Clinical Trials Register

Summary
EudraCT Number:	2022-002754-74
Sponsor's Protocol Code Number:	67896062PAH1013
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-11-15
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2022-002754-74

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

67896062PAH1013

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/012/2023

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ACTELION Pharmacteuticals Ltd.
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Actelion Pharmaceuticals Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen-Cilag International NV
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CM
B.5.3.4	Country	Netherlands
B.5.6	E-mail	ClinicalTrialsEU@its.jnj.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/909
D.3 Description of the IMP
D.3.1	Product name	Macitentan
D.3.2	Product code	JNJ-67896062/ACT-064922
D.3.4	Pharmaceutical form	Dispersible tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Macitentan
D.3.9.1	CAS number	441798-33-0
D.3.9.2	Current sponsor code	JNJ-67896062-AAA
D.3.9.3	Other descriptive name	ACT-064992
D.3.9.4	EV Substance Code	SUB89247
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/909
D.3 Description of the IMP
D.3.1	Product name	Macitentan
D.3.2	Product code	JNJ-67896062/ACT-064922
D.3.4	Pharmaceutical form	Dispersible tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Macitentan
D.3.9.1	CAS number	441798-33-0
D.3.9.2	Current sponsor code	JNJ-67896062-AAA
D.3.9.3	Other descriptive name	ACT-064992
D.3.9.4	EV Substance Code	SUB89247
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pulmonary Arterial Hypertension

E.1.1.1

Medical condition in easily understood language

Pulmonary Arterial Hypertension is a condition in which the pressure in the blood vessels going to the lungs (the pulmonary arteries) is higher than normal

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

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	10064911
E.1.2	Term	Pulmonary arterial 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

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

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

E.3

Principal 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.

E.4

Principal 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.

E.5 End points

E.5.1

Primary end point(s)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 4

E.5.2

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).

E.5.2.1

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability; Palatability and Acceptability (exploratory) - Efficacy is exploratory

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetics, and safety and tolerability of macitentan

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Participants aged 1 month to <2 years

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

For participants who cannot access study intervention at the end of the Treatment Extension period, a continued access program will be put in place (eg, post-trial access [PTA], long-term extension study [LTE]) to allow study intervention continuation, if assessed beneficial by the investigator and within local regulations.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-01-04

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-03-06

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials