Back to resultsSafety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
Primary Purpose
Pulmonary Arterial Hypertension, Hypertension, Pulmonary
Status
Completed
Phase
Phase 4
Locations
Japan
Study Type
Interventional
Intervention
Sildenafil
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Arterial Hypertension
Eligibility Criteria
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.
Sites / Locations
- Kitasato University Hospital
- Osaka University Hospital
- Toho University Omori Medical Center
- National Center for Child Health and Development
- Shizuoka Children's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Sildenafil
Arm Description
Outcomes
Primary Outcome Measures
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).
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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].
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.
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.
Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16
Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at 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).
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.
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.
Change From Baseline in Cardiac Output (CO) at Week 16
Cardiac output is simply the amount of blood pumped by the heart per minute.
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.
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).
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).
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.
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.
Full Information
NCT ID
NCT01642407
First Posted
June 15, 2012
Last Updated
January 28, 2021
Sponsor
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01642407
Brief Title
Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
Official Title
A Phase 3, Multi-center, Open-label Study To Investigate Safety, Efficacy, And Tolerability Of Sildenafil Citrate In Pediatric Patients With Pulmonary Arterial Hypertension
Study Type
Interventional
2. Study Status
Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
August 24, 2012 (Actual)
Primary Completion Date
May 20, 2016 (Actual)
Study Completion Date
March 12, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension, Hypertension, Pulmonary
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sildenafil
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Sildenafil
Intervention Description
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
Primary Outcome Measure Information:
Title
Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16
Description
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).
Time Frame
Baseline, Week 16
Title
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16
Description
It was a hemodynamic parameter and measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.
Time Frame
Baseline, Week 16
Title
Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4
Description
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.
Time Frame
Baseline, Week 4
Title
Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8
Description
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.
Time Frame
Baseline, Week 8
Title
Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16
Description
BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation.
Time Frame
Baseline, Week 16
Title
Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16
Description
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.
Time Frame
Baseline, Week 16
Secondary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
Title
Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT)
Description
BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation.
Time Frame
Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
Title
Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 52 and End of Treatment (EOT)
Description
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.
Time Frame
Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
Title
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
Title
Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
Title
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
Description
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.
Time Frame
Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
Title
Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
Description
Only those categories in which at least 1 participant had data were reported.
Time Frame
Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
Title
Number of Participants With Laboratory Abnormalities
Description
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].
Time Frame
Baseline up-to End of treatment (maximum duration of treatment: 119.6 weeks)
Title
Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities
Description
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.
Time Frame
Screening, Week 16, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
Title
Number of Participants With Ocular Examination Abnormalities
Description
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.
Time Frame
Screening up to end of treatment (maximum duration of treatment: 119.6 weeks)
Title
Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16
Time Frame
Baseline, Week 16
Title
Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16
Time Frame
Baseline, Week 16
Title
Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16
Description
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).
Time Frame
Baseline, Week 16
Title
Change From Baseline in Right Atrial Pressure (RAP) at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16
Description
PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Cardiac Output (CO) at Week 16
Description
Cardiac output is simply the amount of blood pumped by the heart per minute.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Cardiac Index (CI) at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16
Description
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).
Time Frame
Baseline, Week 16
Title
Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16
Description
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).
Time Frame
Baseline, Week 16
Title
Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16
Description
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.
Time Frame
Baseline, Week 16
Other Pre-specified Outcome Measures:
Title
Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320
Description
UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.
Time Frame
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
Title
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320
Description
UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.
Time Frame
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
Title
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320
Description
UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.
Time Frame
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
Title
Terminal Half Life (t1/2) of Sildenafil and UK-103,320
Description
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.
Time Frame
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
Title
Apparent Oral Clearance (CL/F) of Sildenafil
Description
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time Frame
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
Title
Apparent Volume of Distribution (Vz/F) of Sildenafil
Description
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.
Time Frame
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
Title
Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Right Ventricular Tei Index at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Right Ventricular Size at Week 16
Time Frame
Baseline, Week 16
Title
Change From Baseline in Tricuspid Valve Annulus Size at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at Week 16
Description
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.
Time Frame
Baseline, Week 16
Title
Number of Participants With Pericardial Effusion
Description
Pericardial effusion is the presence of an abnormal amount of fluid in the pericardial cavity, as determined by echocardiography.
Time Frame
Baseline up to Week 16
Title
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 16
Description
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.
Time Frame
Baseline, Week 16
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pfizer CT.gov Call Center
Organizational Affiliation
Pfizer
Official's Role
Study Director
Facility Information:
Facility Name
Kitasato University Hospital
City
Sagamihara
State/Province
Kanagawa
ZIP/Postal Code
252-0375
Country
Japan
Facility Name
Osaka University Hospital
City
Suita
State/Province
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
Toho University Omori Medical Center
City
Ota-ku
State/Province
Tokyo
ZIP/Postal Code
143-8541
Country
Japan
Facility Name
National Center for Child Health and Development
City
Setagaya-ku
State/Province
Tokyo
ZIP/Postal Code
157-8535
Country
Japan
Facility Name
Shizuoka Children's Hospital
City
Shizuoka
ZIP/Postal Code
420-8660
Country
Japan
12. IPD Sharing Statement
Links:
URL
https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=A1481298&StudyName=Safety%20And%20Efficacy%20Of%20Sildenafil%20In%20Children%20With%20Pulmonary%20Arterial%20Hypertension
Description
To obtain contact information for a study center near you, click here.
Learn more about this trial
Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
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