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

NCT ID: NCT00159913

Last Updated: 2021-02-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 235 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-08-31
• Study Completion Date: 2008-06-30

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.

Conditions

Pulmonary Arterial Hypertension, Children

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Sildenafil Low dose

Group Type: EXPERIMENTAL

Sildenafil citrate

Intervention Type: DRUG

oral; 10 mg; 3 times a day(TID)

Sildenafil Medium dose

Group Type: EXPERIMENTAL

Sildenafil citrate

Intervention Type: DRUG

oral; 10mg, 20mg and 40mg; 3 times a day(TID)

Sildenafil High dose

Group Type: EXPERIMENTAL

Sildenafil citrate

Intervention Type: DRUG

oral; 20mg, 40mg and 80 mg; 3 times a day(TID)

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

oral; 3 times a day(TID)

Interventions

Sildenafil citrate

oral; 20mg, 40mg and 80 mg; 3 times a day(TID)

Intervention Type: DRUG

Sildenafil citrate

oral; 10mg, 20mg and 40mg; 3 times a day(TID)

Intervention Type: DRUG

Placebo

oral; 3 times a day(TID)

Intervention Type: DRUG

Sildenafil citrate

oral; 10 mg; 3 times a day(TID)

Intervention Type: DRUG

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.
• 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).

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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pfizer CT.gov Call Center

Role: STUDY_DIRECTOR

Pfizer

Locations

Pfizer Investigational Site

Palo Alto, California, United States

Pfizer Investigational Site

Stanford, California, United States

Pfizer Investigational Site

Aurora, Colorado, United States

Pfizer Investigational Site

Boston, Massachusetts, United States

Pfizer Investigational Site

Ann Arbor, Michigan, United States

Pfizer Investigational Site

St Louis, Missouri, United States

Pfizer Investigational Site

New York, New York, United States

Pfizer Investigational Site

Columbus, Ohio, United States

Pfizer Investigational Site

Charleston, South Carolina, United States

Pfizer Investigational Site

Seattle, Washington, United States

Pfizer Investigational Site

São Paulo, São Paulo, Brazil

Pfizer Investigational Site

Edmonton, Alberta, Canada

Pfizer Investigational Site

Santiago, RM, Chile

Pfizer Investigational Site

Medellín, Antioquia, Colombia

Pfizer Investigational Site

Bogota, Cundinamarca, Colombia

Pfizer Investigational Site

Guatemala City, , Guatemala

Pfizer Investigational Site

Budapest, , Hungary

Pfizer Investigational Site

Budapest, , Hungary

Pfizer Investigational Site

Deszk, , Hungary

Pfizer Investigational Site

Szeged, , Hungary

Pfizer Investigational Site

Szeged, , Hungary

Pfizer Investigational Site

Hyderabad, Andhra Pradesh, India

Pfizer Investigational Site

Kerala, Kochi,, India

Pfizer Investigational Site

Bologna, , Italy

Pfizer Investigational Site

Tokyo, , Japan

Pfizer Investigational Site

George Town, Pulau Pinang, Malaysia

Pfizer Investigational Site

George Town, Pulau Pinang, Malaysia

Pfizer Investigational Site

Del. Tlalpan, Mexico City, Mexico

Pfizer Investigational Site

Tlalpan, Mexico DF, Mexico

Pfizer Investigational Site

Lima, , Peru

Pfizer Investigational Site

Krakow, , Poland

Pfizer Investigational Site

Krakow, , Poland

Pfizer Investigational Site

Warsaw, , Poland

Pfizer Investigational Site

Warsaw, , Poland

Pfizer Investigational Site

Zabrze, , Poland

Pfizer Investigational Site

Moscow, , Russia

Pfizer Investigational Site

Moscow, , Russia

Pfizer Investigational Site

Lund, , Sweden

Pfizer Investigational Site

Kaohsiung City, , Taiwan

Pfizer Investigational Site

Taipei, , Taiwan

Pfizer Investigational Site

Taipei, , Taiwan

Countries

United States; Brazil; Canada; Chile; Colombia; Guatemala; Hungary; India; Italy; Japan; Malaysia; Mexico; Peru; Poland; Russia; Sweden; Taiwan

References

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.

Reference Type: DERIVED

PMID: 31908813 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31538282 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28676038 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22963001 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22128226 (View on PubMed)

Related Links

https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=A1481131&StudyName=A%20Randomized%2C%20Double-Blind%2C%20Placebo-Controlled%20Study%20of%20Sildenafil%20in%20Children%20with%20Pulmonary%20Arterial%20Hypertension.

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Other Identifiers

A1481131

Identifier Type: -

Identifier Source: org_study_id