| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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
|
|
| 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 |
|
| 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
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of the trial are not applicable
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Macitentan:
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. In case of enrollment of participants
below 18 years old, parent(s) (preferably both if available or as per local
requirements) must sign the ICF. Assent is also required of children
capable of understanding the nature of the study (typically 7 years of
age and older) as described in Informed Consent Process
2.Participant treated with oral macitentan at the end of a sponsor
parent study and:
a) The indication of the parent study is included in this ISA (PAH or
CTEPH for adults, PAH for pediatric participants)
b) Participant has completed the parent study
c) No alternative means of access to study intervention (or equivalent
approved therapy) have been
identified
d) Participant may continue to benefit from treatment with the study
intervention
e. Pediatric participant is at least 2 years old
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 this ISA
(Appendix A.3, Contraceptive and Barrier Guidance) until 30 days after
the last intake of the study intervention.
Fixed Dose Combination of macitentan + tadalafil
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 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 this ISA (ie, PAH)
b. Participant has completed the parent study
c. No alternative means of access to study intervention (or equivalent
approved therapy) 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 this ISA
(Appendix C.3, Contraceptive and Barrier Guidance) until 30 days after
the last intake of the study intervention |
|
| E.4 | Principal exclusion criteria |
General exclusion criteria
1. Participants prematurely discontinued the study intervention in their
parent study (participant's or investigator's decision).
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.
3. Serum aspartate (AST) and/or alanine aminotransferases (ALT) >3 ×(ULN) .
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. Systemic 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. Systemic 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.
9. Treatment with an ERA (other than the study intervention).
Macitentan and Tadalafil exclusion criteria:
1. Known allergies, hypersensitivity, or intolerance to macitentan or
tadalafil or their excipients
2. Hemoglobin
3. Serum aspartate (AST) and/or alanine aminotransferases (ALT) >3 ×
(ULN) range.
4. Known and documented severe hepatic impairment ie, Child-Pugh
Class C.
5. Severe renal impairment (estimated glomerular filtration rate (eGFR)/creatinine clearance
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 (tadalafil).
7. Systemic treatment with a strong CYP3A4 inhibitor (eg, ketoconazole,
itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir,
and saquinavir).
8. Systemic 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
judgment and risk-benefit assessment.
9. Treatment with a strong CYP3A4 inducer (eg, rifabutin, rifampin, rifampicin,
rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) 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.
14. Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive
or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias;
significant left ventricular dysfunction; or left ventricular outflow obstruction, as per
the investigator’s opinion
15. Known permanent atrial fibrillation, as per the investigator's opinion
16. Documented pulmonary veno-occlusive disease (PVOD)
17. Any known factor or disease that may interfere with the participant’s safety per the
investigator’s judgment
|
|
| 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from baseline until End-of-Study (EOS) |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints not applicable.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints not applicable. |
|
| 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 |
|
| 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 |
| Ukraine |
| Taiwan |
| Belarus |
| China |
| India |
| Korea, Republic of |
| Russian Federation |
| South Africa |
| Belgium |
| Bulgaria |
| France |
| Poland |
| Romania |
| Türkiye |
|
| 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
|
| 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. |
|
| 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 |
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