Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension

NCT01642407 | Completed Phase 4 Results

• 1 other identifier: A1481298
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Pulmonary Arterial Hypertension; Hypertension, Pulmonary

Outcome Measures

Primary Outcomes (7)

• Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16

  PVRI equals pulmonary vascular resistance (PVR) times body surface area (BSA) (PVRI = PVR\*BSA). PVR is the resistance to blood flow through the pulmonary circulation and it was measured in Wood units. Wood unit =80 dyne\*seconds per centimetre\^5 (dyne\*sec/cm\^5).

  Baseline, Week 16

• Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16

  It was a hemodynamic parameter and measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position.

  Baseline, Week 16

• Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 4

  WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of participants in each functional class were reported.

  Baseline, Week 4

• Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 8

  WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of participants in each functional class were reported.

  Baseline, Week 8

• Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Week 16

  WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into "Improved", "No change" and "Worsened". Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of participants in each functional class were reported.

  Baseline, Week 16

• Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16

  BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation.

  Baseline, Week 16

• Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 16

  NT pro-BNP is a cardiac marker, having the prognostic value for participants with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage.

  Baseline, Week 16

Secondary Outcomes (21)

• Change From Baseline in World Health Organization (WHO) Functional Class in Participants With Pulmonary Arterial Hypertension (PAH) at Weeks 28, 40, 52, 64, 76, 88, 100, 112 and 124

  Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124

• Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT)

  Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)

• Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT Pro-BNP) at Week 52 and End of Treatment (EOT)

  Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)

• Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)

• Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)

Other Outcomes (14)

• Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320

  Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16

• Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320

  Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16

• Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320

  Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16

Study Arms (1)

Sildenafil

EXPERIMENTAL

Drug: Sildenafil

Interventions

Sildenafil DRUG

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

Sildenafil

Eligibility Criteria

• Age: 1 Year - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

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

Study Sites (5)

Kitasato University Hospital

Sagamihara, Kanagawa, 252-0375, Japan

Location

Osaka University Hospital

Suita, Osaka, 565-0871, Japan

Location

Toho University Omori Medical Center

Ōta-ku, Tokyo, 143-8541, Japan

Location

National Center for Child Health and Development

Setagaya-ku, Tokyo, 157-8535, Japan

Location

Shizuoka Children's Hospital

Shizuoka, 420-8660, Japan

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Hypertension, Pulmonary

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2012
• First Posted: July 17, 2012
• Study Start: August 24, 2012
• Primary Completion: May 20, 2016
• Study Completion: March 12, 2018
• Last Updated: February 1, 2021
• Results First Posted: April 4, 2017

Record last verified: 2021-01

Locations

JP (5)