Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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Pulmonary arterial hypertension (PAH) is a rare, progressive, and life-threatening disease. In many patients, the course of PAH is a steady deterioration and reduced life expectancy. Sildenafil was approved by the European Commission for the treatment of PAH in pediatric patients in May 2011, making it the first agent to be approved for the treatment of children with PAH. The approval was based on the largest placebo-controlled study to be conducted in this population. The recommended dose in pediatric patients aged 1 year to 17 years old is 10 mg TID in patients ≤ 20 kg and 20 mg TID for patients > 20 kg. Higher doses are not recommended in pediatrics patients. This study is an open-label, multi-center study to investigate safety, efficacy and pharmacokinetics of sildenafil citrate in Japanese pediatric patients with PAH.

Official Title
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A Phase 3, Multi-center, Open-label Study To Investigate Safety, Efficacy, And Tolerability Of Sildenafil Citrate In Pediatric Patients With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension, Hypertension, Pulmonary

Intervention / Treatment
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* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects weighing ≥8 kg. Subjects who have symptomatic pulmonary arterial hypertension due to one of the following conditions: Idiopathic pulmonary arterial hypertension; or Heritable pulmonary arterial hypertension; or Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts. If the defect(s) is repaired, the subject's condition should be stabilized hemodynamically; or Pulmonary arterial hypertension associated with d-transposition of the great arteries repaired within the first 30 days of life; or Pulmonary arterial hypertension in subjects who have undergone surgical repair of other congenital heart lesions and the condition should be stabilized hemodynamically and do not have clinically significant residual left-sided heart disease. Subjects with a mean pulmonary artery pressure ≥25 mmHg at rest, PCWP ≤15 mmHg, and PVRI ≥3 Wood units x m2. If PCWP is not available, then mean LA pressure ≤15 mmHg or LVEDP ≤15 mmHg in the absence of left atrial obstruction. Exclusion Criteria: Left-sided heart disease. Subjects with Down syndrome. Subjects with Obstructive Sleep Apnea, regardless of treatment status. Pericardial constriction. Subjects with significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation. Acutely decompensated heart failure within previous 30 days from screening. Subjects who have had an atrial septostomy within previous 6 months of screening. Subjects with hemodynamic instability or hypo- or hypertension at screening. Subjects with a history of stroke, myocardial infarction or life threatening arrhythmia within 6 months of screening. Subjects with moderate to severe restrictive pulmonary disease (Total Lung Capacity or Forced Vital Capacity ≤60% of normal) or history of severe lung disease. Subjects with bronchopulmonary dysplasia (BPD) and other chronic lung diseases. Subjects with history of pulmonary embolism. Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION). Subjects who are known to be HIV positive. Subjects with impairment of renal function (serum creatinine >2.5 × ULN) or hepatic function (ALT and/or AST >3 × ULN; and/or bilirubin ≥2 mg/dL). Hematological abnormalities (e.g., severe anemia, Hgb <10 g/dL, leukopenia, WBC <2500/µL). Subjects with severe hepatic dysfunction (Child-Pugh classification C). Change in class of medication for CHF or PAH within the 10 days prior to qualifying right heart catheterization. Subjects who are currently prescribed and/or taking nitrates or nitric oxide donors in any form. Subjects taking chronic arginine supplementation. Subjects who have received parenteral inotropic medication or parenteral vasodilators within 30 days of Day 1. Subjects who are receiving alpha-blockers, nicorandil, amiodarone or potent cytochrome P450 3A4 inhibitors. Subjects receiving chronic treatment with off-label sildenafil within 30 days of Day 1 are excluded. Subjects receiving an endothelin antagonist，PED5 inhibitor or, prostacyclin/prostacyclin analogue within 30 days of randomization are excluded except for beraprost. Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 28 days after last dose of investigational product. Current or past illicit drug use or alcoholism excepting if abstinence can be documented for ≥1 year. Participation in another clinical trial of an investigational drug or device (including placebo) within 30 days of screening for entry into the present study. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil<br> | Drug: Sildenafil<br>* Body weight > 20 kg: 20 mg TID (60 mg/day) Body weight ≤ 20 kg: 10 mg TID (30 mg/day) Treatment duration: 16 weeks in Part 1, until until sildenafil obtained marketing approval in Part 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16 | 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). | Baseline, Week 16 | 
| Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16 | It was a hemodynamic parameter and measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position. | Baseline, Week 16 | 
| Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | 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. | Baseline, Week 4 | 
| Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8 | 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. | Baseline, Week 8 | 
| Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 16 | 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. | Baseline, Week 16 | 
| Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16 | BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation. | Baseline, Week 16 | 
| Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16 | 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. | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Weeks 28, 40, 52, 64, 76, 88, 100, 112 and 124 | 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. | Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | 
| Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT) | BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation. | Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks) | 
| Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 52 and End of Treatment (EOT) | 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. | Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks) | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks) | 
| Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks) | 
| Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | 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. | Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | 
| Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Only those categories in which at least 1 participant had data were reported. | Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | 
| Number of Participants With Laboratory Abnormalities | 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]. | Baseline up-to End of treatment (maximum duration of treatment: 119.6 weeks) | 
| Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | 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. | Screening, Week 16, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks) | 
| Number of Participants With Ocular Examination Abnormalities | 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. | Screening up to end of treatment (maximum duration of treatment: 119.6 weeks) | 
| Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16 |  | Baseline, Week 16 | 
| Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16 |  | Baseline, Week 16 | 
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 | 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). | Baseline, Week 16 | 
| Change From Baseline in Right Atrial Pressure (RAP) at Week 16 | 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. | Baseline, Week 16 | 
| Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 | PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure. | Baseline, Week 16 | 
| Change From Baseline in Cardiac Output (CO) at Week 16 | Cardiac output is simply the amount of blood pumped by the heart per minute. | Baseline, Week 16 | 
| Change From Baseline in Cardiac Index (CI) at Week 16 | 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. | Baseline, Week 16 | 
| Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 | 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). | Baseline, Week 16 | 
| Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16 | 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). | Baseline, Week 16 | 
| Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16 | 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. | Baseline, Week 16 | 
| Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16 | 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. | Baseline, Week 16 |