Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

PVRI equals pulmonary vascular resistance (PVR) times body surface area (BSA) (PVRI = PVR*BSA). PVR is the resistance to blood flow through the pulmonary circulation and it was measured in Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5).

It was a hemodynamic parameter and measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.

WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of participants in each functional class were reported.

WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of participants in each functional class were reported.

WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of participants in each functional class were reported.

BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation.

NT pro-BNP is a cardiac marker, having the prognostic value for participants with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage.

WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of participants in each functional class were reported.

BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation.

NT pro-BNP is a cardiac marker, having the prognostic value for participants with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage.

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was 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. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-serious AEs.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was 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. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-serious AEs.

BP measurement is recorded as supine and sitting systolic and diastolic systemic blood pressure: 1) Systolic blood pressure when heart is contracting and it is the maximum arterial pressure during contraction of left ventricle. 2) Diastolic BP when heart is relaxing and it is the minimum arterial pressure during relaxation and dilation of ventricles. Only those categories in which at least 1 participant had data were reported.

Only those categories in which at least 1 participant had data were reported.

Laboratory abnormality criteria: Hematology (hemoglobin, hematocrit, red blood cell count [less than {<}]0.8*lower limit of normal [LLN]; platelets <0.5*LLN, greater than [>]1.75*upper limit of normal [ULN], white blood cells <0.6*LLN, >1.5*ULN; lymphocytes, neutrophils <0.8*LLN, >1.2*ULN, eosinophils, basophils, monocytes >1.2*ULN); liver function (total and direct bilirubin >1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase >3.0*ULN, total protein, albumin <0.8*LLN, >1.2*ULN); renal (creatinine, blood urea nitrogen >1.3*ULN); electrolytes (sodium <0.95*LLN, >1.05*ULN, potassium, chloride <0.9*LLN, >1.1*ULN; other (glucose <0.6*LLN or >1.5*ULN ); urinalysis (dipstick) urine glucose, urine protein, urine blood/Hemoglobin, [greater than or equal to {>=}1].

Criteria for clinically significant abnormality in ECG parameters: Maximum corrected QT interval (QTc) from 450 millisecond (msec) to less than (<) 480 msec, Maximum QTcB interval (Bazett's Correction) from 450 msec to <480 msec, Maximum QTcF interval (Fredericia's Correction) from 450 msec to <480 msec, maximum QTc interval increase from baseline of 30 msec to <60 msec and >=60 msec.

Ocular examination measures included external examination of the eye, funduscopy, assessments of visual acuity, and color vision. Ocular examination findings were considered abnormal based on investigator's decision.

The resistance to blood flow through the pulmonary circulation is known as PVR. It is largely influenced by the caliber of the pulmonary arteries and capillaries and was measured in terms of Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5).

RAP is the blood pressure in the right atrium of the heart. It reflects the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system. RAP was measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.

PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure.

Cardiac output is simply the amount of blood pumped by the heart per minute.

Cardiac index is a hemodynamic parameter that relates the cardiac output from left ventricle in one minute to BSA, thus relating heart performance to the size of the individual. CI was calculated as cardiac output in systemic circulation divided by BSA.

The resistance to blood flow through the systemic circulation is known as SVR. This can be used in measuring blood pressure, blood flow and cardiac function and measured in terms of Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5).

SVRI equals systemic vascular resistance (SVR) times BSA. SVR is the resistance to blood flow through the systemic circulation and it was measured in Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5).

SvO2 is the percentage of mixed venous oxygen (amount of oxygen bound to hemoglobin in venous blood). Change from baseline in percentage of mixed venous oxygen was reported in this outcome measure.

SaO2 is the percentage of arterial oxygen (amount of oxygen bound to hemoglobin in arterial blood). Change from baseline in percentage of arterial oxygen was reported in this outcome measure.

UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.

UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.

UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.

Terminal half-life is the time measured for the plasma concentration to decrease by one half of its original concentration. UK-103,320 was a main metabolite of sildenafil and was produced by cytochrome P450 3A4.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Acceleration time and ejection time are quantitative Doppler parameters and ratio of acceleration time to ejection time is a useful tool to evaluate the severity of aortic stenosis.

The right ventricular Tei Index is an index of myocardial performance. It is defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time.

The tricuspid valve lies between the right atrium and the right ventricle and is placed in a more apical position than the mitral valve. The annulus separates the right atrium from the right ventricle. Change from baseline in tricuspid valve annulus size (in cm) was reported in this outcome measure.

Tricuspid regurgitation (insufficiency) is the failure of the tricuspid valve to close properly during systole, leading to the leaking of blood from the right ventricle into the right atrium. Change from baseline in TR-PG peak (in mmHg) was reported in this outcome measure.

Pulmonary regurgitation (PR) or insufficiency is a valvular heart disease characterized by an incomplete closure of the pulmonary valve leading to a diastolic reflux into the right ventricle. Change from baseline in PR-PG end-diastole (in mmHg) was reported in this outcome measure.

Pericardial effusion is the presence of an abnormal amount of fluid in the pericardial cavity, as determined by echocardiography.

Tricuspid annular plane systolic excursion is a parameter depicting global right ventricular function. Change from baseline in TAPSE (in cm) was reported in this outcome measure.