Macitentan pharmacokinetics (PK) in children below 2 years of age

• Register: EUCTR
• Last refreshed on: 29 April 2024
• Main ID: EUCTR2022-002754-74-PL
• Date of registration: 15/11/2022
• Prospective Registration: Yes
• Primary sponsor: ACTELION Pharmacteuticals Ltd.
• Public title: Macitentan pharmacokinetics (PK) in children below 2 years of age
• Scientific title: A multicenter, open-label, single-arm study to assess the pharmacokinetics and safety of macitentan in children aged 1 month to <2 years with pulmonary arterial hypertension
• Target sample size: 10
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2022-002754-74
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany, Poland

Contacts

• Name: Clinical Registry Group
• Affiliation: Janssen-Cilag International NV

• Name: Clinical Registry Group
• Affiliation: Janssen-Cilag International NV

Key inclusion & exclusion criteria

Inclusion criteria:
Age
1. Pediatric participants aged 1 month to <2 years (at Screening).

Type of Participant and Disease Characteristic
2. Pulmonary arterial hypertension including participants with Down syndrome. Diagnosis must have been confirmed by (historical, any time before screening) right heart catheterization mPAP =25 mmHg, pulmonary arterial wedge pressure (PAWP) =15 mmHg, pulmonary vascular resistance index >3Wood units × m2) where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced left atrium pressure or left ventricular end diastolic pressure (in the absence of mitral stenosis) assessed by heart catheterization.
a. Idiopathic PAH, or
b. Heritable PAH, or
c. PAH associated with congenital heart disease
i. Eisenmenger syndrome (Qp/Qs <1.5 and saturation of peripheral oxygen =90% measured by pulse oximetry at room air), or
ii. Inoperable open left-to-right shunts (with a PVR >8 WU and Qp/Qs <2), or
iii. Co-incidental shunt (ie, not explaining hemodynamically the presence of PAH), or
iv. Post-operative PAH (persisting/recurring/developing =6 months after repair of shunt), or
d. Drug or toxin induced PAH, or
e. PAH associated with HIV.
3. WHO FC I, II, or III.
4. PAH-specific treatment-naive participants or participants on PAH specific monotherapy or combination of 2 therapies. Use of macitentan before or during screening is allowed.

Weight
5. Body weight of =3.5 kg.
Are the trial subjects under 18? yes
Number of subjects for this age range: 10
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Medical Conditions
1. PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis.
2. Persistent pulmonary hypertension of the newborn.
3. 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 participants with Fontan-palliation.
4. Pulmonary hypertension due to lung disease.
5. Known diagnosis of bronchopulmonary dysplasia.
6. Pulmonary vein stenosis.
7. Known concomitant life-threatening disease with life expectancy <12 months.
8. Alanine transaminase and/or AST >3 ×ULN.
9. Severe hepatic impairment, eg, Child-Pugh Class C.
10. Hemoglobin or hematocrit <75% of the lower limit of normal range (for age).
11. Clinical signs of hypotension which in the investigator’s judgment would preclude initiation of a PAH-specific therapy.
12. Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 µmol/L).
13. Known allergies, hypersensitivity, or intolerance to ERAs or macitentan or its excipients.
14. Known hereditary fructose intolerance.

Prior/Concomitant Therapy
15. Triple combination therapy with PAH-specific treatments.
16. Treatment with intravenous or subcutaneous prostanoids within 4 weeks before Visit 2 (Day 1) unless given for vasoreactive testing.
17. Any PAH-related surgical intervention planned, or participants listed for organ transplantation related to PAH.
18. 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 Visit 2 (Day 1).
19. 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 Visit 2 (Day 1).
20. Systemic treatment with moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole and amiodarone), or administration of a combination of a moderate CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a moderate CYP2C9 inhibitor (eg, miconazole, piperine) within 4 weeks prior to Visit 2 (Day 1).
21. Switching PAH treatment from an ERA (eg, bosentan, ambrisentan) to macitentan when a participant’s clinical condition is unstable or undergoing continuous deterioration.

Prior/Concurrent Clinical Study Experience
22. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks prior to Visit 2 (Day 1) or is currently enrolled in an investigational study.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Pulmonary Arterial Hypertension
MedDRA version: 21.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Product Name: Macitentan
Product Code: JNJ-67896062/ACT-064922
Pharmaceutical Form: Dispersible tablet
INN or Proposed INN: Macitentan
CAS Number: 441798-33-0
Current Sponsor code: JNJ-67896062-AAA
Other descriptive name: ACT-064992
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Product Name: Macitentan
Product Code: JNJ-67896062/ACT-064922
Pharmaceutical Form: Dispersible tablet
INN or Proposed INN: Macitentan
CAS Number: 441798-33-0
Current Sponsor code: JNJ-67896062-AAA
Other descriptive name: ACT-064992
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Primary Outcome(s)

Secondary Objective: The Secondary Objectives are:
- To evaluate the safety and tolerability of macitentan in children aged 1 month to <2 years. Overall safety will be assessed.
- To evaluate the PK of macitentan and its active metabolite (aprocitentan) in children aged 1 month to <2 years.

Main Objective: The Primary Objective is to evaluate the pharmacokinetics of macitentan and its active metabolite (aprocitentan) in children aged 1 month to <2 years.

Timepoint(s) of evaluation of this end point: Week 4

Primary end point(s): Primary endpoint is trough concentrations of macitentan and its active metabolite (aprocitentan) at Week 4 (steady-state).

Secondary Outcome(s)

Secondary end point(s): Secondary end points are:
1. Adverse events and serious adverse events.
2. Adverse events leading to premature discontinuation of macitentan.
3. Adverse events of special interest.
4. Marked laboratory abnormalities.
5. Change from baseline in selected laboratory parameters to all scheduled assessment timepoints.
6. Change from baseline in vital signs (blood pressure, heart rate) to all scheduled assessment timepoints.
7. Growth (body weight and length/height) from baseline to all scheduled assessment timepoints.
8. Concentrations of macitentan and its active metabolite (aprocitentan) at 2, 5, and 24 hours after the first dose of macitentan for macitentan naive participants.
9. Trough concentrations of macitentan and its active metabolite (aprocitentan) at Week 8 (steady-state conditions).

Timepoint(s) of evaluation of this end point: 1-7. Throughout the study.
8. 2, 5, and 24 hours after the first dose of macitentan
9. Week 8

Secondary ID(s)

2022-002754-74-DE

67896062PAH1013

Source(s) of Monetary Support

Actelion Pharmaceuticals Ltd