| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
|
| 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 |
| To determine the effect of BPS-MR on the change from Baseline in hemodynamic parameters at week 12 |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effect of an iMTD and two Fixed Doses (FD) levels of BPS-MR on:
• Exercise capacity 2 to 3 hours after dosing, at Weeks 6 and 12;
• Exercise capacity at the end of the dosing interval, at Week 12;
• Borg Dyspnea score 2 to 3 hours after dosing (at Weeks 6 and 12) and at the end the dosing interval (at week 12);
• World Health Organisation (WHO) Functional Class, at Weeks 6 and 12;
• Pro-B-Type Natriuretic Peptide (Pro-BNP) plasma concentrations, at Weeks 6 and 12;
• Safety (adverse events, clinical laboratory parameters, electrocardiogram (ECG) findings, physical examination, vital signs); and
• BPS/314d plasma concentrations, at Week 12.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion and exclusion criteria are to be assessed at Screening and Baseline prior to starting study drug. Each patient must meet the following criteria to be enrolled in this study:
1. IRB approved Written informed consent has been obtained.
2. Male or female, age 18 to 75 years (inclusive).
3. Established diagnosis of pulmonary arterial hypertension as either idiopathic or familial PAH, collagen vascular disease associated PAH, PAH induced by anorexigens or PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥ 5 years).
4. Clinically stable PAH as determined by the Investigator.
5. Able to walk unassisted.
6. Has a complete, unencouraged 6MWT distance of 150 to 450 meters (inclusive) at screening.
7. Previous (at any time) right heart cardiac catheterization with findings consistent with PAH, specifically mean Pulmonary Arterial Pressure (PAPm) ≥25 mmHg (at rest), Pulmonary Capillary Wedge Pressure (PCWP) (or left ventricular end diastolic pressure) ≤15 mmHg, and Pulmonary Vascular Resistance (PVR) >3 mmHg/L/min.
8. Previous (at any time) chest radiograph consistent with the diagnosis of PAH.
9. Has been on a stable course of an ERA or PDE-5 inhibitor or both for a minimum of 60-days prior to Baseline.
10. Women of child-bearing potential (defined as less than 1 year post-menopausal or not surgically sterile) must be using an acceptable method of birth control or practicing abstinence. If sexually active, female patients must use a double barrier method of birth control, such as a condom and spermicidal. Patient must have a negative pregnancy test at the Screening and Baseline visits;
11. Willing and able to comply with study requirements and restrictions.
|
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from the study.
1. Has pulmonary venous hypertension, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, or chronic thromboembolic pulmonary hypertension;
2. Has a history of interstitial lung disease, unless:
• Pulmonary Function Testing conducted within 6 months of the Baseline visit demonstrates a Total Lung Capacity ≥ 70% of predicted.
3. Has a history of obstructive lung disease, unless:
• Pulmonary Function Testing conducted within 6 months of the Baseline visit demonstrates a forced expiratory volume in 1 second/forced vital capacity (FEV1 / FVC) ratio of ≥ 50%.
4. Is pregnant and or lactating.
5. Changed or discontinued any PAH medication within 60 days prior to the Baseline visit including, but not limited to, an ERA, PDE-5 inhibitor or calcium channel blockers (with the exception of anticoagulants)
6. Has an ongoing hemorrhagic condition (e.g. upper digestive tract hemorrhage, hemoptysis, etc), or has a pre-existing condition that, in the Investigator’s judgment may increase the risk for developing hemorrhage during the study (e.g. hemophilia). Transient hemorrhage (e.g. epistaxis, normal menstrual bleeding, gingival bleeding, hemorrhoidal hemorrhage, etc.) will not preclude enrollment.
7. Has donated blood or plasma, or has lost a volume of blood >450mL within 6-weeks of the Baseline visit.
8. Has received any investigational medication, device or therapy within 30 days prior to the Baseline visit or be scheduled to receive another investigational drug, device or therapy during the course of the study.
9. Has received any prostanoid therapy at any time.
10. Has any preexisting disease known to cause pulmonary hypertension other than collagen vascular disease.
11. Has any musculoskeletal disease or any other disease that would limit ambulation.
12. Has any form of unrepaired or recently repaired (< 5 years) congenital systemic-to-pulmonary shunt other than patent foramen ovale.
13. History of pulmonary embolism or deep venous thrombosis.
14. History of ischemic heart disease, including previous myocardial infarction, or symptomatic coronary artery disease, or history of left sided myocardial disease as evidenced by a mean PCWP (or a left ventricular end diastolic pressure) > 15mmHg or left ventricular ejection fraction < 40% as assessed by either multigated angiogram, angiography or echocardiography, or left ventricular shortening fraction < 22% as assessed by echocardiography. Note that patients in whom abnormal left ventricular function is attributed entirely to impaired left ventricular filling due to the effects of right ventricular overload (i.e. right ventricular hypertrophy and / or dialatation) will be excluded.
15. Presence of atrial fibrillation (determined from 12-lead ECG at screening).
16. Any other clinically significant illness that, in the opinion of the Investigator, might put the patient at risk of harm durin the study or might adversely affect the interpretation of the study data. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The Primary efficacy endpoint is the change from Baseline in hemodynamic parameters at week 12 of the study and will be based on the RHC measures including mean pulmonary arterial pressure, cardiac index, pulmonary vascular resistance and pulmonary vascular resistance index. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 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.8.3 |
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 | 13 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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