A Study of Macitentan in Japanese Pediatric Participants With Pulmonary Arterial Hypertension

Janssen Pharmaceutical K.K.7 enrolled

Overview

The purpose of this study is to evaluate the effect of macitentan on hemodynamic measures at Week 24 in pediatric populations.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pulmonary Arterial Hypertension

Interventions

MacitentanDRUG

Macitentan will be administered orally as a tablet.

Eligibility

Sex: ALLMin age: 3 MonthsMax age: 15 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Pulmonary arterial hypertension (PAH) belonging to the nice 2013 updated classification group 1 * PAH diagnosis confirmed by historical right heart catheterization where in the absence of pulmonary vein obstruction and/or significant lung disease pulmonary artery wedge pressure (PAWP) can be replaced by left atrium pressure (LAP) or left ventricular end diastolic pressure (LVEDP) (in absence of mitral stenosis) assessed by heart catheterization * World Health Organization (WHO) functional class (FC) I to IV * PAH-specific treatment-naïve participants or participants on PAH-specific treatment * A female of childbearing potential must have a negative highly sensitive serum beta-human chorionic gonadotropin (beta-hCG) test at screening and a negative urine pregnancy test at the first administration of study intervention * A female participant must not get pregnant and must agree not to donate eggs during the study and for a period of up to 4 weeks following the end of study Exclusion Criteria: * Participants with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn * Participants with the following diseases: pulmonary vein stenosis; bronchopulmonary dysplasia * Severe hepatic impairment, example, Child-Pugh Class C, at screening * Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 4 weeks after the last dose of study intervention * Known allergies, hypersensitivity, or intolerance to macitentan or its excipients * Participant with PAH associated with open shunts, with congenital cardiac abnormalities such as univentricular heart, with pulmonary hypertension due to lung disease, and renal dysfunction

Locations (11)

Nagano Children's Hospital

Azumino-shi, Japan

Institute of Science Tokyo Hospital

Bunkyō City, Japan

Fukuoka Children's Hospital

Fukuoka, Japan

Outcomes

Primary Outcomes

Fold Change From Baseline at Week 24 in Pulmonary Vascular Resistance Index (PVRI)

PVRI fold change at Week 24 was calculated as 100\*(PVRI at Week 24 divided by PVRI at baseline). PVR was determined by right heart catheterization.

Time frame: Baseline (Day 1), Week 24

Change From Baseline in Hematology Parameter: Neutrophils Band Form (NBF)

Change from baseline in hematology parameters: NBF was reported. Data for each parameters was planned to be reported at specified timepoints only.

Time frame: Baseline (Day 1), Weeks 8, 16, 20, 40, 52

Secondary Outcomes

Change From Baseline to Week 24 in Hemodynamic Variable: Pulmonary Vascular Resistance (PVR)

Change from baseline to Week 24 in hemodynamic variable: PVR was reported. PVR is calculated as: PVR= (Mean pulmonary artery pressure \[mPAP\]-Pulmonary artery wedge pressure \[PAWP)/ Cardiac output \[CO\].

Time frame: Baseline (Day 1), Week 24

Change From Baseline to Week 24 in Hemodynamic Variable: Mean Right Atrial Pressure (mRAP)

Change from baseline to Week 24 in hemodynamic variable: mRAP was reported.

Time frame: Baseline (Day 1), Week 24

Change From Baseline to Week 24 in Hemodynamic Variable: Mean Pulmonary Arterial Pressure (mPAP)

Change from baseline to Week 24 in hemodynamic variable: mPAP was reported. mPAP is calculated as: 2\*diastolic pulmonary arterial pressure (dPAP) + systolic pulmonary arterial pressure (sPAP)/3.

Time frame: Baseline (Day 1), Week 24

Change From Baseline to Week 24 in Hemodynamic Variable: Cardiac Index (CI)

Change from baseline to Week 24 in hemodynamic variable: CI was reported. CI was calculated as: CO/Body surface area (BSA).

Data from ClinicalTrials.gov

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Okayama University Hospital

Toho University Medical Center Omori Hospital

Ōta-ku, Japan

Hokkaido University Hospital

Sapporo, Japan

National Center for Child Health and Development

Setagaya Ku, Japan

Tokyo Women's Medical University Hospital

Shinjuku-ku, Japan

National Cerebral and Cardiovascular Center

Suita-Shi, Japan

Osaka University Hospital

Suita-shi, Japan

...and 1 more locations

Time frame: Baseline (Day 1), Week 24

Change From Baseline to Week 24 in Hemodynamic Variable: Cardiac Output (CO)

Change from baseline to Week 24 in hemodynamic variable: CO was reported.

Time frame: Baseline (Day 1), Week 24

Change From Baseline to Week 24 in Hemodynamic Variable: Total Pulmonary Resistance (TPR)

Change from baseline to Week 24 in hemodynamic variable: TPR was reported. TPR was calculated as: (mPAP/CO)\*80.

Time frame: Baseline (Day 1), Week 24

Percent Change From Baseline to Week 24 in Hemodynamic Variable: Mixed Venous Oxygen Saturation (SvO[2])

Percent change from baseline to Week 24 in hemodynamic variable: SvO(2) was reported.

Time frame: Baseline (Day 1), Week 24

Number of Participants With Change From Baseline at Weeks 4, 8, 12, 16, 20, 24, 28, 40, and 52 in World Health Organization (WHO) Functional Class (FC)

WHO-FC for participants with pulmonary arterial hypertension (PAH) ranges: Class I (no limitation in physical activity, ordinary physical activity did not cause undue dyspnea or fatigue, chest pain or near syncope), Class II (slight limitation of physical activity, comfortable at rest, ordinary physical activity caused undue dyspnea or fatigue, chest pain, or near syncope), Class III (marked limitation of physical activity, comfortable at rest, less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope) and Class IV (cannot perform a physical activity without any symptoms, signs of right heart failure, dyspnea and/or fatigue may be present even at rest, discomfort is increased by any physical activity). Participants who improve in WHO FC are reported below. Improvement was defined as reduction in FC.

Time frame: Weeks 4, 8, 12, 16, 20, 24, 28, 40, and 52

Number of Participants With Change From Baseline at Weeks 4, 8, 12, 16, 20, 24, 28, 40, and 52 in Panama Functional Class (FC)

Panama FC for PAH ranges: Class I (asymptomatic, growing normally, attending nursery/school regularly, no limitation of physical activity, playing sports with his/her classmates), Class II (slight limitation of physical activity, unduly dyspnoeic and fatigued when playing with his/her classmates, comfortable at rest, grow along own centiles, nursery/school attendance 75% normal, no chest pain), Class IIIa (marked limitation of physical activity, no attempt at sports, comfortable at rest, less than ordinary activity (example: dressing) causes undue dyspnea, fatigue, syncope and/or presyncope or chest pain, nursery/schooling compromised \<50% normal attendance), Class IIIb (growth compromised, poor appetite, supplemental feeding, same as class IIIa) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Participants who improve in Panama FC are reported below. Improvement was defined as reduction in Panama FC.

Time frame: Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52

Change From Baseline to Weeks 24 and 52 in 6-minute Walk Distance (6MWD) as Measured by the 6-minute Walk Test (6MWT)

Change from baseline to Weeks 24 and 52 in 6MWD as measured by 6MWT was reported. 6MWD was the distance that a participant could walk in 6 minutes. Rest periods were allowed if the participant could no longer continue. If the participant need to rest, he/she may pause, lean against the wall and continue walking whenever he/she feels able. The timer continued to run even if the participant stopped to rest.

Time frame: Baseline (Day 1), Weeks 24 and 52

Change From Baseline to Weeks 12, 24, 28, 40, and 52 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

Change from baseline to Weeks 12, 24, 28, 40, and 52 in NT-proBNP was reported.

Time frame: Baseline (Day 1), Week 12, 24, 28, 40, and 52

Change From Baseline to Weeks 12, 24, and 52 in Tricuspid Annular Plane Systolic Excursion (TAPSE)

Change from baseline to Weeks 12, 24, and 52 in TAPSE was reported. It was calculated as: original TAPSE value/body surface area (BSA). TAPSE was a dimension used to evaluate Right Ventricle (RV) longitudinal systolic function; it measured the extent of systolic motion of the lateral portion of the tricuspid ring towards the apex.

Time frame: Baseline (Day 1), Weeks 12, 24, and 52

Change From Baseline to Week 12, 24, and 52 in Left Ventricular Eccentricity Index (LVEI)

Change from baseline to Weeks 12, 24, and 52 in LVEI was reported. It included diastolic (D) LVEI and systolic (S) LVEI. Left ventricular (LV) internal diameters were measured using the parasternal short axis view at the level of the papillary muscles: D1: LV internal diameter perpendicular to interventricular septum at end-diastole; D2: LV internal diameter parallel to interventricular septum, and at right angle from D1, at end-diastole; S1: LV internal diameter perpendicular to interventricular septum at end-systole; S2: LV internal diameter parallel to interventricular septum, and at a right angle from S1, at end-systole. The LVEI was a ratio that was calculated by sponsor as: LVEI diastole = D2/D1; LVEI systole = S2/S1.

Time frame: Baseline (Day 1), Weeks 12, 24 and 52

Change From Baseline to Week 12, 24, and 52 in Quality of Life (QoL) as Assessed by Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales Short Form (SF-15)

Change from baseline to Weeks 12, 24, and 52 in QoL as assessed by PedsQL 4.0 generic core scales SF-15 was reported. The PedsQL 4.0 questionnaire generic core scales score SF-15 assessed general physical, emotional, social and school functioning on a 5-point Likert scale from 0 to 4 with 0= if it is never a problem, 1= if it is almost never a problem, 2= if it is sometime a problem, 3= if it is often a problem, 4 if it is almost always a problem. Scores were transformed on a scale from 0 to 100. Higher scores indicated better health related QoL. The QoL questionnaire was completed by parent(s)/caregiver(s) and by participants.

Time frame: Baseline (Day 1), Weeks 12, 24, and 52

Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Number of Hours of Daytime Activity

Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: number of hours of daytime activity was reported.

Time frame: Baseline (Day 1), Weeks 12, 24, and 52

Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Mean Count Per Minute of Daily Activity

Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: mean count per minute of daily activity was reported.

Time frame: Baseline (Day 1), Weeks 12, 24, and 52

Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Mean Daily Time Spent in Light Physical Activity

Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: mean daily time spent in light physical activity was reported.

Time frame: Baseline (Day 1), Weeks 12, 24, and 52

Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Mean Daily Time Spent in Moderate to Vigorous Physical Activity

Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: mean daily time spent in moderate to vigorous physical activity was reported.

Time frame: Baseline (Day 1), Weeks 12, 24, and 52

Change From Baseline to Week 24 and Week 52 in Borg Dyspnea Index (BDI)

Change from baseline to Weeks 24 and 52 in BDI was reported. BDI was a 10-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores ranged from 0 (no shortness of breath) to 10 (worst shortness of breath you have ever had). Higher score indicated worse outcome.

Time frame: Baseline (Day 1), Weeks 24 and 52

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Number of participants with TEAEs was reported. An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs are defined as any AE occurring at or after the initial administration of study intervention through the day of last dose plus 30 days.

Time frame: From Baseline (Day 1) up to Week 56

Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)

Number of participants with TESAEs was reported. An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TESAEs are defined as any SAE occurring at or after the initial administration of study intervention through the day of last dose plus 30 days.

Time frame: From Baseline (Day 1) up to Week 56

Number of Participants With AEs Leading to Premature Discontinuation of Study Drug

Number of participants with AEs leading to premature discontinuation of study drug was reported. An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention.

Time frame: From Baseline (Day 1) up to Week 52

Number of Participants With TEAEs of Special Interest

Number of participants with TEAEs of special interest was reported. It included anemia/decreased hemoglobin level, oedema/fluid retention, hepatic impairment and hypotension. TEAEs are defined as any AE occurring at or after the initial administration of study intervention through the day of last dose plus 30 days.

Time frame: From Baseline (Day 1) up to Week 56

Number of Participants With Postbaseline Markedly Abnormal Hematology Laboratory Values

Number of participants with postbaseline markedly abnormal hematology laboratory values was reported. It included Hematocrit:\<0.28% of blood cells (\<0.32M\[%\]), Hemoglobin: \< 100 grams per liter (g/L), Leukocytes: \<3.0 10\^9 cells per Liter (L), and Leukocytes: \<3.0 10\^9 cells/L. Abnormality was judged at the discretion of investigator. Data is reported for categories where at least one participant had abnormality.

Time frame: Weeks 20, 40, 52

Number of Participants With Postbaseline Markedly Abnormal Clinical Chemistry Laboratory Values: Potassium and Calcium

Number of participants with postbaseline markedly abnormal clinical chemistry laboratory values was reported. It included Potassium: \>6.0 millimoles per liter (mmol/L) and Calcium: \<1.75 mmol/L. Abnormality was judged at the discretion of investigator. Data is reported for categories where at least one participant had abnormality.

Time frame: Week 4

Number of Participants With Postbaseline Markedly Abnormal Clinical Chemistry Laboratory Values: Alkaline Phosphatase (ALP)

Number of participants with postbaseline markedly abnormal clinical chemistry laboratory values (ALP) was reported. It included Alkaline Phosphatase (ALP): \> 2.5 \* Upper Limit of Normal (ULN). Abnormality was judged at the discretion of investigator. Participants were assessed at Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52. Data is reported for categories where at least one participant had abnormality at any time point: Weeks 20, 40, and 52 reported.

Time frame: Week 28

Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Lymphocytes, Monocytes, Eosinophils, and Basophils

Change from baseline in hematology parameters: platelets, leukocytes, lymphocytes, monocytes, eosinophils, and basophils was reported. Data for each parameters was planned to be reported at specified timepoints only.