A Randomized, Double-Blind, Placebo-Controlled Study of Sildenafil in Children With Pulmonary Arterial Hypertension.

• ClinicalTrials.gov Identifier: NCT00159913
• Recruitment Status: Completed
• First Posted: September 12, 2005
• Results First Posted: July 21, 2009
• Last Update Posted: February 18, 2021
• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• Information provided by (Responsible Party): Pfizer ( Pfizer's Upjohn has merged with Mylan to form Viatris Inc. )

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
Pulmonary Arterial Hypertension, Children	Drug: Sildenafil citrate; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• 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: August 2003
• Actual Primary Completion Date: June 2008
• Actual Study Completion Date: June 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 :

1. Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population [ Time Frame: 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%.
2. Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population [ Time Frame: 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 :

1. Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP) [ Time Frame: 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.
2. Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI) [ Time Frame: 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.
3. Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER) [ Time Frame: 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%
4. Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2) [ Time Frame: 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%
5. Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR) [ Time Frame: Baseline, Week 16 ]
   Change calculated as (mean PAP - PCWP)/COpulm in PVR is observed value at Week 16 minus Baseline value.
6. Change From Baseline to Week 16 in Cardiac Index (CI) [ Time Frame: 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).
7. Change From Baseline to Week 16 in Right Atrial Pressure (RAP) [ Time Frame: 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.
8. Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale [ Time Frame: 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.
9. Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales [ Time Frame: 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.
10. Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class [ Time Frame: 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

• Ages Eligible for Study: 1 Year to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, California

Pfizer Investigational Site

Palo Alto, California, United States, 94304

Pfizer Investigational Site

Stanford, California, United States, 94305

United States, Colorado

Pfizer Investigational Site

Aurora, Colorado, United States, 80045

United States, Massachusetts

Pfizer Investigational Site

Boston, Massachusetts, United States, 02115

United States, Michigan

Pfizer Investigational Site

Ann Arbor, Michigan, United States, 48109

United States, Missouri

Pfizer Investigational Site

Saint Louis, Missouri, United States, 63110

United States, New York

Pfizer Investigational Site

New York, New York, United States, 10032

United States, Ohio

Pfizer Investigational Site

Columbus, Ohio, United States, 43205

United States, South Carolina

Pfizer Investigational Site

Charleston, South Carolina, United States, 29425

United States, Washington

Pfizer Investigational Site

Seattle, Washington, United States, 98105

Brazil

Pfizer Investigational Site

São Paulo, SP, Brazil, 04012-909

Canada, Alberta

Pfizer Investigational Site

Edmonton, Alberta, Canada, T6G 2B7

Chile

Pfizer Investigational Site

Santiago, RM, Chile

Colombia

Pfizer Investigational Site

Medellin, Antioquia, Colombia, 0

Pfizer Investigational Site

Bogota, Cundinamarca, Colombia, 0

Guatemala

Pfizer Investigational Site

Guatemala, Guatemala

Hungary

Pfizer Investigational Site

Budapest, Hungary, 1083

Pfizer Investigational Site

Budapest, Hungary, 1096

Pfizer Investigational Site

Deszk, Hungary, 6722

Pfizer Investigational Site

Szeged, Hungary, 6720

Pfizer Investigational Site

Szeged, Hungary, 6726

India

Pfizer Investigational Site

Hyderabad, Andra Pradesh, India, 500 001

Pfizer Investigational Site

Kerala, Kochi,, India, 682 026

Italy

Pfizer Investigational Site

Bologna, Italy, 40138

Japan

Pfizer Investigational Site

Tokyo, Japan

Malaysia

Pfizer Investigational Site

Penang, Malaysia, 10050

Pfizer Investigational Site

Penang, Malaysia, 10900

Mexico

Pfizer Investigational Site

Del. Tlalpan, Mexico D.F., Mexico, 14080

Pfizer Investigational Site

Tlalpan, Mexico DF, Mexico, 14080

Peru

Pfizer Investigational Site

Lima, Peru, L13

Poland

Pfizer Investigational Site

Krakow, Poland, 30-663

Pfizer Investigational Site

Krakow, Poland, 31-202

Pfizer Investigational Site

Warszawa, Poland, 04-628

Pfizer Investigational Site

Warszawa, Poland, 04-730

Pfizer Investigational Site

Zabrze, Poland, 41-800

Russian Federation

Pfizer Investigational Site

Moscow, Russian Federation, 121552

Pfizer Investigational Site

Moscow, Russian Federation, 127412

Sweden

Pfizer Investigational Site

Lund, Sweden, 221 85

Taiwan

Pfizer Investigational Site

Kaohsiung, Taiwan, 81346

Pfizer Investigational Site

Taipei, Taiwan, 100

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

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Russell S, Beghetti M, Oudiz R, Balagtas C, Zhang M, Ivy D. Effects of oral sildenafil on exercise capacity in children with pulmonary arterial hypertension: a randomised trial. Open Heart. 2019 Dec 3;6(2):e001149. doi: 10.1136/openhrt-2019-001149. eCollection 2019.

Chanu P, Gao X, Bruno R, Claret L, Harnisch L. A modeling and simulation-based assessment of the impact of confounding factors on the readout of a sildenafil survival trial in pulmonary arterial hypertension. J Pharmacokinet Pharmacodyn. 2019 Oct;46(5):499-509. doi: 10.1007/s10928-019-09654-3. Epub 2019 Sep 20.

Beghetti M, Rudzinski A, Zhang M. Efficacy and safety of oral sildenafil in children with Down syndrome and pulmonary hypertension. BMC Cardiovasc Disord. 2017 Jul 4;17(1):177. doi: 10.1186/s12872-017-0569-3.

Cappelleri JC, Hwang LJ, Mardekian J, Mychaskiw MA. Assessment of measurement properties of peak VO(2) in children with pulmonary arterial hypertension. BMC Pulm Med. 2012 Sep 10;12:54. doi: 10.1186/1471-2466-12-54.

Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BK, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012 Jan 17;125(2):324-34. doi: 10.1161/CIRCULATIONAHA.110.016667. Epub 2011 Nov 29.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT00159913
• Other Study ID Numbers: A1481131
• First Posted: September 12, 2005
• Results First Posted: July 21, 2009
• Last Update Posted: February 18, 2021
• Last Verified: January 2021

Additional relevant MeSH terms:

Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Vascular Diseases; Cardiovascular Diseases; Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Sildenafil Citrate; Citric Acid; Sodium Citrate; Anticoagulants; Calcium Chelating Agents; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Urological Agents