Hypertension, Pulmonary, Pulmonary Arterial Hypertension
Conditions
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.
Interventions
DRUGSildenafil
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
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16 | 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 N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16 | 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 Brain Natriuretic Peptide (BNP) at Week 16 | 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 16 | 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 World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8 | 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 4 | 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 Mean Pulmonary Artery Pressure (mPAP) at Week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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 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) | 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. |
| Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 | 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). |
| 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) | 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 | Baseline, 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 | Baseline, 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 | Baseline up-to End of treatment (maximum duration of treatment: 119.6 weeks) | 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 Ocular Examination Abnormalities | Screening up to end of treatment (maximum duration of treatment: 119.6 weeks) | 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 | 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 | 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 | 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 Systemic Vascular Resistance Index (SVRI) at Week 16 | 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 | 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 | 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. |
| Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 | Baseline, Week 16 | PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure. |
| 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 | 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) | Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks) | 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) | Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks) | 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 Cardiac Output (CO) at Week 16 | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Right Ventricular Size at Week 16 | Baseline, Week 16 | — |
| Change From Baseline in Tricuspid Valve Annulus Size at Week 16 | 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 | 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 | 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 | 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 | 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. |
| Apparent Volume of Distribution (Vz/F) of Sildenafil | 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. |
| Apparent Oral Clearance (CL/F) of Sildenafil | 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. |
| Terminal Half Life (t1/2) of Sildenafil and UK-103,320 | 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. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320 | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320 | 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 | 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. |
| Change From Baseline in Right Ventricular Tei Index at Week 16 | 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 Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16 | 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. |
Countries
Japan
Participant flow
Pre-assignment details
The study was conducted at 3 sites in Japan. Data reported is based on data cut-off date of 26 December 2016.
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Participants received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Day 1 (Baseline), Weeks 4, 8, and 16 in Part 1 of the study. Participants who completed Part 1 and required continuing treatment with Sildenafil, received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks). Participants with \<= 20 kg of body weight received 10 mg dose, thrice daily as powder for oral suspension and participants with \> 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part 1 (Screening Till Week 16) | Insufficient clinical response | 3 |
| Part 2(Week17 to Maximum of 119.6 Weeks) | Change of treatment plan | 1 |
| Part 2(Week17 to Maximum of 119.6 Weeks) | Coil Embolization | 1 |
Baseline characteristics
| Characteristic | Sildenafil |
|---|---|
| Age, Categorical <=18 years | 6 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 6.7 years STANDARD_DEVIATION 5.4 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16 | Baseline | 132.62 picogram per milliliter | Standard Deviation 135.08 |
| Sildenafil | Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16 | Change at Week 16 | -64.10 picogram per milliliter | Standard Deviation 129.638 |
Primary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16 | Baseline | 58.5 millimeter of mercury (mmHg) | Standard Deviation 22.94 |
| Sildenafil | Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16 | Change at Week 16 | -6.5 millimeter of mercury (mmHg) | Standard Deviation 15.15 |
Primary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16 | Baseline | 843.03 picogram per milliliter | Standard Deviation 1120.9 |
| Sildenafil | Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16 | Change at Week 16 | -546.85 picogram per milliliter | Standard Deviation 1107.621 |
Primary
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).
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16 | Baseline | 18.567 wood units*meter^2 | Standard Deviation 11.7629 |
| Sildenafil | Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16 | Change at Week 16 | -4.113 wood units*meter^2 | Standard Deviation 6.377 |
Primary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, Overall Number of participants analyzed signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 16 | Improved | 1 participants | 0.71 |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 16 | No change | 3 participants | — |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 16 | Worsened | 0 participants | — |
Primary
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.
Time frame: Baseline, Week 4
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | Baseline: Class I | 2 participants | 0.58 |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | Baseline: Class II | 3 participants | 0.58 |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | Baseline: Class III | 1 participants | — |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | Baseline: Class IV | 0 participants | — |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | Week 4: Improved | 1 participants | — |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | Week 4: No change | 5 participants | — |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4 | Week 4: Worsened | 0 participants | — |
Primary
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.
Time frame: Baseline, Week 8
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here,'N' (Overall number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8 | Improved | 1 participants | 0.71 |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8 | No change | 4 participants | — |
| Sildenafil | Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8 | Worsened | 0 participants | — |
Secondary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16 | Baseline | 95.08 percentage of arterial oxygen | Standard Deviation 2.73 |
| Sildenafil | Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16 | Change at Week 16 | -0.80 percentage of arterial oxygen | Standard Deviation 1.691 |
Secondary
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.
Time frame: Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug.Here 'Overall number of participants analyzed' specifies number of participants who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT) | Baseline | 100.17 picograms per milliliter | Standard Deviation 151.478 |
| Sildenafil | Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT) | Change at Week 52 | -85.17 picograms per milliliter | Standard Deviation 155.088 |
| Sildenafil | Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT) | Change at EoT | -85.17 picograms per milliliter | Standard Deviation 155.088 |
Secondary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Cardiac Index (CI) at Week 16 | Baseline | 3.070 liter per minute per meter square | Standard Deviation 0.746 |
| Sildenafil | Change From Baseline in Cardiac Index (CI) at Week 16 | Change at Week 16 | 0.658 liter per minute per meter square | Standard Deviation 1.8912 |
Secondary
Change From Baseline in Cardiac Output (CO) at Week 16
Cardiac output is simply the amount of blood pumped by the heart per minute.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Cardiac Output (CO) at Week 16 | Baseline | 2.620 liter per minute | Standard Deviation 0.9879 |
| Sildenafil | Change From Baseline in Cardiac Output (CO) at Week 16 | Change at Week 16 | 0.420 liter per minute | Standard Deviation 0.9076 |
Secondary
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.
Time frame: Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
Population: Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Baseline: Supine Heart rate | 100.2 beats per minute (bpm) | Standard Deviation 15.91 |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Baseline: Sitting Heart rate | 96.0 beats per minute (bpm) | — |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 4: Supine Heart rate | -1.0 beats per minute (bpm) | Standard Deviation 12.08 |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 4: Sitting Heart rate | -22.0 beats per minute (bpm) | — |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 8: Supine Heart rate | -0.5 beats per minute (bpm) | Standard Deviation 9.11 |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 8: Sitting Heart rate | 0.0 beats per minute (bpm) | — |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 16: Supine Heart rate | 3.0 beats per minute (bpm) | Standard Deviation 28.69 |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 16: Sitting Heart rate | 4.0 beats per minute (bpm) | — |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 28: Supine Heart rate | 6.7 beats per minute (bpm) | Standard Deviation 14.36 |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 40: Supine Heart rate | 10.0 beats per minute (bpm) | Standard Deviation 16.97 |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 52: Supine Heart rate | -2.0 beats per minute (bpm) | Standard Deviation 11.31 |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 64: Supine Heart rate | 17.0 beats per minute (bpm) | — |
| Sildenafil | Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | Change at Week 76: Supine Heart rate | -8.0 beats per minute (bpm) | — |
Secondary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16 | Baseline | 65.30 percentage of mixed venous oxygen | Standard Deviation 8.549 |
| Sildenafil | Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16 | Change at Week 16 | 5.38 percentage of mixed venous oxygen | Standard Deviation 12.426 |
Secondary
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.
Time frame: Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
Population: EEfficacy analysis set included all participants who received at least 1 dose of study drug.Here 'Overall number of participants analyzed' specifies number of participants who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 52 and End of Treatment (EOT) | Baseline | 841.73 picograms per milliliter | Standard Deviation 1323.533 |
| Sildenafil | Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 52 and End of Treatment (EOT) | Change at Week 52 | -754.90 picograms per milliliter | Standard Deviation 1335.37 |
| Sildenafil | Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 52 and End of Treatment (EOT) | Change at EoT | -754.90 picograms per milliliter | Standard Deviation 1335.37 |
Secondary
Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16 | Baseline: Systolic Pressure | 82.5 mmHg | Standard Deviation 35.51 |
| Sildenafil | Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16 | Baseline: Diastolic Pressure | 42.0 mmHg | Standard Deviation 18.19 |
| Sildenafil | Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16 | Change at Week 16: Systolic Pressure | -9.8 mmHg | Standard Deviation 18.01 |
| Sildenafil | Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16 | Change at Week 16: Diastolic Pressure | -3.5 mmHg | Standard Deviation 13.99 |
Secondary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 | Baseline | 8.5 mmHg | Standard Deviation 0.84 |
| Sildenafil | Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 | Change at Week 16 | 2.5 mmHg | Standard Deviation 1 |
Secondary
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).
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 | Baseline | 21.372 Wood units | Standard Deviation 11.3408 |
| Sildenafil | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 | Change at Week 16 | -6.145 Wood units | Standard Deviation 10.3499 |
Secondary
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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Right Atrial Pressure (RAP) at Week 16 | Baseline | 6.5 mmHg | Standard Deviation 2.88 |
| Sildenafil | Change From Baseline in Right Atrial Pressure (RAP) at Week 16 | Change at Week 16 | 1.3 mmHg | Standard Deviation 2.36 |
Secondary
Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16 | Baseline: Systolic Pressure | 95.3 mmHg | Standard Deviation 15.2 |
| Sildenafil | Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16 | Baseline: Diastolic Pressure | 60.2 mmHg | Standard Deviation 19.3 |
| Sildenafil | Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16 | Change at Week 16: Systolic Pressure | 0.3 mmHg | Standard Deviation 10.21 |
| Sildenafil | Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16 | Change at Week 16: Diastolic Pressure | -1.5 mmHg | Standard Deviation 14.25 |
Secondary
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).
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16 | Baseline | 23.855 Wood units*meter^2 | Standard Deviation 12.148 |
| Sildenafil | Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16 | Change at Week 16 | -2.378 Wood units*meter^2 | Standard Deviation 3.9096 |
Secondary
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).
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 | Baseline | 26.545 Wood units | Standard Deviation 3.0768 |
| Sildenafil | Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 | Change at Week 16 | -3.403 Wood units | Standard Deviation 4.4409 |
Secondary
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.
Time frame: Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
Population: Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | 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 | Change at Week 4: Sitting Diastolic BP | 23.0 mmHg | — |
| Sildenafil | 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: Supine Systolic BP | 95.4 mmHg | Standard Deviation 13.41 |
| Sildenafil | 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: Supine Diastolic BP | 55.8 mmHg | Standard Deviation 10.87 |
| Sildenafil | 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: Sitting Systolic BP | 110.0 mmHg | — |
| Sildenafil | 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: Sitting Diastolic BP | 60.0 mmHg | — |
| Sildenafil | 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 | Change at Week 4: Supine Systolic BP | 5.6 mmHg | Standard Deviation 9.91 |
| Sildenafil | 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 | Change at Week 4: Supine Diastolic BP | 1.6 mmHg | Standard Deviation 13.65 |
| Sildenafil | 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 | Change at Week 4: Sitting Systolic BP | 16.0 mmHg | — |
| Sildenafil | 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 | Change at Week 8: Supine Systolic BP | 7.8 mmHg | Standard Deviation 14.93 |
| Sildenafil | 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 | Change at Week 8: Supine Diastolic BP | 2.3 mmHg | Standard Deviation 12.28 |
| Sildenafil | 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 | Change at Week 8: Sitting Systolic BP | -6.0 mmHg | — |
| Sildenafil | 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 | Change at Week 8: Sitting Diastolic BP | -3.0 mmHg | — |
| Sildenafil | 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 | Change at Week 16: Supine Systolic BP | 7.7 mmHg | Standard Deviation 17.62 |
| Sildenafil | 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 | Change at Week 16: Supine Diastolic BP | -1.3 mmHg | Standard Deviation 12.22 |
| Sildenafil | 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 | Change at Week 16: Sitting Systolic BP | 8.0 mmHg | — |
| Sildenafil | 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 | Change at Week 16: Sitting Diastolic BP | 10.0 mmHg | — |
| Sildenafil | 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 | Change at Week 28: Supine Systolic BP | 7.0 mmHg | Standard Deviation 19.31 |
| Sildenafil | 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 | Change at Week 28: Supine Diastolic BP | 1.7 mmHg | Standard Deviation 9.29 |
| Sildenafil | 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 | Change at Week 40: Supine Systolic BP | -7.5 mmHg | Standard Deviation 3.54 |
| Sildenafil | 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 | Change at Week 40: Supine Diastolic BP | 2.0 mmHg | Standard Deviation 0 |
| Sildenafil | 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 | Change at Week 52: Supine Systolic BP | 2.0 mmHg | Standard Deviation 15.56 |
| Sildenafil | 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 | Change at Week 52: Supine Diastolic BP | 10.0 mmHg | Standard Deviation 5.66 |
| Sildenafil | 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 | Change at Week 64: Supine Systolic BP | 1.0 mmHg | — |
| Sildenafil | 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 | Change at Week 64: Supine Diastolic BP | 8.0 mmHg | — |
| Sildenafil | 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 | Change at Week 76: Supine Systolic BP | -13.0 mmHg | — |
| Sildenafil | 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 | Change at Week 76: Supine Diastolic BP | 3.0 mmHg | — |
Secondary
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.
Time frame: Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
Population: Efficacy analysis set was used in this analysis. Here, 'Overall number of participants analyzed' specifies number of participants who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study and 'Number analyzed' = Participants evaluable for this outcome measure for specified categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sildenafil | 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: Class I | 1 Participants |
| Sildenafil | 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: Class II | 2 Participants |
| Sildenafil | 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: Class III | 0 Participants |
| Sildenafil | 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: Class IV | 0 Participants |
| Sildenafil | 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 | Week 28: Improved | 1 Participants |
| Sildenafil | 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 | Week 28: No Change | 2 Participants |
| Sildenafil | 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 | Week 28: Worsened | 0 Participants |
| Sildenafil | 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 | Week 40: Improved | 1 Participants |
| Sildenafil | 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 | Week 40: No Change | 2 Participants |
| Sildenafil | 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 | Week 40: Worsened | 0 Participants |
| Sildenafil | 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 | Week 52: Improved | 1 Participants |
| Sildenafil | 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 | Week 52: No Change | 2 Participants |
| Sildenafil | 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 | Week 52: Worsened | 0 Participants |
| Sildenafil | 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 | Week 64: Improved | 1 Participants |
| Sildenafil | 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 | Week 64: No Change | 1 Participants |
| Sildenafil | 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 | Week 64: Worsened | 0 Participants |
| Sildenafil | 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 | Week 76: Improved | 1 Participants |
| Sildenafil | 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 | Week 76: No Change | 0 Participants |
| Sildenafil | 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 | Week 76: Worsened | 1 Participants |
| Sildenafil | 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 | Week 88: Improved | 1 Participants |
| Sildenafil | 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 | Week 88: No Change | 0 Participants |
| Sildenafil | 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 | Week 88: Worsened | 0 Participants |
| Sildenafil | 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 | Week 100: Improved | 1 Participants |
| Sildenafil | 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 | Week 100: No Change | 0 Participants |
| Sildenafil | 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 | Week 100: Worsened | 0 Participants |
| Sildenafil | 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 | Week 112: Improved | 1 Participants |
| Sildenafil | 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 | Week 112: No Change | 0 Participants |
| Sildenafil | 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 | Week 112: Worsened | 0 Participants |
| Sildenafil | 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 | Week 124: Improved | 1 Participants |
| Sildenafil | 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 | Week 124: No Change | 0 Participants |
| Sildenafil | 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 | Week 124:Worsened | 0 Participants |
Secondary
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.
Time frame: Screening, Week 16, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure for specified categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sildenafil | Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | Screening | 4 Participants |
| Sildenafil | Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | Week 16 | 5 Participants |
| Sildenafil | Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | Week 52 | 1 Participants |
| Sildenafil | Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | End of Treatment | 1 Participants |
Secondary
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, \[greater than or equal to {\>=}1\].
Time frame: Baseline up-to End of treatment (maximum duration of treatment: 119.6 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sildenafil | Number of Participants With Laboratory Abnormalities | 4 Participants |
Secondary
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.
Time frame: Screening up to end of treatment (maximum duration of treatment: 119.6 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sildenafil | Number of Participants With Ocular Examination Abnormalities | 0 Participants |
Secondary
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.
Time frame: Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sildenafil | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| Sildenafil | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Secondary
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.
Time frame: Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sildenafil | Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Sildenafil | Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Other Pre-specified
Apparent Oral Clearance (CL/F) of Sildenafil
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
Population: PK parameter analysis set included all participants who have at least 1 of PK parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Apparent Oral Clearance (CL/F) of Sildenafil | 41.73 liter per hour | Geometric Coefficient of Variation 77 |
Other Pre-specified
Apparent Volume of Distribution (Vz/F) of Sildenafil
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
Population: PK parameter analysis set included all participants who have at least 1 of PK parameters of interest. Here, Overall Number of participants analyzed signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sildenafil | Apparent Volume of Distribution (Vz/F) of Sildenafil | 77.90 liter |
Other Pre-specified
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320
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
Population: PK parameter analysis set included all participants who have at least 1 of PK parameters of interest.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320 | Sildenafil | 338.9 nanogram*hour per millimeter | Geometric Coefficient of Variation 54 |
| Sildenafil | Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320 | UK-103,320 | 210.2 nanogram*hour per millimeter | Geometric Coefficient of Variation 74 |
Other Pre-specified
Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at 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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at Week 16 | Baseline | 29.0 mmHg | Standard Deviation 14.73 |
| Sildenafil | Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at Week 16 | Change at Week 16 | 3.5 mmHg | Standard Deviation 13.44 |
Other Pre-specified
Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at 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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16 | Baseline | 0.3038 ratio | Standard Deviation 0.09675 |
| Sildenafil | Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16 | Change at Week 16 | 0.0175 ratio | Standard Deviation 0.10261 |
Other Pre-specified
Change From Baseline in Right Ventricular Size at Week 16
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Right Ventricular Size at Week 16 | Baseline | 3.37 centimeter (cm) | Standard Deviation 1.216 |
| Sildenafil | Change From Baseline in Right Ventricular Size at Week 16 | Change at Week 16 | -0.40 centimeter (cm) | Standard Deviation 0.408 |
Other Pre-specified
Change From Baseline in Right Ventricular Tei Index at 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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Right Ventricular Tei Index at Week 16 | Baseline | 0.7540 ratio | Standard Deviation 0.48602 |
| Sildenafil | Change From Baseline in Right Ventricular Tei Index at Week 16 | Change at Week 16 | -0.0440 ratio | Standard Deviation 0.37618 |
Other Pre-specified
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 16 | Baseline | 1.47 cm | Standard Deviation 0.437 |
| Sildenafil | Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 16 | Change at Week 16 | 0.18 cm | Standard Deviation 0.32 |
Other Pre-specified
Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at 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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at Week 16 | Baseline | 73.0 mmHg | Standard Deviation 39.31 |
| Sildenafil | Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at Week 16 | Change at Week 16 | -6.0 mmHg | Standard Deviation 33.94 |
Other Pre-specified
Change From Baseline in Tricuspid Valve Annulus Size at 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.
Time frame: Baseline, Week 16
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Change From Baseline in Tricuspid Valve Annulus Size at Week 16 | Baseline | 2.190 cm | Standard Deviation 0.5636 |
| Sildenafil | Change From Baseline in Tricuspid Valve Annulus Size at Week 16 | Change at Week 16 | -0.103 cm | Standard Deviation 0.3727 |
Other Pre-specified
Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320
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
Population: Pharmacokinetic (PK) parameter analysis set included all participants who have at least 1 of PK parameters of interest.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sildenafil | Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320 | Sildenafil | 138.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 73 |
| Sildenafil | Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320 | UK-103,320 | 73.66 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 48 |
Other Pre-specified
Number of Participants With Pericardial Effusion
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
Population: Efficacy analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sildenafil | Number of Participants With Pericardial Effusion | 0 participants |
Other Pre-specified
Terminal Half Life (t1/2) of Sildenafil and UK-103,320
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
Population: PK parameter analysis set included all participants who have at least 1 of PK parameters of interest. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sildenafil | Terminal Half Life (t1/2) of Sildenafil and UK-103,320 | Sildenafil | 1.785 hour |
| Sildenafil | Terminal Half Life (t1/2) of Sildenafil and UK-103,320 | UK-103,320 | 2.110 hour |
Other Pre-specified
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320
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
Population: PK parameter analysis set included all participants who have at least 1 of PK parameters of interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sildenafil | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320 | Sildenafil | 1.00 hour |
| Sildenafil | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320 | UK-103,320 | 1.00 hour |