A Randomized, Double-Blind, Placebo-Controlled Study of Sildenafil in Children With Pulmonary Arterial Hypertension.
Sponsor
Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00159913
Collaborator
(none)
235
41
4
58
5.7
0.1
Study Details
Study Description
Brief Summary
This is a clinical research study designed to evaluate sildenafil for the treatment of Pulmonary Arterial Hypertension in children, aged 1 to 17 years. The purpose of the study is to assess the efficacy, safety, and pharmacokinetics of 16 weeks of chronic treatment with oral sildenafil given in three different doses, compared to placebo (inactive treatment). Efficacy will be measured by exercise and hemodynamics. Patients who complete this trial may be eligible to take part in an extension study, in which all patients will receive active treatment of sildenafil.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
235 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind, Placebo Controlled, Dose Ranging, Parallel Group Study of Oral Sildenafil in the Treatment of Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension.
Study Start Date
:
Aug 1, 2003
Actual Primary Completion Date
:
Jun 1, 2008
Actual Study Completion Date
:
Jun 1, 2008
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sildenafil Low dose
|
Drug: Sildenafil citrate
oral; 10 mg; 3 times a day(TID)
|
| Experimental: Sildenafil Medium dose
|
Drug: Sildenafil citrate
oral; 10mg, 20mg and 40mg; 3 times a day(TID)
|
| Experimental: Sildenafil High dose
|
Drug: Sildenafil citrate
oral; 20mg, 40mg and 80 mg; 3 times a day(TID)
|
| Placebo Comparator: Placebo
|
Drug: Placebo
oral; 3 times a day(TID)
|
Outcome Measures
Primary Outcome Measures
- Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population [Baseline, Week 16]
Peak VO2 (normalized for body weight) at trough plasma levels assessed by CPX testing (bicycle ergometry)at the end of treatment (Week 16 for those who completed the study). Mean Percent change = [(week 16 value minus baseline mean)/mean at baseline]*100%.
- Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population [Baseline, Week 16]
Peak VO2 (normalized for body weight) at trough plasma levels assessed by CPX testing (bicycle ergometry)at the end of treatment (Week 16 for those who completed the study). Mean Percent change = [(week 16 value minus baseline mean)/mean at baseline]*100%.
Secondary Outcome Measures
- Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) [Baseline, Week 16]
mPAP, a hemodynamic parameter, was measured using a pressure transducer positioned at the mid-axillary line with the patient in the supine position. Change is observed value at Week 16 minus Baseline value.
- Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) [Baseline, Week 16]
PVRI equals Pulmonary Vascular Resistance (PVR) times Body Surface Area (BSA). Wood unit = 80dyn•s/cm5. Change is observed value at Week 16 minus Baseline value.
- Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) [Baseline, Week 16]
RER is the ratio of carbon dioxide produced to oxygen consumed [VCO2/VO2]). Percent change is [(Week 16 value minus Baseline value)/Baseline value] * 100%
- Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) [Baseline, Week 16]
Time to maximum VO2 was assessed on the subset of subjects who are developmentally able to perform the exercise test. Percent change is [(value at Week 16 minus Baseline value)/Baseline value] * 100%
- Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) [Baseline, Week 16]
Change calculated as (mean PAP - PCWP)/COpulm in PVR is observed value at Week 16 minus Baseline value.
- Change From Baseline to Week 16 in Cardiac Index (CI) [Baseline, Week 16]
CI is observed value at Week 16 minus Baseline value. Calculated as cardiac output in systemic circulation (COsys) / body surface area (BSA).
- Change From Baseline to Week 16 in Right Atrial Pressure (RAP) [Baseline, Week 16]
RAP was measured using a pressure transducer positioned at the mid-axillary line with the patient in the supine position. Change is observed value at Week 16 minus Baseline value.
- Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale [Baseline, Week 16]
CHQ-PF28: validated generic Quality of Life (QoL) questionnaire for subjects >= 5 years. Includes 12 domain scores of QoL concepts including physical functioning, social & school activities, mental health, parent/family concepts. Scores range 0-100: lower scores = lower QoL. Change is observed value at Week 16 minus Baseline value.
- Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales [Baseline, Week 16]
CHQ-PF28: validated generic Quality of Life (QoL) questionnaire for subjects >= 5 years. Includes 12 domain scores of QoL concepts including physical functioning, social & school activities, mental health, parent/family concepts. Scores range 0-100: lower scores = lower QoL. Change is observed value at Week 16 minus Baseline value.
- Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class [Baseline, Week 16]
WHO PH functional class definitions adapted from New York Heart Association Criteria for Functional Capacity and Therapeutic Class Definitions. Class I = PH without resulting limitation of physical activity, Class II = PH resulting in slight limitation of physical activity, Class III = PH resulting in marked limitation of physical activity, Class IV = PH with inability to carry out any physical activity without symptoms. Improved by 1 class = Class 4 to 3, Class 3 to 2, Class 2 to 1. Improved by 2 classes = Class 4 to 2, Class 3 to 1. Change is observed value at Week 16 minus Baseline value.
Eligibility Criteria
Criteria
Ages Eligible for Study:
1 Year
to 17 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Male or female subjects aged from 1 to 17 years old and weighing >= 8 kg 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).
-
Females of child bearing potential who were sexually active must have been practicing a suitable method of birth control so that in the opinion of the investigator, they would not become pregnant during the study.
-
Subjects who have symptomatic pulmonary arterial hypertension due to: primary pulmonary hypertension; pulmonary arterial hypertension in the presence of a small or hemodynamically insignificant congenital systemic to pulmonary shunt lesion that in the opinion of the investigator is not the cause of pulmonary hypertension; collagen vascular disease; congenital systemic-to-pulmonary shunts with a baseline resting room air oxygen saturation >= 88% unrepaired or repaired at least 6 months prior to screening; d-transposition of the great arteries repaired within the first 30 days of life; or surgical repair of other congenital heart lesions at least 6 months prior to screening and do not have clinically significant residual left-sided heart disease consistent with the exclusion criteria.
-
Subjects, developmentally able to exercise, whose CPX exercise test functional capacity is within the following parameters: Peak VO2 >= 10 mL/kg/min and <= 28 mL/kg/min during screening CPX test;
-
Written informed consent and assent where applicable before the subject is screened for the study.
-
Subjects who undergo a large shift in altitude (defined as approximately 5000 feet or 1524 meters) in order to participate in the study must reside at the "in study" altitude for at least 90 days prior to baseline and during the study period.
Exclusion Criteria:
-
Subjects with pulmonary hypertension secondary to sickle cell disease, any other disease known to be associated with PAH, or any etiology other than those specified in the inclusion criteria.
-
Left-sided heart disease, including aortic or mitral valve disease (greater than mild), restrictive or congestive cardiomyopathy; PCWP or LVEDP > 15 mmHg; LVEF < 40% determined by MUGA, angiography or echocardiography; LV shortening fraction < 22% determined by echocardiography, symptomatic coronary disease (demonstrable ischemia).
-
Pericardial constriction; significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation; acutely decompensated heart failure within previous 30 days from screening; atrial septostomy within previous 6 months of screening;
-
Hemodynamic instability or hypo- or hypertension at screening, i.e., SBP outside of 70-140 mmHg.
-
A history of stroke, myocardial infarction or life threatening arrhythmia within 6 months of screening.
-
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.
-
History of pulmonary embolism.
-
Subjects whose CPX test is limited by conditions other than pulmonary hypertension-associated dyspnea or fatigue.
-
Subjects who are known to be HIV positive
-
Subjects with impairment of renal function (serum creatinine > 2.5x ULN ) or hepatic function (ALT and/or AST > 3x ULN; and/or bilirubin >= 2 mg/dL). Hematological abnormalities (e.g., severe anemia, Hgb < 10 g/dL, leukopenia, WBC < 2500/mL).
-
Subjects who previously received bosentan and whose liver function tests taken at screening are > 2x ULN.
-
Subjects with any medical condition which in the opinion of the investigator may interfere with treatment, evaluation of safety, and/or efficacy.
-
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. Acute vasodilator testing with nitric oxide is permitted during hemodynamic evaluation; taking chronic arginine supplementation including Heart Bar; therapy involving parenteral inotropic medication or parenteral vasodilators within 3 months of screening; current therapy with alpha-blockers, potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole and protease inhibitors), Ritonavir or Nicorandil; chronic treatment with off-label sildenafil, an endothelin antagonist or prostacyclin/prostacyclin analogue within 30 days of randomization.
-
Pregnant or lactating female.
-
Any medical or psychological condition or social circumstances that would impair their ability to participate reliably in the study or who were not likely to complete the study for any reason; 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.
-
Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Pfizer Investigational Site | Palo Alto | California | United States | 94304 |
| 2 | Pfizer Investigational Site | Stanford | California | United States | 94305 |
| 3 | Pfizer Investigational Site | Aurora | Colorado | United States | 80045 |
| 4 | Pfizer Investigational Site | Boston | Massachusetts | United States | 02115 |
| 5 | Pfizer Investigational Site | Ann Arbor | Michigan | United States | 48109 |
| 6 | Pfizer Investigational Site | Saint Louis | Missouri | United States | 63110 |
| 7 | Pfizer Investigational Site | New York | New York | United States | 10032 |
| 8 | Pfizer Investigational Site | Columbus | Ohio | United States | 43205 |
| 9 | Pfizer Investigational Site | Charleston | South Carolina | United States | 29425 |
| 10 | Pfizer Investigational Site | Seattle | Washington | United States | 98105 |
| 11 | Pfizer Investigational Site | São Paulo | SP | Brazil | 04012-909 |
| 12 | Pfizer Investigational Site | Edmonton | Alberta | Canada | T6G 2B7 |
| 13 | Pfizer Investigational Site | Santiago | RM | Chile | |
| 14 | Pfizer Investigational Site | Medellin | Antioquia | Colombia | 0 |
| 15 | Pfizer Investigational Site | Bogota | Cundinamarca | Colombia | 0 |
| 16 | Pfizer Investigational Site | Guatemala | Guatemala | ||
| 17 | Pfizer Investigational Site | Budapest | Hungary | 1083 | |
| 18 | Pfizer Investigational Site | Budapest | Hungary | 1096 | |
| 19 | Pfizer Investigational Site | Deszk | Hungary | 6722 | |
| 20 | Pfizer Investigational Site | Szeged | Hungary | 6720 | |
| 21 | Pfizer Investigational Site | Szeged | Hungary | 6726 | |
| 22 | Pfizer Investigational Site | Hyderabad | Andra Pradesh | India | 500 001 |
| 23 | Pfizer Investigational Site | Kerala | Kochi, | India | 682 026 |
| 24 | Pfizer Investigational Site | Bologna | Italy | 40138 | |
| 25 | Pfizer Investigational Site | Tokyo | Japan | ||
| 26 | Pfizer Investigational Site | Penang | Malaysia | 10050 | |
| 27 | Pfizer Investigational Site | Penang | Malaysia | 10900 | |
| 28 | Pfizer Investigational Site | Del. Tlalpan | Mexico D.F. | Mexico | 14080 |
| 29 | Pfizer Investigational Site | Tlalpan | Mexico DF | Mexico | 14080 |
| 30 | Pfizer Investigational Site | Lima | Peru | L13 | |
| 31 | Pfizer Investigational Site | Krakow | Poland | 30-663 | |
| 32 | Pfizer Investigational Site | Krakow | Poland | 31-202 | |
| 33 | Pfizer Investigational Site | Warszawa | Poland | 04-628 | |
| 34 | Pfizer Investigational Site | Warszawa | Poland | 04-730 | |
| 35 | Pfizer Investigational Site | Zabrze | Poland | 41-800 | |
| 36 | Pfizer Investigational Site | Moscow | Russian Federation | 121552 | |
| 37 | Pfizer Investigational Site | Moscow | Russian Federation | 127412 | |
| 38 | Pfizer Investigational Site | Lund | Sweden | 221 85 | |
| 39 | Pfizer Investigational Site | Kaohsiung | Taiwan | 81346 | |
| 40 | Pfizer Investigational Site | Taipei | Taiwan | 100 | |
| 41 | Pfizer Investigational Site | Taipei | Taiwan | 11217 |
Sponsors and Collaborators
- Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
ClinicalTrials.gov Identifier:
NCT00159913
Other Study ID Numbers:
- A1481131
First Posted:
Sep 12, 2005
Last Update Posted:
Feb 18, 2021
Last Verified:
Jan 1, 2021
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 32 centers in North, Latin and South America, Europe and Asia. |
|---|---|
| Pre-assignment Detail | Of the 324 subjects screened, 235 subjects were randomized. 234 received treatment. One subject(sildenafil medium dose group) withdrew prior to taking any study treatment as the hemodynamic entrance criteria were not met. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Placebo |
|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Period Title: Overall Study | ||||
| STARTED | 42 | 55 | 77 | 60 |
| COMPLETED | 40 | 55 | 75 | 58 |
| NOT COMPLETED | 2 | 0 | 2 | 2 |
Baseline Characteristics
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Placebo | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. | Total of all reporting groups |
| Overall Participants | 42 | 55 | 77 | 60 | 234 |
| Age, Customized (participants) [Number] | |||||
| 1-4 Years |
0
0%
|
9
16.4%
|
19
24.7%
|
7
11.7%
|
35
15%
|
| 5-12 Years |
25
59.5%
|
28
50.9%
|
36
46.8%
|
37
61.7%
|
126
53.8%
|
| 13-17 Years |
17
40.5%
|
18
32.7%
|
22
28.6%
|
16
26.7%
|
73
31.2%
|
| >= 18 Years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
25
59.5%
|
31
56.4%
|
51
66.2%
|
38
63.3%
|
145
62%
|
| Male |
17
40.5%
|
24
43.6%
|
26
33.8%
|
22
36.7%
|
89
38%
|
Outcome Measures
| Title | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population |
|---|---|
| Description | Peak VO2 (normalized for body weight) at trough plasma levels assessed by CPX testing (bicycle ergometry)at the end of treatment (Week 16 for those who completed the study). Mean Percent change = [(week 16 value minus baseline mean)/mean at baseline]*100%. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population included all subjects randomised and who received at least one dose of study medication. All subjects developmentally able to perform the exercise test. Subjects assumed developmentally able if they had a CPX exercise assessment at any visit during study using a LOCF (end-of-treatment)approach for handling missing data. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 24 | 26 | 27 | 77 | 29 |
| Mean (Standard Deviation) [percent change] |
6.44
(20.16)
|
13.40
(19.50)
|
10.58
(15.51)
|
10.24
(18.39)
|
0.53
(15.91)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.056 |
| Comments | No adjustments for multiple comparisons have been made. | |
| Method | ANCOVA | |
| Comments | Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 7.71 | |
| Confidence Interval |
() 95% -0.19 to 15.60 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.98 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 3.81 | |
| Confidence Interval |
() 95% -6.11 to 13.73 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 5.00 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 11.33 | |
| Confidence Interval |
() 95% 1.72 to 20.94 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 4.84 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 7.98 | |
| Confidence Interval |
() 95% -1.64 to 17.60 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 4.85 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) |
|---|---|
| Description | mPAP, a hemodynamic parameter, was measured using a pressure transducer positioned at the mid-axillary line with the patient in the supine position. Change is observed value at Week 16 minus Baseline value. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, using a LOCF (end-of-treatment) approach for handling missing data. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 39 | 55 | 71 | 165 | 56 |
| Mean (Standard Deviation) [mm Hg] |
0.9
(12.3)
|
-3.9
(12.0)
|
-7.4
(15.4)
|
-4.3
(13.9)
|
-0.4
(15.9)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.172 |
| Comments | ||
| Method | ANCOVA | |
| Comments | Covariates:etiology, wt grp, capability performing exercise test. Normality assumptions not met with main analysis: alternative=excluding outliers | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -3.1 | |
| Confidence Interval |
() 95% -7.5 to 1.3 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.2 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 1.6 | |
| Confidence Interval |
() 95% -4.5 to 7.6 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.1 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -3.5 | |
| Confidence Interval |
() 95% -8.9 to 1.9 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.7 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -7.3 | |
| Confidence Interval |
() 95% -12.4 to -2.1 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.6 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) |
|---|---|
| Description | PVRI equals Pulmonary Vascular Resistance (PVR) times Body Surface Area (BSA). Wood unit = 80dyn•s/cm5. Change is observed value at Week 16 minus Baseline value. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, LOCF |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 36 | 49 | 67 | 152 | 50 |
| Mean (Standard Deviation) [wood units. m2] |
0.1
(10.9)
|
-2.9
(11.5)
|
-5.1
(14.7)
|
-3.2
(13.0)
|
1.6
(9.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.041 |
| Comments | ||
| Method | ANCOVA | |
| Comments | Covariates:etiology, wt grp, capability performing exercise test. Normality assumptions not met w/ main analysis: alternative=natural log transformed | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -4.1 | |
| Confidence Interval |
() 95% -8.0 to -0.2 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.0 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.6 | |
| Confidence Interval |
() 95% -5.9 to 4.7 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.7 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -4.5 | |
| Confidence Interval |
() 95% -9.3 to 0.3 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.4 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -7.2 | |
| Confidence Interval |
() 95% -11.7 to -2.7 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.3 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) |
|---|---|
| Description | RER is the ratio of carbon dioxide produced to oxygen consumed [VCO2/VO2]). Percent change is [(Week 16 value minus Baseline value)/Baseline value] * 100% |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, LOCF (end-of-treatment) approach for handling missing values. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 24 | 26 | 27 | 77 | 29 |
| Mean (Standard Deviation) [percent change] |
-0.00
(0.13)
|
-0.05
(0.12)
|
-0.02
(0.11)
|
-0.03
(0.12)
|
-0.03
(0.11)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.795 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The model included the covariates etiology and weight group | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.61 | |
| Confidence Interval |
() 95% -4.07 to 5.30 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.36 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 2.62 | |
| Confidence Interval |
() 95% -3.31 to 8.54 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.99 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -1.29 | |
| Confidence Interval |
() 95% -7.09 to 4.50 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.92 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.52 | |
| Confidence Interval |
() 95% -5.24 to 6.28 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.90 |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) |
|---|---|
| Description | Time to maximum VO2 was assessed on the subset of subjects who are developmentally able to perform the exercise test. Percent change is [(value at Week 16 minus Baseline value)/Baseline value] * 100% |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, LOCF (end-of-treatment) approach for handling missing values. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 24 | 26 | 27 | 77 | 29 |
| Mean (Standard Deviation) [percent change] |
64.83
(103.69)
|
64.42
(102.70)
|
31.33
(107.04)
|
52.95
(104.40)
|
8.84
(96.09)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.139 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The model included the covariates etiology and weight group | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 9.24 | |
| Confidence Interval |
() 95% -3.05 to 21.54 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 6.20 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 10.34 | |
| Confidence Interval |
() 95% -5.21 to 25.90 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 7.84 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 11.43 | |
| Confidence Interval |
() 95% -3.78 to 26.64 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 7.67 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 5.96 | |
| Confidence Interval |
() 95% -9.16 to 21.08 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 7.62 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) |
|---|---|
| Description | Change calculated as (mean PAP - PCWP)/COpulm in PVR is observed value at Week 16 minus Baseline value. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, using LOCF (end of treatment) approach for handling missing data |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 36 | 49 | 67 | 152 | 50 |
| Mean (Standard Deviation) [wood units] |
-0.1
(10.4)
|
-3.3
(10.5)
|
-5.2
(15.7)
|
-3.4
(13.1)
|
0.1
(11.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.172 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The model included the covariates etiology, weight group and capability of performing the exercise test | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -2.9 | |
| Confidence Interval |
() 95% -7.1 to 1.3 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.1 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.2 | |
| Confidence Interval |
() 95% -5.5 to 5.9 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.9 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -3.4 | |
| Confidence Interval |
() 95% -8.5 to 1.7 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.6 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -5.5 | |
| Confidence Interval |
() 95% -10.3 to -0.7 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.4 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Cardiac Index (CI) |
|---|---|
| Description | CI is observed value at Week 16 minus Baseline value. Calculated as cardiac output in systemic circulation (COsys) / body surface area (BSA). |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, using LOCF (end of treatment) approach for handling missing data. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 37 | 49 | 68 | 154 | 52 |
| Mean (Standard Deviation) [liters/minute/meters squared] |
0.20
(1.17)
|
0.02
(1.44)
|
0.24
(2.19)
|
0.16
(1.76)
|
-0.60
(2.12)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.015 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The model included the covariates etiology, weight group and capability of performing the exercise test | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.74 | |
| Confidence Interval |
() 95% 0.14 to 1.34 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.30 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.71 | |
| Confidence Interval |
() 95% -0.10 to 1.52 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.41 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.61 | |
| Confidence Interval |
() 95% -0.12 to 1.35 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.37 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.89 | |
| Confidence Interval |
() 95% 0.21 to 1.58 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.35 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Right Atrial Pressure (RAP) |
|---|---|
| Description | RAP was measured using a pressure transducer positioned at the mid-axillary line with the patient in the supine position. Change is observed value at Week 16 minus Baseline value. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, using LOCF (end of treatment) approach for missing data. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 39 | 55 | 71 | 165 | 56 |
| Mean (Standard Deviation) [mm Hg] |
7.92
(2.85)
|
8.05
(4.42)
|
7.75
(4.14)
|
7.89
(3.95)
|
8.11
(3.61)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.440 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The model included the covariates etiology, weight group and capability of performing the exercise test | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.50 | |
| Confidence Interval |
() 95% -1.77 to 0.77 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.64 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.17 | |
| Confidence Interval |
() 95% -1.91 to 1.57 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.88 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.19 | |
| Confidence Interval |
() 95% -1.73 to 1.36 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.78 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -1.14 | |
| Confidence Interval |
() 95% -2.61 to 0.33 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.75 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale |
|---|---|
| Description | CHQ-PF28: validated generic Quality of Life (QoL) questionnaire for subjects >= 5 years. Includes 12 domain scores of QoL concepts including physical functioning, social & school activities, mental health, parent/family concepts. Scores range 0-100: lower scores = lower QoL. Change is observed value at Week 16 minus Baseline value. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, includes subjects >= 5 years with a valid questionnaire available in the subject's first language. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 31 | 29 | 43 | 103 | 40 |
| Mean (Standard Deviation) [score on scale] |
14.0
(13.1)
|
9.8
(11.8)
|
5.9
(10.5)
|
9.4
(12.1)
|
8.3
(12.0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.750 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The covariates included in the model were baseline scale, etiology, weight and capability of performing the exercise test. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.62 | |
| Confidence Interval |
() 95% -4.45 to 3.21 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.93 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.87 | |
| Confidence Interval |
() 95% -4.21 to 5.95 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.57 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.24 | |
| Confidence Interval |
() 95% -4.68 to 5.15 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.49 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -2.96 | |
| Confidence Interval |
() 95% -7.37 to 1.45 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.23 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales |
|---|---|
| Description | CHQ-PF28: validated generic Quality of Life (QoL) questionnaire for subjects >= 5 years. Includes 12 domain scores of QoL concepts including physical functioning, social & school activities, mental health, parent/family concepts. Scores range 0-100: lower scores = lower QoL. Change is observed value at Week 16 minus Baseline value. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, includes subjects >= 5years with a valid questionnaire available in the subject's first language. |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 34 | 30 | 45 | 109 | 41 |
| Mean (Standard Deviation) [score on scale] |
5.1
(6.9)
|
4.1
(8.1)
|
4.3
(10.0)
|
4.5
(8.6)
|
5.6
(10.3)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.784 |
| Comments | ||
| Method | ANCOVA | |
| Comments | The covariates included in the model were baseline scale, etiology, weight and capability of performing the exercise test. | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.42 | |
| Confidence Interval |
() 95% -3.41 to 2.58 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.51 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.41 | |
| Confidence Interval |
() 95% -3.49 to 4.30 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.97 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -2.11 | |
| Confidence Interval |
() 95% -5.99 to 1.77 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.96 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.46 | |
| Confidence Interval |
() 95% -3.06 to 3.97 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 1.77 |
|
| Estimation Comments | ||
| Title | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class |
|---|---|
| Description | WHO PH functional class definitions adapted from New York Heart Association Criteria for Functional Capacity and Therapeutic Class Definitions. Class I = PH without resulting limitation of physical activity, Class II = PH resulting in slight limitation of physical activity, Class III = PH resulting in marked limitation of physical activity, Class IV = PH with inability to carry out any physical activity without symptoms. Improved by 1 class = Class 4 to 3, Class 3 to 2, Class 2 to 1. Improved by 2 classes = Class 4 to 2, Class 3 to 1. Change is observed value at Week 16 minus Baseline value. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population, LOCF |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 31 | 34 | 55 | 120 | 35 |
| No change |
25
|
24
|
38
|
84
|
31
|
| Improved by 1 class |
6
|
10
|
16
|
32
|
4
|
| Improved by 2 classes |
0
|
0
|
1
|
1
|
0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.184 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Proportional odds method. Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.83 | |
| Confidence Interval |
() 95% 0.75 to 4.45 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.409 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Proportional odds method. Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.60 | |
| Confidence Interval |
() 95% 0.18 to 2.01 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.146 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Proportional odds method. Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 2.25 | |
| Confidence Interval |
() 95% 0.75 to 6.69 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.006 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Proportional odds method. Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 4.52 | |
| Confidence Interval |
() 95% 1.56 to 13.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population |
|---|---|
| Description | Peak VO2 (normalized for body weight) at trough plasma levels assessed by CPX testing (bicycle ergometry)at the end of treatment (Week 16 for those who completed the study). Mean Percent change = [(week 16 value minus baseline mean)/mean at baseline]*100%. |
| Time Frame | Baseline, Week 16 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Per Protocol Population |
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo |
|---|---|---|---|---|---|
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. |
| Measure Participants | 23 | 23 | 27 | 73 | 24 |
| Mean (Standard Deviation) [percent change] |
5.43
(20.69)
|
15.66
(21.48)
|
9.34
(17.13)
|
10.10
(19.87)
|
2.81
(13.17)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Combined Sildenafil, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.179 |
| Comments | ||
| Method | ANCOVA | |
| Comments | Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates | |
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 5.89 | |
| Confidence Interval |
() 95% -2.74 to 14.53 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 4.35 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Low Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 1.14 | |
| Confidence Interval |
() 95% -9.49 to 11.77 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 5.35 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil Medium Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 11.30 | |
| Confidence Interval |
() 95% 0.66 to 21.96 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 5.36 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Sildenafil High Dose, Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 5.24 | |
| Confidence Interval |
() 95% -5.02 to 15.50 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 5.16 |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||
| Arm/Group Title | Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo | |||||
| Arm/Group Description | Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group. | Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112 | This includes all subjects in the low, medium and high dose groups. | Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. | |||||
All Cause Mortality |
||||||||||
| Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | |||||
Serious Adverse Events |
||||||||||
| Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/ (NaN) | 1/ (NaN) | 7/ (NaN) | 9/ (NaN) | 2/ (NaN) | |||||
| Cardiac disorders | ||||||||||
| Bradycardia | 0/42 (0%) | 0/55 (0%) | 1/77 (1.3%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Cardiac failure congestive | 0/42 (0%) | 0/55 (0%) | 1/77 (1.3%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Cyanosis | 1/42 (2.4%) | 0/55 (0%) | 0/77 (0%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Ventricular arrhythmia | 0/42 (0%) | 0/55 (0%) | 1/77 (1.3%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Gastrointestinal disorders | ||||||||||
| Diarrhoea | 0/42 (0%) | 0/55 (0%) | 0/77 (0%) | 0/174 (0%) | 1/60 (1.7%) | |||||
| Haematochezia | 1/42 (2.4%) | 0/55 (0%) | 0/77 (0%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| General disorders | ||||||||||
| Pyrexia | 0/42 (0%) | 0/55 (0%) | 1/77 (1.3%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Infections and infestations | ||||||||||
| Gastroenteritis | 0/42 (0%) | 0/55 (0%) | 1/77 (1.3%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Pneumonia | 0/42 (0%) | 1/55 (1.8%) | 2/77 (2.6%) | 3/174 (1.7%) | 0/60 (0%) | |||||
| Pneumonia bacterial | 0/42 (0%) | 0/55 (0%) | 0/77 (0%) | 0/174 (0%) | 1/60 (1.7%) | |||||
| Upper respiratory tract infection | 0/42 (0%) | 1/55 (1.8%) | 1/77 (1.3%) | 2/174 (1.1%) | 0/60 (0%) | |||||
| Nervous system disorders | ||||||||||
| Syncope | 1/42 (2.4%) | 0/55 (0%) | 0/77 (0%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||
| Bronchospasm | 0/42 (0%) | 0/55 (0%) | 1/77 (1.3%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Dyspnoea | 1/42 (2.4%) | 0/55 (0%) | 0/77 (0%) | 1/174 (0.6%) | 0/60 (0%) | |||||
| Stridor | 0/42 (0%) | 0/55 (0%) | 1/77 (1.3%) | 1/174 (0.6%) | 0/60 (0%) | |||||
Other (Not Including Serious) Adverse Events |
||||||||||
| Sildenafil Low Dose | Sildenafil Medium Dose | Sildenafil High Dose | Combined Sildenafil | Placebo | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 22/ (NaN) | 37/ (NaN) | 44/ (NaN) | 102/ (NaN) | 29/ (NaN) | |||||
| Blood and lymphatic system disorders | ||||||||||
| Anaemia | 0/42 (0%) | 2/55 (3.6%) | 0/77 (0%) | 2/174 (1.1%) | 1/60 (1.7%) | |||||
| Eye disorders | ||||||||||
| Conjunctivitis | 0/42 (0%) | 0/55 (0%) | 2/77 (2.6%) | 2/174 (1.1%) | 2/60 (3.3%) | |||||
| Gastrointestinal disorders | ||||||||||
| Abdominal pain | 1/42 (2.4%) | 0/55 (0%) | 2/77 (2.6%) | 3/174 (1.7%) | 3/60 (5%) | |||||
| Abdominal pain lower | 0/42 (0%) | 0/55 (0%) | 3/77 (3.9%) | 3/174 (1.7%) | 0/60 (0%) | |||||
| Abdominal pain upper | 0/42 (0%) | 3/55 (5.5%) | 3/77 (3.9%) | 6/174 (3.4%) | 1/60 (1.7%) | |||||
| Diarrhoea | 2/42 (4.8%) | 3/55 (5.5%) | 7/77 (9.1%) | 12/174 (6.9%) | 4/60 (6.7%) | |||||
| Dyspepsia | 0/42 (0%) | 2/55 (3.6%) | 0/77 (0%) | 2/174 (1.1%) | 1/60 (1.7%) | |||||
| Nausea | 0/42 (0%) | 4/55 (7.3%) | 4/77 (5.2%) | 8/174 (4.6%) | 0/60 (0%) | |||||
| Vomiting | 3/42 (7.1%) | 5/55 (9.1%) | 11/77 (14.3%) | 19/174 (10.9%) | 4/60 (6.7%) | |||||
| General disorders | ||||||||||
| Chest pain | 2/42 (4.8%) | 1/55 (1.8%) | 2/77 (2.6%) | 5/174 (2.9%) | 2/60 (3.3%) | |||||
| Fatigue | 2/42 (4.8%) | 0/55 (0%) | 2/77 (2.6%) | 4/174 (2.3%) | 1/60 (1.7%) | |||||
| Pyrexia | 3/42 (7.1%) | 8/55 (14.5%) | 8/77 (10.4%) | 19/174 (10.9%) | 1/60 (1.7%) | |||||
| Infections and infestations | ||||||||||
| Bronchitis | 2/42 (4.8%) | 5/55 (9.1%) | 3/77 (3.9%) | 8/174 (4.6%) | 1/60 (1.7%) | |||||
| Influenza | 0/42 (0%) | 2/55 (3.6%) | 0/77 (0%) | 2/174 (1.1%) | 0/60 (0%) | |||||
| Laryngitis | 1/42 (2.4%) | 0/55 (0%) | 1/77 (1.3%) | 2/174 (1.1%) | 2/60 (3.3%) | |||||
| Nasopharyngitis | 3/42 (7.1%) | 3/55 (5.5%) | 2/77 (2.6%) | 8/174 (4.6%) | 4/60 (6.7%) | |||||
| Pharyngitis | 3/42 (7.1%) | 3/55 (5.5%) | 1/77 (1.3%) | 7/174 (4%) | 0/60 (0%) | |||||
| Pneumonia | 0/42 (0%) | 2/55 (3.6%) | 0/77 (0%) | 2/174 (1.1%) | 0/60 (0%) | |||||
| Rhinitis | 1/42 (2.4%) | 3/55 (5.5%) | 1/77 (1.3%) | 5/174 (2.9%) | 1/60 (1.7%) | |||||
| Upper respiratory tract infection | 4/42 (9.5%) | 8/55 (14.5%) | 6/77 (7.8%) | 18/174 (10.3%) | 4/60 (6.7%) | |||||
| Musculoskeletal and connective tissue disorders | ||||||||||
| Pain in extremity | 2/42 (4.8%) | 0/55 (0%) | 0/77 (0%) | 2/174 (1.1%) | 2/60 (3.3%) | |||||
| Nervous system disorders | ||||||||||
| Dizziness | 2/42 (4.8%) | 2/55 (3.6%) | 2/77 (2.6%) | 6/174 (3.4%) | 2/60 (3.3%) | |||||
| Headache | 5/42 (11.9%) | 6/55 (10.9%) | 12/77 (15.6%) | 23/174 (13.2%) | 8/60 (13.3%) | |||||
| Renal and urinary disorders | ||||||||||
| Enuresis | 0/42 (0%) | 2/55 (3.6%) | 0/77 (0%) | 2/174 (1.1%) | 0/60 (0%) | |||||
| Reproductive system and breast disorders | ||||||||||
| Erection increased | 0/42 (0%) | 1/55 (1.8%) | 2/77 (2.6%) | 3/174 (1.7%) | 0/60 (0%) | |||||
| Spontaneous penile erection | 0/42 (0%) | 2/55 (3.6%) | 1/77 (1.3%) | 3/174 (1.7%) | 0/60 (0%) | |||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||
| Cough | 2/42 (4.8%) | 4/55 (7.3%) | 2/77 (2.6%) | 8/174 (4.6%) | 3/60 (5%) | |||||
| Epistaxis | 1/42 (2.4%) | 2/55 (3.6%) | 3/77 (3.9%) | 6/174 (3.4%) | 2/60 (3.3%) | |||||
| Haemoptysis | 1/42 (2.4%) | 2/55 (3.6%) | 0/77 (0%) | 3/174 (1.7%) | 1/60 (1.7%) | |||||
| Nasal congestion | 0/42 (0%) | 0/55 (0%) | 0/77 (0%) | 0/174 (0%) | 2/60 (3.3%) | |||||
| Rhinorrhoea | 0/42 (0%) | 4/55 (7.3%) | 2/77 (2.6%) | 6/174 (3.4%) | 0/60 (0%) | |||||
| Skin and subcutaneous tissue disorders | ||||||||||
| Rash macular | 0/42 (0%) | 2/55 (3.6%) | 1/77 (1.3%) | 3/174 (1.7%) | 0/60 (0%) | |||||
| Vascular disorders | ||||||||||
| Flushing | 1/42 (2.4%) | 1/55 (1.8%) | 0/77 (0%) | 2/174 (1.1%) | 3/60 (5%) | |||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Pfizer has the right to review disclosures, requesting a delay of < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
| Name/Title | Pfizer ClinicalTrials.gov Call Center |
|---|---|
| Organization | Pfizer, Inc. |
| Phone | 1-800-718-1021 |
| ClinicalTrials.govCallCenter@pfizer.com |
Responsible Party:
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
ClinicalTrials.gov Identifier:
NCT00159913
Other Study ID Numbers:
- A1481131
First Posted:
Sep 12, 2005
Last Update Posted:
Feb 18, 2021
Last Verified:
Jan 1, 2021