Pulmonary Arterial Hypertension, Children
Conditions
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.
Interventions
DRUGSildenafil citrate
oral; 20mg, 40mg and 80 mg; 3 times a day(TID)
DRUGPlacebo
oral; 3 times a day(TID)
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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 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. |
Countries
Brazil, Canada, Chile, Colombia, Guatemala, Hungary, India, Italy, Japan, Malaysia, Mexico, Peru, Poland, Russia, Sweden, Taiwan, United States
Participant flow
Recruitment details
The study was conducted at 32 centers in North, Latin and South America, Europe and Asia.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Low Dose 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. | 42 |
| Sildenafil Medium Dose 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 | 55 |
| Sildenafil High Dose 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 | 77 |
| Placebo Subjects randomized to this arm recieved placebo TID (three times daily) for 112 days. | 60 |
| Total | 234 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Sildenafil Low Dose | Total | Placebo | Sildenafil High Dose | Sildenafil Medium Dose |
|---|---|---|---|---|---|
| Age, Customized 13-17 Years | 17 participants | 73 participants | 16 participants | 22 participants | 18 participants |
| Age, Customized 1-4 Years | 0 participants | 35 participants | 7 participants | 19 participants | 9 participants |
| Age, Customized >= 18 Years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized 5-12 Years | 25 participants | 126 participants | 37 participants | 36 participants | 28 participants |
| Sex: Female, Male Female | 25 Participants | 145 Participants | 38 Participants | 51 Participants | 31 Participants |
| Sex: Female, Male Male | 17 Participants | 89 Participants | 22 Participants | 26 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / — | 37 / — | 44 / — | 102 / — | 29 / — |
| serious Total, serious adverse events | 1 / — | 1 / — | 7 / — | 9 / — | 2 / — |
Outcome results
Primary
Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population | 6.44 percent change | Standard Deviation 20.16 |
| Sildenafil Medium Dose | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population | 13.40 percent change | Standard Deviation 19.5 |
| Sildenafil High Dose | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population | 10.58 percent change | Standard Deviation 15.51 |
| Combined Sildenafil | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population | 10.24 percent change | Standard Deviation 18.39 |
| Placebo | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population | 0.53 percent change | Standard Deviation 15.91 |
p-value: 0.05695% CI: [-0.19, 15.6]ANCOVA
95% CI: [-6.11, 13.73]ANCOVA
95% CI: [1.72, 20.94]ANCOVA
95% CI: [-1.64, 17.6]ANCOVA
Primary
Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population
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
Population: Per Protocol Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population | 5.43 percent change | Standard Deviation 20.69 |
| Sildenafil Medium Dose | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population | 15.66 percent change | Standard Deviation 21.48 |
| Sildenafil High Dose | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population | 9.34 percent change | Standard Deviation 17.13 |
| Combined Sildenafil | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population | 10.10 percent change | Standard Deviation 19.87 |
| Placebo | Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population | 2.81 percent change | Standard Deviation 13.17 |
p-value: 0.17995% CI: [-2.74, 14.53]ANCOVA
95% CI: [-9.49, 11.77]ANCOVA
95% CI: [0.66, 21.96]ANCOVA
95% CI: [-5.02, 15.5]ANCOVA
Secondary
Change From Baseline to Week 16 in Cardiac Index (CI)
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
Population: ITT population, using LOCF (end of treatment) approach for handling missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in Cardiac Index (CI) | 0.20 liters/minute/meters squared | Standard Deviation 1.17 |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in Cardiac Index (CI) | 0.02 liters/minute/meters squared | Standard Deviation 1.44 |
| Sildenafil High Dose | Change From Baseline to Week 16 in Cardiac Index (CI) | 0.24 liters/minute/meters squared | Standard Deviation 2.19 |
| Combined Sildenafil | Change From Baseline to Week 16 in Cardiac Index (CI) | 0.16 liters/minute/meters squared | Standard Deviation 1.76 |
| Placebo | Change From Baseline to Week 16 in Cardiac Index (CI) | -0.60 liters/minute/meters squared | Standard Deviation 2.12 |
p-value: 0.01595% CI: [0.14, 1.34]ANCOVA
95% CI: [-0.1, 1.52]ANCOVA
95% CI: [-0.12, 1.35]ANCOVA
95% CI: [0.21, 1.58]ANCOVA
Secondary
Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale
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
Population: ITT population, includes subjects \>= 5 years with a valid questionnaire available in the subject's first language.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale | 14.0 score on scale | Standard Deviation 13.1 |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale | 9.8 score on scale | Standard Deviation 11.8 |
| Sildenafil High Dose | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale | 5.9 score on scale | Standard Deviation 10.5 |
| Combined Sildenafil | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale | 9.4 score on scale | Standard Deviation 12.1 |
| Placebo | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale | 8.3 score on scale | Standard Deviation 12 |
p-value: 0.7595% CI: [-4.45, 3.21]ANCOVA
95% CI: [-4.21, 5.95]ANCOVA
95% CI: [-4.68, 5.15]ANCOVA
95% CI: [-7.37, 1.45]ANCOVA
Secondary
Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales
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
Population: ITT population, includes subjects \>= 5years with a valid questionnaire available in the subject's first language.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales | 5.1 score on scale | Standard Deviation 6.9 |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales | 4.1 score on scale | Standard Deviation 8.1 |
| Sildenafil High Dose | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales | 4.3 score on scale | Standard Deviation 10 |
| Combined Sildenafil | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales | 4.5 score on scale | Standard Deviation 8.6 |
| Placebo | Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales | 5.6 score on scale | Standard Deviation 10.3 |
p-value: 0.78495% CI: [-3.41, 2.58]ANCOVA
95% CI: [-3.49, 4.3]ANCOVA
95% CI: [-5.99, 1.77]ANCOVA
95% CI: [-3.06, 3.97]ANCOVA
Secondary
Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP)
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
Population: ITT population, using a LOCF (end-of-treatment) approach for handling missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) | 0.9 mm Hg | Standard Deviation 12.3 |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) | -3.9 mm Hg | Standard Deviation 12 |
| Sildenafil High Dose | Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) | -7.4 mm Hg | Standard Deviation 15.4 |
| Combined Sildenafil | Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) | -4.3 mm Hg | Standard Deviation 13.9 |
| Placebo | Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) | -0.4 mm Hg | Standard Deviation 15.9 |
p-value: 0.17295% CI: [-7.5, 1.3]ANCOVA
95% CI: [-4.5, 7.6]ANCOVA
95% CI: [-8.9, 1.9]ANCOVA
95% CI: [-12.4, -2.1]ANCOVA
Secondary
Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI)
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
Population: ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) | 0.1 wood units. m2 | Standard Deviation 10.9 |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) | -2.9 wood units. m2 | Standard Deviation 11.5 |
| Sildenafil High Dose | Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) | -5.1 wood units. m2 | Standard Deviation 14.7 |
| Combined Sildenafil | Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) | -3.2 wood units. m2 | Standard Deviation 13 |
| Placebo | Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) | 1.6 wood units. m2 | Standard Deviation 9.2 |
p-value: 0.04195% CI: [-8, -0.2]ANCOVA
95% CI: [-5.9, 4.7]ANCOVA
95% CI: [-9.3, 0.3]ANCOVA
95% CI: [-11.7, -2.7]ANCOVA
Secondary
Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR)
Change calculated as (mean PAP - PCWP)/COpulm in PVR is observed value at Week 16 minus Baseline value.
Time frame: Baseline, Week 16
Population: ITT population, using LOCF (end of treatment) approach for handling missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) | -0.1 wood units | Standard Deviation 10.4 |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) | -3.3 wood units | Standard Deviation 10.5 |
| Sildenafil High Dose | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) | -5.2 wood units | Standard Deviation 15.7 |
| Combined Sildenafil | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) | -3.4 wood units | Standard Deviation 13.1 |
| Placebo | Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) | 0.1 wood units | Standard Deviation 11.8 |
p-value: 0.17295% CI: [-7.1, 1.3]ANCOVA
95% CI: [-5.5, 5.9]ANCOVA
95% CI: [-8.5, 1.7]ANCOVA
95% CI: [-10.3, -0.7]ANCOVA
Secondary
Change From Baseline to Week 16 in Right Atrial Pressure (RAP)
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
Population: ITT population, using LOCF (end of treatment) approach for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in Right Atrial Pressure (RAP) | 7.92 mm Hg | Standard Deviation 2.85 |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in Right Atrial Pressure (RAP) | 8.05 mm Hg | Standard Deviation 4.42 |
| Sildenafil High Dose | Change From Baseline to Week 16 in Right Atrial Pressure (RAP) | 7.75 mm Hg | Standard Deviation 4.14 |
| Combined Sildenafil | Change From Baseline to Week 16 in Right Atrial Pressure (RAP) | 7.89 mm Hg | Standard Deviation 3.95 |
| Placebo | Change From Baseline to Week 16 in Right Atrial Pressure (RAP) | 8.11 mm Hg | Standard Deviation 3.61 |
p-value: 0.4495% CI: [-1.77, 0.77]ANCOVA
95% CI: [-1.91, 1.57]ANCOVA
95% CI: [-1.73, 1.36]ANCOVA
95% CI: [-2.61, 0.33]ANCOVA
Secondary
Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class
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
Population: ITT population, LOCF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sildenafil Low Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 2 classes | 0 units |
| Sildenafil Low Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 1 class | 6 units |
| Sildenafil Low Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | No change | 25 units |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 1 class | 10 units |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | No change | 24 units |
| Sildenafil Medium Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 2 classes | 0 units |
| Sildenafil High Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 1 class | 16 units |
| Sildenafil High Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 2 classes | 1 units |
| Sildenafil High Dose | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | No change | 38 units |
| Combined Sildenafil | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | No change | 84 units |
| Combined Sildenafil | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 1 class | 32 units |
| Combined Sildenafil | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 2 classes | 1 units |
| Placebo | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 2 classes | 0 units |
| Placebo | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | Improved by 1 class | 4 units |
| Placebo | Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class | No change | 31 units |
p-value: 0.18495% CI: [0.75, 4.45]Regression, Logistic
p-value: 0.40995% CI: [0.18, 2.01]Regression, Logistic
p-value: 0.14695% CI: [0.75, 6.69]Regression, Logistic
p-value: 0.00695% CI: [1.56, 13.1]Regression, Logistic
Secondary
Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER)
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
Population: ITT population, LOCF (end-of-treatment) approach for handling missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) | -0.00 percent change | Standard Deviation 0.13 |
| Sildenafil Medium Dose | Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) | -0.05 percent change | Standard Deviation 0.12 |
| Sildenafil High Dose | Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) | -0.02 percent change | Standard Deviation 0.11 |
| Combined Sildenafil | Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) | -0.03 percent change | Standard Deviation 0.12 |
| Placebo | Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) | -0.03 percent change | Standard Deviation 0.11 |
p-value: 0.79595% CI: [-4.07, 5.3]ANCOVA
95% CI: [-3.31, 8.54]ANCOVA
95% CI: [-7.09, 4.5]ANCOVA
95% CI: [-5.24, 6.28]ANCOVA
Secondary
Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2)
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
Population: ITT population, LOCF (end-of-treatment) approach for handling missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Low Dose | Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) | 64.83 percent change | Standard Deviation 103.69 |
| Sildenafil Medium Dose | Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) | 64.42 percent change | Standard Deviation 102.7 |
| Sildenafil High Dose | Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) | 31.33 percent change | Standard Deviation 107.04 |
| Combined Sildenafil | Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) | 52.95 percent change | Standard Deviation 104.4 |
| Placebo | Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) | 8.84 percent change | Standard Deviation 96.09 |
p-value: 0.13995% CI: [-3.05, 21.54]ANCOVA
95% CI: [-5.21, 25.9]ANCOVA
95% CI: [-3.78, 26.64]ANCOVA
95% CI: [-9.16, 21.08]ANCOVA