A Randomized, Double-Blind, Placebo-Controlled Study of Sildenafil in Children With Pulmonary Arterial Hypertension.
Condition: Pulmonary Arterial Hypertension, Children
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Sildenafil citrate; Sildenafil citrate; Placebo; Sildenafil citrate
Intervention description: oral; 20mg, 40mg and 80 mg; 3 times a day(TID); oral; 10mg, 20mg and 40mg; 3 times a day(TID); oral; 3 times a day(TID); oral; 10 mg; 3 times a day(TID)
Intervention MeSH terms: Sildenafil Citrate; Citric Acid; Sodium Citrate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 235.0
Sex: All
Minimum age: 1 Year
Maximum age: 17 Years
Healthy volunteers: No

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.
    

Eligibility 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).