Clinical trial NCT00159913: A Randomized, Double-Blind, Placebo-Controlled Study of Sildenafil in Children With Pulmonary Arterial Hypertension.
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension, Children
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2005-09-12
Enrollment: 235
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population
timeFrame: Baseline, Week 16
Secondary outcomes:
measure: Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP)
timeFrame: Baseline, Week 16
measure: Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI)
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER)
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2)
timeFrame: Baseline, Week 16
measure: Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR)
timeFrame: Baseline, Week 16
measure: Change From Baseline to Week 16 in Cardiac Index (CI)
timeFrame: Baseline, Week 16
measure: Change From Baseline to Week 16 in Right Atrial Pressure (RAP)
timeFrame: Baseline, Week 16
measure: Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale
timeFrame: Baseline, Week 16
measure: Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales
timeFrame: Baseline, Week 16
measure: Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class
timeFrame: Baseline, Week 16
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Pfizer Investigational Site
state: California
city: Stanford
country: United States
facility: Pfizer Investigational Site
state: California
city: Aurora
country: United States
facility: Pfizer Investigational Site
state: Colorado
city: Boston
country: United States
facility: Pfizer Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Pfizer Investigational Site
state: Michigan
city: Saint Louis
country: United States
facility: Pfizer Investigational Site
state: Missouri
city: New York
country: United States
facility: Pfizer Investigational Site
state: New York
city: Columbus
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Charleston
country: United States
facility: Pfizer Investigational Site
state: South Carolina
city: Seattle
country: United States
facility: Pfizer Investigational Site
state: Washington
city: São Paulo
country: Brazil
facility: Pfizer Investigational Site
state: SP
city: Edmonton
country: Canada
facility: Pfizer Investigational Site
state: Alberta
city: Santiago
country: Chile
facility: Pfizer Investigational Site
state: RM
city: Medellin
country: Colombia
facility: Pfizer Investigational Site
state: Antioquia
city: Bogota
country: Colombia
facility: Pfizer Investigational Site
state: Cundinamarca
city: Guatemala
country: Guatemala
facility: Pfizer Investigational Site
city: Budapest
country: Hungary
facility: Pfizer Investigational Site
city: Budapest
country: Hungary
facility: Pfizer Investigational Site
city: Deszk
country: Hungary
facility: Pfizer Investigational Site
city: Szeged
country: Hungary
facility: Pfizer Investigational Site
city: Szeged
country: Hungary
facility: Pfizer Investigational Site
city: Hyderabad
country: India
facility: Pfizer Investigational Site
state: Andra Pradesh
city: Kerala
country: India
facility: Pfizer Investigational Site
state: Kochi,
city: Bologna
country: Italy
facility: Pfizer Investigational Site
city: Tokyo
country: Japan
facility: Pfizer Investigational Site
city: Penang
country: Malaysia
facility: Pfizer Investigational Site
city: Penang
country: Malaysia
facility: Pfizer Investigational Site
city: Del. Tlalpan
country: Mexico
facility: Pfizer Investigational Site
state: Mexico D.F.
city: Tlalpan
country: Mexico
facility: Pfizer Investigational Site
state: Mexico DF
city: Lima
country: Peru
facility: Pfizer Investigational Site
city: Krakow
country: Poland
facility: Pfizer Investigational Site
city: Krakow
country: Poland
facility: Pfizer Investigational Site
city: Warszawa
country: Poland
facility: Pfizer Investigational Site
city: Warszawa
country: Poland
facility: Pfizer Investigational Site
city: Zabrze
country: Poland
facility: Pfizer Investigational Site
city: Moscow
country: Russian Federation
facility: Pfizer Investigational Site
city: Moscow
country: Russian Federation
facility: Pfizer Investigational Site
city: Lund
country: Sweden
facility: Pfizer Investigational Site
city: Kaohsiung
country: Taiwan
facility: Pfizer Investigational Site
city: Taipei
country: Taiwan
facility: Pfizer Investigational Site
city: Taipei
country: Taiwan
facility: Pfizer Investigational Site
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.