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Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01642407
First received: June 15, 2012
Last updated: February 15, 2017
Last verified: February 2017
  Purpose

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.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Hypertension, Pulmonary
Drug: Sildenafil
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • 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 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 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 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.

  • 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 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 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.


Secondary Outcome Measures:
  • Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 28, 40 and 52 [ Time Frame: Baseline, Week 28, 40, 52 ]
    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 Brain Natriuretic Peptide (BNP) at Week 52 [ Time Frame: Baseline, Week 52 ]
    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 [ Time Frame: Baseline, Week 52 ]
    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) [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 20 weeks) ]
    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.

  • Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 28 days after last dose of study drug (up to 20 weeks) ]
    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.

  • Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Week 4, 8 and 16 [ Time Frame: Baseline, Week 4, 8, 16 ]
    BP measurement is recorded as 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.

  • Change From Baseline in Heart Rate at Week 4, 8 and 16 [ Time Frame: Baseline, Week 4, 8, 16 ]
  • Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to Week 16 ]
    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 [ Time Frame: Baseline up to Week 16 ]
    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 [ Time Frame: Baseline up to Week 16 ]
    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 [ Time Frame: Baseline, Week 16 ]
  • Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16 [ Time Frame: Baseline, Week 16 ]
  • Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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 [ Time Frame: Baseline, 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.


Other Outcome Measures:
  • Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320 [ Time Frame: Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16 ]
    UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.

  • Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320 [ Time Frame: Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16 ]
    UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320 [ Time Frame: Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16 ]
    UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4.

  • Terminal Half Life (t1/2) of Sildenafil and UK-103,320 [ Time Frame: Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16 ]
    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.

  • Apparent Oral Clearance (CL/F) of Sildenafil [ Time Frame: Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16 ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

  • Apparent Volume of Distribution (Vz/F) of Sildenafil [ Time Frame: Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16 ]
    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.

  • Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16 [ Time Frame: Baseline, Week 16 ]
    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.

  • Change From Baseline in Right Ventricular Tei Index at Week 16 [ Time Frame: Baseline, Week 16 ]
    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.

  • Change From Baseline in Right Ventricular Size at Week 16 [ Time Frame: Baseline, Week 16 ]
  • Change From Baseline in Tricuspid Valve Annulus Size at Week 16 [ Time Frame: Baseline, Week 16 ]
    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.

  • Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at Week 16 [ Time Frame: Baseline, Week 16 ]
    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.

  • Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at Week 16 [ Time Frame: Baseline, Week 16 ]
    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.

  • Number of Participants With Pericardial Effusion [ Time Frame: Baseline up to Week 16 ]
    Pericardial effusion is the presence of an abnormal amount of fluid in the pericardial cavity, as determined by echocardiography.

  • Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 16 [ Time Frame: Baseline, Week 16 ]
    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.


Enrollment: 5
Study Start Date: August 2012
Estimated Study Completion Date: December 2017
Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sildenafil Drug: Sildenafil
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

  Eligibility

Ages Eligible for Study:   1 Year to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01642407

Locations
Japan
Kitasato University Hospital
Sagamihara, Kanagawa, Japan, 252-0375
Osaka University Hospital
Suita, Osaka, Japan, 565-0871
Toho University Omori Medical Center
Ota-ku, Tokyo, Japan, 143-8541
National Center for Child Health and Development
Setagaya-ku, Tokyo, Japan, 157-8535
Shizuoka Children's Hospital
Shizuoka, Japan, 420-8660
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01642407     History of Changes
Other Study ID Numbers: A1481298
Study First Received: June 15, 2012
Results First Received: November 3, 2016
Last Updated: February 15, 2017

Additional relevant MeSH terms:
Hypertension
Familial Primary Pulmonary Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents

ClinicalTrials.gov processed this record on April 24, 2017