E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Portopulmonary hypertension |
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E.1.1.1 | Medical condition in easily understood language |
Portopulmonary Hypertension is a condition in which the pressure in the blood vessels going to the lungs (the pulmonary arteries) is higher than normal due to an underlying liver disease |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067281 |
E.1.2 | Term | Portopulmonary hypertension |
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 |
To evaluate the effect of macitentan on pulmonary vascular resistance (PVR) as compared to placebo in patients with portopulmonary hypertension |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of macitentan as compared to placebo on cardio-pulmonary hemodynamics, hepatic portal vein pressure, disease severity, and exercise capacity in patients with PoPH.
- To evaluate the safety and tolerability of macitentan as compared to placebo in patients with PoPH
- To evaluate the pharmacokinetics (PK) of macitentan and its active metabolite ACT-132577 in subjects with PoPH
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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 |
PK sub-study
At least 20 patients eligible for the open-label treatment period will be enrolled. The plasma PK parameters will be derived by non-compartmental analysis of the plasma concentration-time profiles.
PK endpoints are for both macitentan and ACT-132577:
- The area under the plasma concentration-time curve during one dosing interval (AUCt).
- Maximum plasma concentration (Cmax) during a dosing interval.
- The time to reach maximum plasma concentration (tmax) during a dosing interval. |
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E.3 | Principal inclusion criteria |
1) Male or female 18 years of age with symptomatic PoPH:
Documented diagnosis of portal hypertension
PAH by right-heart catheterization at screening
- Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg
- Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg
2) Pulmonary vascular resistance (PVR) ≥ 4 Wood Units or ≥ 320 dyn.s.cm-5 at screening
3) 6MWD ≥ 50 m at screening |
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E.4 | Principal exclusion criteria |
1. Severe hepatic impairment, as defined by Child-Pugh Class C liver disease or MELD score ≥ 19
2. Systolic blood pressure (SBP) < 90 mmHg at Screening
3. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3 X the upper limit of the normal range (ULN) at Screening
4. Bilirubin ≥ 3 mg/dL at Screening
5. Grades 2, 3, or 4 hepatic encephalopathy
6. History of liver transplantation or transplantation expected within 3 months after randomization
7. Gastrointestinal bleeding or esophageal varices bleeding < 3 months prior to randomization
8. Treatment with endothelin receptor antagonists (ERA), i.v./s.c. or oral prostanoids within 3 months prior to randomization
9. Treatment with interferon within 3 months prior to randomization
10. Treatment with strong cytochrome P450 (CYP) 3A4 inducers within 4 weeks prior to randomization
11. Treatment with strong CYP3A4 inhibitors within 4 weeks prior to randomization |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint
Relative change from Baseline to Week 12 in PVR.
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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) |
Secondary efficacy endpoints
• Change from Baseline to Week 12 in mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), cardiac index (CI), total pulmonary resistance (TPR), and mixed venous oxygen saturation (SVO2), all measured at rest
• Change from Baseline to Week 12 in 6-minute walk distance (6MWD)
• Change from Baseline to Week 12 in WHO functional class
• Change from Baseline to Week 12 in NT-proBNP
Other efficacy endpoints
• Change from Baseline to Week 12 in hepatic venous pressure gradient (HVPG)
• Change from Baseline to Week 12 in Borg dyspnea index |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), cardiac index (CI), total pulmonary resistance (TPR), and mixed venous oxygen saturation (SVO2), all measured at rest: Screening, Day 1, Week 12
- 6-minute walk distance (6MWD): Screening, Day 1, Week 4/8, Week 12
- WHO functional class: Screening, Day 1, Week 4/8, Week 12
- NT-proBNP: Screening, Day 1, Week 12
-Hepatic venous pressure gradient (HVPG): Screening, Week 12
- Borg dyspnea index: Screening, Day 1, Week 4/8, Week 12 |
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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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Brazil |
Czech Republic |
France |
Germany |
Spain |
United Kingdom |
United States |
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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
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LVLS (Last 30-day Safety follow up) |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |