A Long Term Extension Study Evaluating Safety Of Sildenafil Citrate When Used To Treat Pulmonary Arterial Hypertension (PAH) In Children

NCT00159874 | Completed Phase 3 Results DMC

• 1 other identifier: A1481156
• Study Type: interventional
• Target: 234
• Locations: 15 countries
• Sites: 39

Brief Summary

Active treatment, dose-blinded extension study evaluating the safety and long term efficacy of sildenafil citrate in children with PAH.

Conditions

Pulmonary Arterial Hypertension

Keywords

children

Outcome Measures

Primary Outcomes (14)

• Number of Participants Reporting at Least One Adverse Event

  Safety was measured according to standard adverse event collection as described in the adverse event section of the results. Complete tables of the adverse events according to the A1481156 treatment groups are provided in the reported adverse event section.

  Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)

• Number of Participants Reporting Treatment-related Adverse Events

  Safety was measured according to standard adverse event collection as described in the adverse event section of the results.

  Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)

• Number of Participants Reporting at Least One Serious Adverse Event

  Safety was measured according to standard adverse event collection as described in the adverse event section of the results. Complete tables of the serious adverse events according to the A1481156 treatment groups are provided in the reported adverse event section.

  Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)

• Number of Participants Reporting Treatment-related Serious Adverse Events

  All serious adverse events regardless of treatment group or suspected relationship to study drug were reported. Investigators were to provide independent determination of possible causality of any serious adverse event.

  Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)

• Number of Deaths Reported in the Study Prior to the Data Monitoring Committee (DMC) Recommendation of Dose Down Titration

  Deaths were reported immediately independent of the circumstances or suspected cause at any time during the study through the last follow-up visit or 30 days after the last administration of study drug, whichever comes later.

  Pre-DMC Recommendation dose down titration (04 August 2011)

• Number of Deaths Reported During This Study

  Deaths were reported immediately independent of the circumstances or suspected cause at any time during the study through the last follow-up visit or 30 days after the last administration of study drug, whichever comes later.

  Last follow-up visit or 30 days after the last administration of study drug

• Discontinuation Due to Intolerability

  Participant who experienced drug-related intolerance, the participant's dose was reduced by 50%. If, after a dose reduction, the participant continued to appear intolerant, they were discontinued from study treatment.

  Throughout the treatment duration (median treatment duration 1689 to 1744 days)

• Downtitration in Dose Due to Intolerability.

  Based on review of the survival data, DMC concluded that the high dose of sildenafil was associated with a harmful effect on survival when compared to the low dose. The DMC also expressed concern as to the potential dose-response relationship between increasing dose and mortality. Therefore, on 04 August 2011, the DMC recommended discontinuation of the 40 mg and 80 mg three times a day (TID) doses, as well as the 20 mg TID dose in children with body weight ≤20 kg. The protocol was amended per DMC recommendations.

  Pre-DMC recomendation (04 August 2011)

• Number of Participants With Deterioration Post Baseline in Visual Acuity Safety Tests

  Visual Acuity is measured either using the reduced Snellen test or via Teller cards, and was assessed in the left and right eyes separately. There were 9 lines on the reduced Snellen chart which were coded as 6/60, 6/36, 6/24, 6/18, 6/12, 6/9, 6/6, 6/5, 6/4 (where 6/60 was the easiest to read and 6/4 was the most difficult to read). If a participant experienced a visual adverse event the investigator was asked to perform additional ocular assessments either at the visit when the participant reported the visual adverse event or at an unplanned visit.

  Week 36

• Number of Participants With Deterioration Post Baseline in Color Vision Monitoring Safety Tests.

  Colour vision was measured where appropriate via the Farnsworth-Munsell D-15 Hue test. This test was performed in both eyes simultaneously or just in a single specific eye. If using a single eye the same eye was used throughout the study. In case of young participants an age-and-ability-appropriate evaluation such as the Ishihara Test for Unlettered Persons were conducted.

  Week 36

• Pediatric Cognitive Development Status at Week 16.

  Participant's cognitive development status was assessed at A1481156 baseline (Week 16 in A1481131; NCT00159913) using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's cognitive development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.

  Week 16

• Pediatric Cognitive Development Status at Week 52.

  Participant's cognitive development status was assessed at Week 52 using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's cognitive development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.

  Week 52

• Pediatric Motor Development Status at Week 16.

  Participant's motor development status was assessed at A1481156 baseline (Week 16 in A1481131; NCT00159913) using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's motor development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.

  Week 16

• Pediatric Motor Development Status at Week 52

  Participant's motor development status was assessed at Week 52 using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's motor development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.

  Week 52

Secondary Outcomes (17)

• Peak Volume of Oxygen (VO2) Consumed at Year 1 Using a Bicycle Ergometry Cardiopulmonary Exercise Test (CPX)

  1 year

• Percentage Change From Baseline in Percent Predicted Peak VO2 at Year 1.

  Baseline, Year 1

• Percent Change From Baseline in Time to Maximum VO2 at Year 1

  Baseline, Year 1

• Percent Change From Baseline in Respiratory Exchange Ratio at Year 1

  Baseline, Year 1

• Percent Change From Start of Sildenafil in Total Ventilation (VE) to Year 1

  Year 1

Study Arms (3)

Sildenafil high dose

EXPERIMENTAL

As per Protocol Amendment 8 (Aug 2011), all doses in the high dose treatment group were discontinued. Subjects who were receiving these doses and continued in the study were requested to down titrate.

Drug: Sildenafil citrate

Sildenafil Low dose

EXPERIMENTAL

Drug: Sildenafil citrate

Sildenafil medium dose

EXPERIMENTAL

As per Protocol Amendment 8 (August 2011), the dose 40 mg TID in the medium dose treatment group was discontinued. Subjects who were receiving this dose and continued in the study were requested to down titrate.

Drug: Sildenafil citrate

Interventions

Sildenafil citrate DRUG

Oral, subjects with body weight ≥8 - 20 kg: 20 mg 3 times a day (tid) subjects with body weight \>20 - 45 kg: 40 mg 3 times a day (tid) subjects with body weight \>45 kg: 80 mg 3 times a day (tid)

Sildenafil high dose

Eligibility Criteria

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

You may qualify if:

• Patients must complete the 16 Week double-blind efficacy study A1481131.

You may not qualify if:

• Any patient who did not complete Study A1481131.

Sponsors & Collaborators

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

Study Sites (39)

Pfizer Investigational Site

Palo Alto, California, 34304, United States

Location

Pfizer Investigational Site

Palo Alto, California, 94305, United States

Location

Pfizer Investigational Site

Stanford, California, 94305, United States

Location

Pfizer Investigational Site

Aurora, Colorado, 80045, United States

Location

Pfizer Investigational Site

Boston, Massachusetts, 02115, United States

Location

Pfizer Investigational Site

Ann Arbor, Michigan, 48109, United States

Location

Pfizer Investigational Site

St Louis, Missouri, 63110, United States

Location

Pfizer Investigational Site

New York, New York, 10032, United States

Location

Pfizer Investigational Site

Columbus, Ohio, 43205, United States

Location

Pfizer Investigational Site

Charleston, South Carolina, 29425, United States

Location

Pfizer Investigational Site

Seattle, Washington, 98105, United States

Location

Pfizer Investigational Site

São Paulo, São Paulo, 04012-909, Brazil

Location

Pfizer Investigational Site

São Paulo, São Paulo, 04023-062, Brazil

Location

Pfizer Investigational Site

Puente Alto, Santiago Metropolitan, Chile

Location

Pfizer Investigational Site

Medellín, Antioquia, Colombia

Location

Pfizer Investigational Site

Bogota, Cundinamarca, Colombia

Location

Pfizer Investigational Site

Guatemala City, Guatemala

Location

Pfizer Investigational Site

Budapest, 1083, Hungary

Location

Pfizer Investigational Site

Budapest, 1096, Hungary

Location

Pfizer Investigational Site

Szeged, 6720, Hungary

Location

Pfizer Investigational Site

Hyderabad, Andhra Pradesh, 500 001, India

Location

Pfizer Investigational Site

Hyderabad, Andhra Pradesh, 500 073, India

Location

Pfizer Investigational Site

Kochi, Kerala, 682 041, India

Location

Pfizer Investigational Site

Bologna, 40138, Italy

Location

Pfizer Investigational Site

Tokyo, Japan

Location

Pfizer Investigational Site

George Town, Pulau Pinang, 10050, Malaysia

Location

Pfizer Investigational Site

George Town, Pulau Pinang, 10900, Malaysia

Location

Pfizer Investigational Site

George Town, Pulau Pinang, 11600, Malaysia

Location

Pfizer Investigational Site

Mexico City, Mexico City, 14080, Mexico

Location

Pfizer Investigational Site

Krakow, 30-663, Poland

Location

Pfizer Investigational Site

Ruda Śląska, 41-703, Poland

Location

Pfizer Investigational Site

Warsaw, 04-730, Poland

Location

Pfizer Investigational Site

Zabrze, 41-800, Poland

Location

Pfizer Investigational Site

Moscow, 115478, Russia

Location

Pfizer Investigational Site

Moscow, 125412, Russia

Location

Pfizer Investigational Site

Lund, 221 85, Sweden

Location

Pfizer Investigational Site

Kaohsiung City, 81346, Taiwan

Location

Pfizer Investigational Site

Taipei, 100, Taiwan

Location

Pfizer Investigational Site

Taipei, 11217, Taiwan

Location

Related Publications (3)

• 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.

  PMID: 31908813 DERIVED

• 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.

  PMID: 31538282 DERIVED

• Barst RJ, Beghetti M, Pulido T, Layton G, Konourina I, Zhang M, Ivy DD; STARTS-2 Investigators. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014 May 13;129(19):1914-23. doi: 10.1161/CIRCULATIONAHA.113.005698. Epub 2014 Mar 17.

  PMID: 24637559 DERIVED

Related Links

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

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract 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 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2005
• First Posted: September 12, 2005
• Study Start: January 1, 2004
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: February 1, 2021
• Results First Posted: August 11, 2014

Record last verified: 2021-01

Locations

GU (1); BR (2); HU (3); CL (1); US (11); SE (1); ME (1); PL (4); IT (1); IN (3); TW (3); MY (3); RU (2); CO (2); JP (1)