9/L (50 x 10^3/μL) at the Screening Visit
12. Uncontrolled systemic arterial hypertension, systolic > 180 mm Hg or diastolic >110 mm Hg at the Screening Visit or Day 1/Randomization Visit
13. QTcF > 450 msec for males and > 470 msec for females at the Screening Visit in the absence of right bundle branch block
14. History of Long QT Syndrome or Torsade de Pointes
15. Hemoglobin < 80 g/L (8 g/dL) at the Screening Visit
16. Serum ALT or AST lab value that is > 3 x ULN at the Screening Visit
17. Severe renal impairment (eGFR <30 mL/min/1.73m2 at the Screening Visit based on the CKD-EPI equation)
18. Severe hepatic impairment (Child-Pugh Class C with or without cirrhosis) at the Screening Visit
19. Known deficiencies of blood coagulation, inherited, or acquired blood coagulation disorders, factor XII, factor XIII; decreased generation of coagulation factors due to acute or chronic liver diseases, inefficient coagulation e.g., due to autoantibodies against coagulation factors such as in lupus anticoagulant, DIC etc
20. Evidence or history of major bleeding or intracranial hemorrhage
21. History of elevated intracranial pressure
22. Significant history or drug allergy as determined by the Investigator
23. Known or suspected drug hypersensitivity to any component of the trial drug (lactose intolerant subjects are allowed into the study)
24. Clinically relevant history or current psychological abnormality (including alcohol abuse), psychiatric or neurological illness or autonomic neuropathy, which in the opinion of the Investigator could jeopardize or would compromise the subject’s ability to participate in the trial
25. Recent major surgical intervention which in the opinion of the Investigator would compromise the subject’s ability to participate in the trial
26. Pregnant or breast-feeding females
27. Receiving the SARS-CoV-2 vaccination from 1 week prior to the Screening Visit and through 4 weeks post-Day1/Randomization
28. Post COVID-19 chronic symptoms (“Long Haulers”) at Screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint (Phase 2b)
● The placebo-corrected change from baseline in PVR at 24 weeks
Primary Endpoint (Phase 3)
● The placebo-corrected change in 6MWD at Week-24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The effect of AV-101 on PVR will be measured by RHC.
Clinical Worsening Events is defined as:
● Death (all causes)
● Hospitalization for worsening PAH
● Initiation of parenteral prostanoids (sc or iv infusion)
● ≥ 15% decline from baseline in 6MWD accompanied with continued or worsening to WHO FC III or IV symptoms.
The decline in 6MWD must be confirmed with a repeat test on a different day within 2 weeks.
All clinical worsening events will be adjudicated by an independent panel of clinicians experienced with PAH.
An exploratory analysis for clinical worsening will be assessed using the criteria in the IMPRES study:
● Death
● Hospitalization for worsening PAH
● Worsening of WHO FC by at least one level
● Reduction in 6MWD by 15% from baseline confirmed on two visits |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints for Phase 2B:
● Change from baseline at Week 24 in NT-proBNP
● Change from baseline at Week 24 in 6MWD
● Change from baseline at Week 24 in hemodynamic measures (CI, mPAP, mRAP, and SvO2)
● Incidence of Clinical Worsening through 24 Weeks
● Achieving the multi-component improvement parameters
- Percent of subjects who achieve the multi-component parameters by visit
- Time to achieving the multi-component improvement parameters
● Improvement at Week 24 in WHO Function Class status
● Change from baseline at Week 24 in REVEAL Lite 2.0 Score
● Change from baseline at Week 24 in QoL (emPHasis-10) Questionnaire score
Other Phase 2b endpoints:
● Change from baseline at Week 24 in Transthoracic Echo parameters of right ventricular (RV) function.
● Change from baseline at Week 24 in BDI
● Pharmacokinetics (Cmax,ss, Cmin,ss, Cavg, Tmax,ss, AUC0-tau, CL/F,ss, MRCmax,ss, and MRAUC0-tau)
● Safety and tolerability
Key Secondary Endpoints for Phase 3:
● Change from baseline at Week 24 in NT-proBNP
● Time to Clinical Worsening through 24 weeks
● Achieving the multi-component improvement parameters
- Percent of subjects who achieve the multi-component parameters by visit
- Time to achieving the multi-component improvement parameters
● Improvement at Week 24 in WHO Function Class status
● Change from baseline at Week 24 in REVEAL Lite 2.0 Score
● Change from baseline at Week 24 in QoL (PAH-SYMPACT) Questionnaire score
Other Phase 3 endpoints:
● Change from baseline at Week 24 in Transthoracic Echo parameters of RV function
● Change from baseline at Week 24 in BDI
● Pharmacokinetics
● Safety and tolerability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Phase 2b and Phase 3 endpoints will be evaluated at Week 24 except for safety and PK. Safety will be evaluated throughout the study and PK will be evaluated at Week 4 and Week 24. |
|
| 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 | 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) | Yes |
| 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 | Yes |
| 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 | 4 |
| 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 | 43 |
| 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 |
| Australia |
| Chile |
| Colombia |
| Mexico |
| Singapore |
| South Africa |
| Turkey |
| Argentina |
| Austria |
| Belgium |
| Brazil |
| Canada |
| China |
| Czechia |
| Germany |
| Greece |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
| United States |
| France |
|
| 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
|
LVLS
The end of Phase 2b is defined as the Week 24 visit for the last subject(s) who participates in the Phase 2b Part of the study. The end of the Phase 3 Part of the study is defined as the date of last contact with the last subject who participates in the Phase 3 Part of the study (i.e., last subject’s last visit), including subjects in the Intermediate Part. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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