A Prospective, Open-label, Platform Study for Long-term Follow-up of Participants Using Study Intervention in Pulmonary Hypertension Parent Studies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Actelion Pharmaceuticals Ltd.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

22 Apr 2022 → ongoing

Decision date (initial)

2024-03-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Actelion Pharmaceuticals Ltd

External identifiers

EU CT number

2023-506791-27-00

EudraCT number

2021-002297-11

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

To evaluate the long-term safety of the respective study interventions in treated participants

Conditions and MedDRA coding

pulmonary arterial hypertension

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000997-PIP01-10

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trial/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Macitentan: 1. Participant must sign an informed consent form (ICF) (or their legally designated 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 in Master Protocol Section 10.2: Regulatory, Ethical, and Study Oversight Considerations
2. Macitentan: 2.1. Participant treated with oral macitentan at the end of a sponsor parent study and: a. The indication of the parent study included in this ISA (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 e. Pediatric participant is at least 2 years old
3. Macitentan: A female participant of childbearing potential (as defined in Section 10.7) 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. If heterosexually active, 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.
4. Selexipag: 1.1. Participant must sign an informed consent form (ICF) (or their legally designated representative must sign) indicating that participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
5. Selexipag: 2.1. Participant treated with oral selexipag 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
6. Selexipag: A female participant of childbearing potential (as defined in Section 10.7) 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. If heterosexually active, agree to follow contraceptive methods as defined in this ISA (Appendix B.2, Contraceptive and Barrier Guidance) until 30 days after the last intake of the study intervention.
7. Fixed-dose combination: 1.1. Participant must sign an informed consent form (ICF) (or their legally designated representative must sign) indicating that participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
8. Fixed-dose combination: 2.1. 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
9. Fixed-dose combination: A female participant of childbearing potential (as defined in Section 10.7) 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. If heterosexually active, 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

Exclusion criteria 37

1. Macitentan: 1.1. Participants prematurely discontinued the study intervention in their parent study (participant’s or investigator’s decision).
2. Macitentan: 7.1. 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.
3. Macitentan: Interruption of study intervention for more than 4 weeks since the last dose of study intervention taken in the parent study
4. Macitentan: Treatment with an ERA (other than the study intervention).
5. Selexipag: Known allergies, hypersensitivity, or intolerance to selexipag or its excipients (refer to selexipag IB)
6. Selexipag: Suspected or known pulmonary veno-occlusive disease (PVOD)
7. Selexipag: Uncontrolled thyroid disease
8. Selexipag: Severe coronary heart disease or unstable angina, myocardial infarction within the last 6 months, decompensated cardiac failure (if not under close medical supervision), severe arrhythmia, cerebrovascular events (eg, transient ischemic attack, stroke) within the last 3 months, or congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to PH.
9. Selexipag: Known and documented severe hepatic impairment ie, Child-Pugh Class C. For participants with hepatic impairment, Child-Pugh Class (Child-Pugh Score, Section 10.6) should be fully assessed and documented in the source documents at Screening
10. Selexipag: Any disallowed therapy as noted in Section “Concomitant Therapy”: • treatment with a strong CYP2C8 inhibitor (eg, gemfibrozil) • treatment with oral prostacyclin analogs (eg, beraprost, treprostinil) since the last dose of study intervention taken in the parent study • any investigational treatment other than selexipag
11. Selexipag: Renal impairment: End-stage renal impairment (estimated glomerular filtration rate [eGFR] by Modification of Diet in Renal Disease [MDRD] formula or planned dialysis.
12. Macitentan: Female participant being pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study.
13. Fixed-dose combination: Known allergies, hypersensitivity, or intolerance to macitentan or tadalafil or their excipients (refer to the macitentan/tadalafil FDC IB).
14. Fixed-dose combination: 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
15. Fixed-dose combination: Serum aspartate (AST) and/or alanine aminotransferases (ALT)>3×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.
16. Fixed-dose combination: Known and documented severe hepatic impairment ie, Child-Pugh Class C. For participants with hepatic impairment, Child-Pugh Class (Child-Pugh Score, Section 10.6) should be fully assessed and documented in the source documents at Screening.
17. Fixed-dose combination: Severe renal impairment (estimated glomerular filtration rate (eGFR)/creatinine clearance <30 mL/min)
18. Fixed-dose combination: 6.1. 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).
19. Fixed-dose combination: 7.1. Systemic treatment with a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir).
20. Fixed-dose combination: 8.1. 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.
21. Fixed-dose combination: Treatment with a strong CYP3A4 inducer (eg, rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) within 1 month prior to baseline.
22. Fixed-dose combination: Treatment with doxazosin
23. Macitentan: Planned or current treatment with another investigational treatment
24. Fixed-dose combination: Treatment with any form of organic nitrate, either regularly or intermittently
25. Fixed-dose combination: Treatment with an ERA, phosphodiesterase type 5 inhibitor, or soluble guanylate cyclase stimulator
26. Fixed-dose combination: Interruption of study intervention for more than 4 weeks since the last dose of study intervention taken in the parent study.
27. Fixed-dose combination: 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.
28. Fixed-dose combination: Known permanent atrial fibrillation, as per the investigator's opinion
29. Fixed-dose combination: Documented pulmonary veno-occlusive disease (PVOD)
30. Fixed-dose combination: Any known factor or disease that may interfere with the participant’s safety per the investigator’s judgment
31. Macitentan: Known allergies, hypersensitivity, or intolerance to macitentan or its excipients (refer to the macitentan IB)
32. Macitentan: 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.
33. Macitentan: Serum aspartate (AST) and/or alanine aminotransferases (ALT)>3×ULN. 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.
34. Macitentan: Known and documented severe hepatic impairment ie, Child-Pugh Class C. For participants with hepatic impairment, Child-Pugh Class (Child-Pugh Score, Section 10.6) should be fully assessed and documented in the source documents at Screening
35. Macitentan: 5.1. Systemic treatment with a strong cytochrome P450 (CYP)3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)
36. Macitentan: 6.1. 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
37. Selexipag-specific exclusion criteria (children only) added per Amendment 3 -Current suspicion of intussusception or ileus or gastrointestinal obstruction, per the investigator’s judgment -Hemoglobin or hematocrit <75% of the lower limit of normal range

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Frequency of treatment-emergent adverse events (AEs), treatment-emergent AEs leading to discontinuation, serious adverse events (SAEs), and/or deaths from baseline until End-of-Study (EOS)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Actelion Pharmaceuticals Ltd.

Sponsor organisation

Actelion Pharmaceuticals Ltd.

Address

Gewerbestrasse 16

City

Allschwil

Postcode

4123

Country

Switzerland

Scientific contact point

Organisation

Actelion Pharmaceuticals Ltd.

Contact name

CTIS Point of Contact

Public contact point

Organisation

Actelion Pharmaceuticals Ltd.

Contact name

CTIS Point of Contact

Third parties 3

Locations

3 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 43 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications