Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Pfizer
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01642407
First received: June 15, 2012
Last updated: July 21, 2014
Last verified: July 2014
  Purpose

Pulmonary arterial hypertension (PAH) is a rare, progressive, and life-threatening disease. In many patients, the course of PAH is a steady deterioration and reduced life expectancy.

Sildenafil was approved by the European Commission for the treatment of PAH in pediatric patients in May 2011, making it the first agent to be approved for the treatment of children with PAH. The approval was based on the largest placebo-controlled study to be conducted in this population. The recommended dose in pediatric patients aged 1 year to 17 years old is 10 mg TID in patients ≤ 20 kg and 20 mg TID for patients > 20 kg. Higher doses are not recommended in pediatrics patients.

This study is an open-label, multi-center study to investigate safety, efficacy and pharmacokinetics of sildenafil citrate in Japanese pediatric patients with PAH.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Hypertension, Pulmonary
Drug: Sildenafil
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 3, Multi-Center, Open-Label Study To Investigate Safety, Efficacy, And Tolerability Of Sildenafil Citrate In Pediatric Patients With Pulmonary Arterial Hypertension

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Change from Baseline in Pulmonary vascular resistance index (PVRI) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    Change from Baseline in Pulmonary vascular resistance index (PVRI)

  • Change from Baseline in Mean pulmonary artery pressure (mPAP) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
  • Change from Baseline in World Health Organization (WHO) Functional Class in Participants with Pulmonary Arterial Hypertension (PAH) [ Time Frame: Baseline, Week 4, 8, 16 ] [ Designated as safety issue: No ]
  • Change from baseline in B-type Natriuretic Peptide (BNP) at Week 16 [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
  • Change from baseline in N-terminal pro-B-type natriuretic peptide (NT pro-BNP) at Week 16 [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
  • Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment [ Time Frame: Baseline up to Week 16 ] [ Designated as safety issue: Yes ]
  • Change from Baseline in Diastolic Blood Pressure [ Time Frame: Baseline, Week 4, 8, 16 ] [ Designated as safety issue: Yes ]
  • Change from Baseline in Systolic Blood Pressure [ Time Frame: Baseline, Week 4, 8, 16 ] [ Designated as safety issue: Yes ]
  • Number of Participants With Laboratory Test Values of Potential Clinical Importance [ Time Frame: Baseline up to Week 16 ] [ Designated as safety issue: Yes ]
  • Change from baseline in 12-lead electrocardiogram (ECG) [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: Yes ]
  • Change from baseline in Ocular safety [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Change from baseline in Hemodynamic parameters [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
    Change from baseline in Hemodynamic parameters

  • Change from baseline in Echocardiogram parameters [ Time Frame: Baseline, Week 16 ] [ Designated as safety issue: No ]
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Pre-dose, 1, 2, 4 and 8 hrs post-dose ] [ Designated as safety issue: No ]
  • Area Under the Curve from Time Zero to end of dosing interval (AUCtau) [ Time Frame: Pre-dose, 1, 2, 4 and 8 hrs post-dose ] [ Designated as safety issue: No ]
  • Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment [ Time Frame: From Baseline to End of study ] [ Designated as safety issue: Yes ]
  • Change from Baseline in Diastolic Blood Pressure at each visit [ Time Frame: From Baseline to End of study ] [ Designated as safety issue: Yes ]
  • Change from Baseline in Systolic Blood Pressure at each visit [ Time Frame: From Baseline to End of study ] [ Designated as safety issue: Yes ]
  • Number of Participants With Laboratory Test Values of Potential Clinical Importance [ Time Frame: From Baseline to End of study ] [ Designated as safety issue: Yes ]
  • Change from baseline in 12-lead ECG [ Time Frame: Baseline, Week 52, End of treatment ] [ Designated as safety issue: Yes ]
  • Change from baseline in Ocular safety [ Time Frame: Baseline, Week 52, End of treatment ] [ Designated as safety issue: Yes ]
  • Change from Baseline in World Health Organization (WHO) Functional Class in Participants with Pulmonary Arterial Hypertension (PAH) at each visit [ Time Frame: From Baseline to End of treatment ] [ Designated as safety issue: No ]
  • Change from baseline in B-type Natriuretic Peptide (BNP) [ Time Frame: Baseline, Week 52, End of treatment ] [ Designated as safety issue: No ]
  • Change from baseline in N-terminal pro-B-type natriuretic peptide (NT pro-BNP) [ Time Frame: Baseline, Week 52, End of treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 10
Study Start Date: August 2012
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sildenafil Drug: Sildenafil
Body weight > 20 kg: 20 mg TID (60 mg/day) Body weight ≤ 20 kg: 10 mg TID (30 mg/day) Treatment duration: 16 weeks in Part 1, until until sildenafil obtained marketing approval in Part 2

  Eligibility

Ages Eligible for Study:   1 Year to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects weighing ≥8 kg.
  • Subjects who have symptomatic pulmonary arterial hypertension due to one of the following conditions:
  • Idiopathic pulmonary arterial hypertension; or
  • Heritable pulmonary arterial hypertension; or
  • Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts. If the defect(s) is repaired, the subject's condition should be stabilized hemodynamically; or
  • Pulmonary arterial hypertension associated with d-transposition of the great arteries repaired within the first 30 days of life; or
  • Pulmonary arterial hypertension in subjects who have undergone surgical repair of other congenital heart lesions and the condition should be stabilized hemodynamically and do not have clinically significant residual left-sided heart disease.
  • Subjects 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.

Exclusion Criteria:

  • Left-sided heart disease.
  • Subjects with Down syndrome.
  • Subjects with Obstructive Sleep Apnea, regardless of treatment status.
  • Pericardial constriction.
  • Subjects with significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation.
  • Acutely decompensated heart failure within previous 30 days from screening.
  • Subjects who have had an atrial septostomy within previous 6 months of screening.
  • Subjects with hemodynamic instability or hypo- or hypertension at screening.
  • Subjects with a history of stroke, myocardial infarction or life threatening arrhythmia within 6 months of screening.
  • Subjects with 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.
  • Subjects with history of pulmonary embolism.
  • Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION).
  • Subjects who are known to be HIV positive.
  • Subjects with impairment of renal function (serum creatinine >2.5 × ULN) or hepatic function (ALT and/or AST >3 × ULN; and/or bilirubin ≥2 mg/dL). Hematological abnormalities (e.g., severe anemia, Hgb <10 g/dL, leukopenia, WBC <2500/µL).
  • Subjects with severe hepatic dysfunction (Child-Pugh classification C).
  • 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.
  • Subjects taking chronic arginine supplementation.
  • Subjects who have received parenteral inotropic medication or parenteral vasodilators within 30 days of Day 1.
  • Subjects who are receiving alpha-blockers, nicorandil, amiodarone or potent cytochrome P450 3A4 inhibitors.
  • Subjects receiving chronic treatment with off-label sildenafil within 30 days of Day 1 are excluded. Subjects receiving an endothelin antagonist,PED5 inhibitor or, prostacyclin/prostacyclin analogue within 30 days of randomization are excluded except for beraprost.
  • Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 28 days after last dose of investigational product.
  • 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.
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
  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: NCT01642407

Contacts
Contact: Pfizer CT.gov Call Center 1-800-718-1021

Locations
Japan
Kanagawa Children's Medical Center Recruiting
Yokohama, Kanagawa, Japan
Nagano Children's Hospital Recruiting
Azumino, Nagano, Japan
Osaka University Hospital Recruiting
Suita, Osaka, Japan
National Center for Child Health and Development Recruiting
Setagaya-ku, Tokyo, Japan
Tokyo Women's Medical University Hospital Recruiting
Shinjyuku-ku, Tokyo, Japan
Fukuoka Children's Hospital & Medical Center for Infectious Diseases Recruiting
Fukuoka, Japan
Shizuoka Children's Hospital Recruiting
Shizuoka, Japan
Toho University Omori Medical Center Recruiting
Tokyo, Japan
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01642407     History of Changes
Other Study ID Numbers: A1481298
Study First Received: June 15, 2012
Last Updated: July 21, 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
Sildenafil
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 28, 2014