E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Pulmonary hypertension (PH) is a disease associated with abnormally high pressure in the blood vessels of the lungs
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
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 | 10037400 |
E.1.2 | Term | Pulmonary 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 long-term safety of the respective study interventions in treated participants
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of the trial are not applicable
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participant must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that participant understands the purpose of, and procedures required for, the study and is willing to participate in the study. 2.Participant treated with macitentan 10 mg or FDC of macitentan 10 mg and tadalafil 40 mg at the end of a sponsor parent study and: a. The indication of the parent study is included in the protocol b. Participant has completed the parent study c. No alternative means of access to study intervention have been identified d. Participant may continue to benefit from treatment with the study intervention 3. A woman of childbearing potential must: a. have a negative urine or serum pregnancy test prior to first intake of study intervention, b. agree to perform monthly urine pregnancy test up to the end of the safety follow-up period, c. Agree to follow contraceptive methods as defined in the protocol until 30 days after the last intake of the study intervention |
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E.4 | Principal exclusion criteria |
General exclusion criteria 1. Participants prematurely discontinued from their parent study. 2. Female participant being pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study. 3. Planned or current treatment with another investigational treatment. Macitentan exclusion criteria 1. Known allergies, hypersensitivity, or intolerance to macitentan or its excipients (refer to the macitentan IB). 2. Hemoglobin <80 g/L. Participants with hemoglobin <80 g/L at Screening are allowed to enter the study at the discretion of the investigator provided they meet all inclusion criteria. Study treatment is to be initiated as soon as their hemoglobin is ≥80 g/L, assuming it is within the allowed treatment interruption period. 3. Serum aspartate (AST) and/or alanine aminotransferases (ALT) >3 × the upper limit of normal (ULN) range. Participants with AST and/ or ALT >3 × ULN at Screening are allowed to enter the study at the discretion of the investigator, provided they meet all inclusion criteria as long as the liver chemistry abnormality does not meet one of the permanent discontinuation criteria listed for this ISA. Study treatment is to be initiated as soon as their serum AST and/or ALT is ≤3 × ULN, assuming it is within the allowed treatment interruption period. 4. Known and documented severe hepatic impairment ie, Child-Pugh Class C. For participants with hepatic impairment, Child-Pugh Class should be fully assessed and documented in the source documents at Screening. 5. Treatment with a strong cytochrome P450 (CYP)3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir). 6. Treatment with a moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole, amiodarone) or uses a co-administration of a combination of moderate CYP3A4 (eg ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors (eg, miconazole, piperine). If a participant coming from a parent study is currently under such a concomitant treatment, the participant may be enrolled as per the investigator's discretion based on his/her clinical judgement and risk-benefit assessment. 7. Treatment with a strong CYP3A4 inducer (eg, rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John's Wort) within 1 month prior to baseline. 8. Interruption of study intervention for more than 4 weeks since the last dose of study intervention taken in the parent study. Macitentan and Tadalafil exclusion criteria: 1. Known allergies, hypersensitivity, or intolerance to macitentan or tadalafil or their excipients (refer to the macitentan/tadalafil FDC IB). 2. Hemoglobin <80 g/L. Participants with hemoglobin <80 g/L at Enrollment are allowed to enter the study at the discretion of the investigator provided they meet all inclusion criteria. Study treatment is to be initiated as soon as their hemoglobin is ≥80 g/L, assuming it is within the allowed treatment interruption period. 3. Serum aspartate (AST) and/or alanine aminotransferases (ALT) >3 × the upper limit of normal (ULN) range. Participants with serum AST and/ or ALT >3 × ULN at Enrollment are allowed to enter the study at the discretion of the investigator, provided they meet all inclusion criteria, as long as the liver chemistry abnormality does not meet one of the permanent discontinuation criteria listed for this ISA. Study treatment is to be initiated as soon as their serum AST and/or ALT is ≤3 × ULN, assuming it is within the allowed treatment interruption period. 4. Known and documented severe hepatic impairment ie, Child-Pugh Class C. 5. Severe renal impairment (estimated glomerular filtration rate (eGFR)/creatinine clearance <30 mL/min). 6. Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy, regardless of whether or not this episode was in connection with phosphodiesterase type 5 inhibitor treatment. 7. Treatment with a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir). 8. Treatment with a moderate dual CYP3A4/CYP2C9 inhibitor or uses a co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors. 9. Treatment with a strong CYP3A4 inducer within 1 month prior to baseline. 10. Treatment with doxazosin. 11. Treatment with any form of organic nitrate, either regularly or intermittently. 12. Treatment with an ERA, phosphodiesterase type 5 inhibitor, or soluble guanylate cyclase stimulator. 13. Interruption of study intervention for more than 4 weeks since the last dose of study intervention taken in the parent study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Frequency of treatment-emergent adverse events (AEs), treatment-emergent AEs leading to discontinuation, serious adverse events (SAEs), and/or deaths |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
from baseline until End-of-Study (EOS) |
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E.5.2 | Secondary end point(s) |
Secondary endpoints not applicable.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints not applicable. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
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) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
South Africa |
Turkey |
Belarus |
Belgium |
Bulgaria |
China |
India |
Korea, Republic of |
Poland |
Romania |
Russian Federation |
Taiwan |
Ukraine |
France |
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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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The End of Study is considered as the last scheduled study End of Trial or safety follow-up (EOS) visit, whichever comes last for the last participant in the study. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |