Clinical Trial Results:
A Phase 3, Multi-Center, Open-Label Study to Investigate Safety, Efficacy, and Tolerability of Sildenafil Citrate in Pediatric Patients With Pulmonary Arterial Hypertension
Summary
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EudraCT number |
2016-003978-41 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
12 Mar 2018
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Results information
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Results version number |
v3(current) |
This version publication date |
30 Aug 2018
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First version publication date |
24 Nov 2016
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Other versions |
v1 , v2 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
A1481298
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01642407 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Pfizer, Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Apr 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Mar 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate changes of patient status with Sildenafil treatment for individual Japanese
pediatric patients with Pulmonary artery hypertension (PAH).
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Aug 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Japan: 6
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Worldwide total number of subjects |
6
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
2
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Children (2-11 years) |
3
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||
Pre-assignment
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Screening details |
The study was conducted at 3 sites in Japan. Data reported is based on data cut-off date of 26 December 2016. | ||||||||||||
Period 1
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Period 1 title |
Part 1 (Screening till Week 16)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Arms
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Arm title
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Sildenafil | ||||||||||||
Arm description |
Subjects received 10 milligram (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. Subjects 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). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Sildenafil 10 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Sildenafil 10 mg per milliliter oral suspension orally thrice on Day 1, Weeks 4, 8 and 16
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Investigational medicinal product name |
Sildenafil 20 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Sildenafil 20 mg tablet orally thrice on Day 1, Weeks 4, 8 and 16
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Period 2
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Period 2 title |
Part 2(Week17 to maximum of 119.6 weeks)
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Arms
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Arm title
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Sildenafil | ||||||||||||
Arm description |
Subjects received 10 milligram (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. Subjects 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). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Sildenafil 10 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Sildenafil 10 mg per milliliter oral suspension orally thrice on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks).
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Investigational medicinal product name |
Sildenafil 20 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received Sildenafil 20 mg tablet orally thrice on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks).
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Baseline characteristics reporting groups
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Reporting group title |
Sildenafil
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Reporting group description |
Subjects received 10 milligram (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. Subjects 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). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets. | ||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sildenafil
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Reporting group description |
Subjects received 10 milligram (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. Subjects 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). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets. | ||
Reporting group title |
Sildenafil
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Reporting group description |
Subjects received 10 milligram (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. Subjects 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). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets. |
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End point title |
Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16 [1] | ||||||||||||
End point description |
PVRI equals pulmonary vascular resistance (PVR) times body surface area (BSA) (PVRI = PVR*BSA). PVR is the resistance to blood flow through the pulmonary circulation and it was measured in Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
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End point type |
Primary
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End point timeframe |
Baseline, Week 16
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16 [2] | ||||||||||||
End point description |
It was a hemodynamic parameter and measured using a pressure transducer positioned at the mid-axillary line with the subject in the supine position. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
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End point type |
Primary
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End point timeframe |
Baseline, Week 16
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 4 [3] | ||||||||||||||||||||
End point description |
WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Primary
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End point timeframe |
Baseline, Week 4
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 8 [4] | ||||||||||||
End point description |
WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here,'N' (Number of Subjects Analyzed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 8
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 16 [5] | ||||||||||||
End point description |
WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, Number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 16
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Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16 [6] | ||||||||||||
End point description |
BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
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End point type |
Primary
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End point timeframe |
Baseline, Week 16
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Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT pro-BNP) at Week 16 [7] | ||||||||||||
End point description |
NT pro-BNP is a cardiac marker, having the prognostic value for subjects with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
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End point type |
Primary
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End point timeframe |
Baseline, Week 16
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Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Weeks 28, 40, 52, 64, 76, 88, 100, 112 and 124 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set was used in this analysis. Here, Number of subjects analyzed specifies number of subjects who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study and ‘n’ = subjects evaluable for this endpoint for specified categories.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT) | ||||||||||||||
End point description |
BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here 'Number of subjects analyzed' specifies number of subjects who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT pro-BNP) at Week 52 and End of Treatment (EOT) | ||||||||||||||
End point description |
NT pro-BNP is a cardiac marker, having the prognostic value for subjects with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here 'Number of subjects analyzed' specifies number of subjects who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||
End point description |
An AE was any untoward medical occurrence attributed to study drug in a subject 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. Safety analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||
End point description |
Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject 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. Safety analysis set included all subjects who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
BP measurement is recorded as supine and sitting systolic and diastolic systemic blood pressure: 1) Systolic blood pressure when heart is contracting and it is the maximum arterial pressure during contraction of left ventricle. 2) Diastolic BP when heart is relaxing and it is the minimum arterial pressure during relaxation and dilation of ventricles. Only those categories in which at least 1 subject had data were reported. Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint for specified categories. Standard deviation was not analyzed since only 1 subject was evaluable and has been denoted by '99999'.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124 | ||||||||||||||||||||||||||||||||||
End point description |
Only those categories in which at least 1 subject had data were reported. Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint for specified categories. Standard deviation was not analyzed since only 1 subject was evaluable and has been denoted by '99999'.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Laboratory Abnormalities | ||||||
End point description |
Laboratory abnormality criteria: Hematology (hemoglobin, hematocrit, red blood cell count [less than {<}]0.8*lower limit of normal [LLN]; platelets <0.5*LLN, greater than [>]1.75*upper limit of normal [ULN], white blood cells <0.6*LLN, >1.5*ULN; lymphocytes, neutrophils <0.8*LLN, >1.2*ULN, eosinophils, basophils, monocytes >1.2*ULN); liver function (total and direct bilirubin >1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase >3.0*ULN, total protein, albumin <0.8*LLN, >1.2*ULN); renal (creatinine, blood urea nitrogen >1.3*ULN); electrolytes (sodium <0.95*LLN, >1.05*ULN, potassium, chloride <0.9*LLN, >1.1*ULN; other (glucose <0.6*LLN or >1.5*ULN ); urinalysis (dipstick) urine glucose, urine protein, urine blood/Hemoglobin, [greater than or equal to {>=}1]. Safety analysis set included all subjects who received at least 1 dose of study drug.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Baseline up-to End of treatment (maximum duration of treatment: 119.6 weeks)
|
||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||||||||||
End point title |
Number of Subjects With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | ||||||||||||||
End point description |
Criteria for clinically significant abnormality in ECG parameters: Maximum corrected QT interval (QTc) from 450 millisecond (msec) to less than (<) 480 msec, Maximum QTcB interval (Bazett’s Correction) from 450 msec to <480 msec, Maximum QTcF interval (Fredericia’s Correction) from 450 msec to <480 msec, maximum QTc interval increase from baseline of 30 msec to <60 msec and >=60 msec. Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint for specified categories.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Screening, Week 16, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
|
||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects With Ocular Examination Abnormalities | ||||||
End point description |
Ocular examination measures included external examination of the eye, funduscopy, assessments of visual acuity, and color vision. Ocular examination findings were considered abnormal based on investigator’s decision. Safety analysis set included all subjects who received at least 1 dose of study drug.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Screening up to end of treatment (maximum duration of treatment: 119.6 weeks)
|
||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16 | ||||||||||||||||
End point description |
Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16 | ||||||||||||||||
End point description |
Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 | ||||||||||||
End point description |
The resistance to blood flow through the pulmonary circulation is known as PVR. It is largely influenced by the caliber of the pulmonary arteries and capillaries and was measured in terms of Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Right Atrial Pressure (RAP) at Week 16 | ||||||||||||
End point description |
RAP is the blood pressure in the right atrium of the heart. It reflects the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system. RAP was measured using a pressure transducer positioned at the mid-axillary line with the subject in the supine position. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 | ||||||||||||
End point description |
PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Cardiac Output (CO) at Week 16 | ||||||||||||
End point description |
Cardiac output is simply the amount of blood pumped by the heart per minute. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Cardiac Index (CI) at Week 16 | ||||||||||||
End point description |
Cardiac index is a hemodynamic parameter that relates the cardiac output from left ventricle in one minute to BSA, thus relating heart performance to the size of the individual. CI was calculated as cardiac output in systemic circulation divided by BSA. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 | ||||||||||||
End point description |
The resistance to blood flow through the systemic circulation is known as SVR. This can be used in measuring blood pressure, blood flow and cardiac function and measured in terms of Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16 | ||||||||||||
End point description |
SVRI equals systemic vascular resistance (SVR) times BSA. SVR is the resistance to blood flow through the systemic circulation and it was measured in Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16 | ||||||||||||
End point description |
SvO2 is the percentage of mixed venous oxygen (amount of oxygen bound to hemoglobin in venous blood). Change from baseline in percentage of mixed venous oxygen was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16 | ||||||||||||
End point description |
SaO2 is the percentage of arterial oxygen (amount of oxygen bound to hemoglobin in arterial blood). Change from baseline in percentage of arterial oxygen was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320 | ||||||||||||
End point description |
UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4. Pharmacokinetic (PK) parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320 | ||||||||||||
End point description |
UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320 | ||||||||||||
End point description |
UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Terminal Half Life (t1/2) of Sildenafil and UK-103,320 | ||||||||||||
End point description |
Terminal half-life is the time measured for the plasma concentration to decrease by one half of its original concentration. UK-103,320 was a main metabolite of sildenafil and was produced by cytochrome P450 3A4. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Apparent Oral Clearance (CL/F) of Sildenafil | ||||||||
End point description |
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
|
||||||||
End point type |
Other pre-specified
|
||||||||
End point timeframe |
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Apparent Volume of Distribution (Vz/F) of Sildenafil | ||||||||
End point description |
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest. Here, Number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Other pre-specified
|
||||||||
End point timeframe |
Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16 | ||||||||||||
End point description |
Acceleration time and ejection time are quantitative Doppler parameters and ratio of acceleration time to ejection time is a useful tool to evaluate the severity of aortic stenosis. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Right Ventricular Tei Index at Week 16 | ||||||||||||
End point description |
The right ventricular Tei Index is an index of myocardial performance. It is defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Right Ventricular Size at Week 16 | ||||||||||||
End point description |
Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Tricuspid Valve Annulus Size at Week 16 | ||||||||||||
End point description |
The tricuspid valve lies between the right atrium and the right ventricle and is placed in a more apical position than the mitral valve. The annulus separates the right atrium from the right ventricle. Change from baseline in tricuspid valve annulus size (in cm) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at Week 16 | ||||||||||||
End point description |
Tricuspid regurgitation (insufficiency) is the failure of the tricuspid valve to close properly during systole, leading to the leaking of blood from the right ventricle into the right atrium. Change from baseline in TR-PG peak (in mmHg) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at Week 16 | ||||||||||||
End point description |
Pulmonary regurgitation (PR) or insufficiency is a valvular heart disease characterized by an incomplete closure of the pulmonary valve leading to a diastolic reflux into the right ventricle. Change from baseline in PR-PG end-diastole (in mmHg) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects With Pericardial Effusion | ||||||
End point description |
Pericardial effusion is the presence of an abnormal amount of fluid in the pericardial cavity, as determined by echocardiography. Efficacy analysis set included all subjects who received at least 1 dose of study drug.
|
||||||
End point type |
Other pre-specified
|
||||||
End point timeframe |
Baseline up to Week 16
|
||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 16 | ||||||||||||
End point description |
Tricuspid annular plane systolic excursion is a parameter depicting global right ventricular function. Change from baseline in TAPSE (in cm) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 16
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Baseline up to 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
|
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
|
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Reporting groups
|
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Reporting group title |
Sildenafil
|
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Reporting group description |
Subjects 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. Subjects 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). Subjects with <= 20 kg of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with > 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
21 Aug 2012 |
Addition of Part 2 (Long term administration of the investigational drug) |
||
20 Jan 2016 |
Changed the target sample size of subjects. |
||
25 Aug 2017 |
Addition that after approval for additional indication for pediatric PAH, "clinical study" was read as "post-marketing clinical study", Changed the treatment period of Part 2. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. |