E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension (PAH) |
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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. |
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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 |
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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 |
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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 |
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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 |
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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. |
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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. |
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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. |
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E.3 | Principal inclusion criteria |
Key Inclusion Criteria:
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. 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. |
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E.4 | Principal exclusion criteria |
Key Exclusion Criteria:
1. PH belonging to Groups 2 to 5 of the 2018 NICE classification 2. 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 3. Pregnant or breast-feeding females
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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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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 ● Incidence of Clinical Worsening through 24 Weeks ● 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
Key Secondary Endpoints for Phase 3: ● Change from baseline at Week 24 in NT-proBNP ● Time to Clinical Worsening through 24 weeks ● 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 |
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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. |
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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
| 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 | 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 |
Argentina |
Australia |
Brazil |
Canada |
Chile |
China |
Colombia |
Israel |
Mexico |
Puerto Rico |
Singapore |
South Africa |
United States |
Austria |
France |
Latvia |
Poland |
Sweden |
Netherlands |
Spain |
Czechia |
Germany |
Greece |
Italy |
Belgium |
Ireland |
Portugal |
Turkey |
United Kingdom |
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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
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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 |
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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 |