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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00159913
First received: September 8, 2005
Last updated: January 23, 2014
Last verified: January 2014
  Purpose

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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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.

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    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.


Enrollment: 235
Study Start Date: August 2003
Study Completion Date: June 2008
Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)

  Eligibility

Ages Eligible for Study:   1 Year to 17 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00159913

  Hide Study 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
St. 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, 1096
Pfizer Investigational Site
Budapest, Hungary, 1083
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, 127412
Pfizer Investigational Site
Moscow, Russian Federation, 121552
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
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided by Pfizer

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00159913     History of Changes
Other Study ID Numbers: A1481131
Study First Received: September 8, 2005
Results First Received: June 2, 2009
Last Updated: January 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases
Citric Acid
Sildenafil
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Chelating Agents
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Cardiovascular Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 23, 2014