A Phase 3, Multi-center, Open-label Study To Investigate Safety, Efficacy, And Tolerability Of Sildenafil Citrate In Pediatric Patients With Pulmonary Arterial Hypertension
Overview
- Phase
- Phase 4
- Intervention
- Sildenafil
- Conditions
- Pulmonary Arterial Hypertension
- Sponsor
- Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
- Enrollment
- 6
- Locations
- 5
- Primary Endpoint
- Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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.
Investigators
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 m
- •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.
Arms & Interventions
Sildenafil
Intervention: Sildenafil
Outcomes
Primary Outcomes
Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16
Time Frame: Baseline, 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.
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16
Time Frame: Baseline, 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 Brain Natriuretic Peptide (BNP) at Week 16
Time Frame: Baseline, Week 16
BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation.
Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4
Time Frame: Baseline, 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 16
Time Frame: Baseline, 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 Pulmonary Vascular Resistance Index (PVRI) at Week 16
Time Frame: Baseline, 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 World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8
Time Frame: Baseline, 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.
Secondary Outcomes
- Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 52 and End of Treatment (EOT)(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)(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)(Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks))
- Number of Participants With Laboratory Abnormalities(Baseline up-to End of treatment (maximum duration of treatment: 119.6 weeks))
- Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT)(Baseline, Week 52 and 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 Systolic and Diastolic Blood Pressure (BP) at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124(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(Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124)
- Number of Participants With Ocular Examination Abnormalities(Screening up to end of treatment (maximum duration of treatment: 119.6 weeks))
- 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(Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124)
- Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16(Baseline, Week 16)
- Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities(Screening, Week 16, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks))
- Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16(Baseline, Week 16)
- Change From Baseline in Right Atrial Pressure (RAP) at Week 16(Baseline, Week 16)
- Change From Baseline in Cardiac Index (CI) at Week 16(Baseline, Week 16)
- Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16(Baseline, Week 16)
- Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16(Baseline, Week 16)
- Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16(Baseline, Week 16)
- Change From Baseline in Cardiac Output (CO) at Week 16(Baseline, Week 16)
- Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16(Baseline, Week 16)
- Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16(Baseline, Week 16)