A multicenter, open-label, randomized study with single-arm extension period to assess the pharmacokinetics, safety and efficacy of macitentan versus standard of care in children with pulmonary arterial hypertension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Actelion Pharmaceuticals Ltd.

Participant type

Pediatric, Patients, Healthy volunteers

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

2 Oct 2017 → 27 Nov 2025

Decision date (initial)

2024-08-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Actelion Pharmaceuticals Ltd. (a Janssen Pharmaceutical company of Johnson & Johnson)"

External identifiers

EU CT number

2023-509845-10-00

EudraCT number

2016-001062-28

ClinicalTrials.gov

NCT02932410

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

To assess the pharmacokinetics, safety and efficacy of macitentan versus standard of care in children with pulmonary arterial hypertension

Secondary objectives 1

1. To assess safety and tolerability of macitentan in children with PAH. To assess efficacy of macitentan in children with PAH.

Conditions and MedDRA coding

Pediatric pulmonary arterial hypertension

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-001032-PIP01-10

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. " 1. Signed informed consent by the parent(s) or legally designated representative AND assent from developmentally capable children prior to initiation of any study-mandated procedure. 2. Criterion modified per Amendment 8 Version 9: Males or females between ≥ 1 month and < 18years of age. 3. Criterion modified per Amendment 8 Version 9: Subjects with body weight ≥ 3.5 kg at randomization. 4. Criterion modified per Amendment 6: PAH diagnosis confirmed by historical RHC (mPAP ≥ 25 mm Hg, and PAWP ≤ 15 mm Hg, and PVRi > 3 WU x m2), where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced by LAP or LVEDP (in absence of mitral stenosis) assessed by heart catheterization. 5. PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects with Down Syndrome) and of following etiologies: iPAH hPAH PAH associated with CHD: − PAH with co-incidental CHD (confirmed by BCAC) − Post-operative PAH (persisting/recurring/developing ≥ 6 months after repair of CHD) Drug or toxin-induced PAH PAH associated with HIV PAH-aCTD 6. WHO FC I to III. 7. PAH-specific treatment-naïve subjects or subjects on PAH-specific treatment (mono-therapy or combination of two therapies)*. 8. Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to EOS . "

Exclusion criteria 1

1. "Etiology 1. Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn. 2. Subjects with PAH associated with open shunts, as specified below: a. Eisenmenger syndrome b. Moderate to large left-to-right shunts. 3. Subjects with the following congenital cardiac abnormalities: a. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, pulmonary atresia with ventricular septal defect, unless operatively repaired and with no residual shunt b. Univentricular heart and/or subjects with Fontan-palliation. 4. Subjects with pulmonary hypertension due to lung disease (e.g., bronchopulmonary dysplasia). 5. Criterion added per Amendment 8 Version 9: Subjects with known diagnosis of bronchopulmonary dysplasia. Treatment and intervention 6. Subjects receiving a combination of > 2 PAH-specific treatments at randomization. 7. Treatment with IV or SC prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing. 8. Criterion added per Amendment 8 Version 9: In children ≥ 2 y.o.: Previous treatment with macitentan at any time. 9. Treatment with another investigational drug within 4 weeks prior to randomization. 10. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH. 11. Treatment with strong inducers of CYP3A4 such as rifabutin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s wort (hypericum perforatum), within 4 weeks prior to randomization. 12. Systemic treatment with strong inhibitors of CYP3A4 such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole within 4 weeks prior to randomization. 13. Criterion modified per Amendment 3.1 Version 4.1: Systemic treatment with moderate dual CYP3A4/ CYP2C9 inhibitor (e.g., fluconazole and amiodarone), or administration of a combination of a moderate CYP3A4 (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a moderate CYP2C9 inhibitor (e.g., miconazole, piperine) within 4 weeks prior to randomization Baseline abnormalities 14. Subjects with pulmonary vein stenosis. 15. Known concomitant life-threatening disease with a life expectancy < 12 months. 16. Hemoglobin or hematocrit < 75% of the lower limit of normal range (LLN). 17. Serum AST and/or ALT > 3 ×ULN. 18. Criterion modified per Amendment 6 Version 7: Severe hepatic impairment, e.g., Child-Pugh Class C [see Appendix 1]. 19. Clinical signs of hypotension which in the investigator’s judgment would preclude initiation of a PAH-specific therapy. 20. Criterion added per Amendment 6 Version 7: Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 µmol/L) Pregnancy and breastfeeding 21. Pregnancy (including family planning) or breastfeeding. Other categories 22. Known hypersensitivity to ERAs, or any of the excipients. 23. Drug or substance abuse, or any condition that, in the opinion of the investigator, may prevent compliance with the protocol or adherence to study treatment. "

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. "In subjects ≥ 2 years of age in the macitentan arm: • Trough (pre-dose) plasma concentrations of macitentan and its active metabolite(ACT-132 577) at Week 12 (steady-state) "
2. "In subjects less than 2 years of age on macitentan: • Trough concentrations of macitentan and its active metabolite (ACT132577) at Week 4 (steady-state)"

Secondary endpoints 4

1. "The secondary endpoints are listed below: • Time to first CEC-confirmed hospitalization for PAH occurring between randomization/Visit 2 and end of core period (EOCP). • Time to CEC-confirmed death due to PAH occurring between randomization/Visit 2 and end of core period (EOCP)."
2. • Time to death (all causes) occurring between randomization/Visit 2 and Study Closure.
3. "Following secondary endpoints are analyzed up to end of randomized macitentan or SoC + 7 days. Baseline is the last non-missing value observed before or on the day of randomization/ Visit 2 • WHO FC status (I or II vs III or IV) at Week 24. • Percent of Baseline plasma NT-proBNP at Week 24. • Change from Baseline to Week 48 in in mean daily time spent in moderate to vigorous physical activity as measured by accelerometry."
4. "• Change from Baseline to Week 24 in tricuspid annular plane systolic excursion (TAPSE), and left ventricular eccentricity index measured by echocardiography (centrally assessed). • Change from Baseline to Week 24 in Quality of Life as measured by the PedsQLTM 4.0 Generic Core Scales Short Form (SF15)1. "

Investigational products

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

Test 2

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 13

Locations

4 EU/EEA countries · 9 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 99 files

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

Application history

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