Pulmonary Arterial HypertensionPhase 3NCT00159874
A Long Term Extension Study Evaluating Safety Of Sildenafil Citrate When Used To Treat Pulmonary Arterial Hypertension (PAH) In Children
A Phase 3 study testing Sildenafil citrate in people with Pulmonary Arterial Hypertension, run by Pfizer's Upjohn has merged with Mylan to form Viatris Inc. at 39 sites in 15 countries.
Trial summary
Active treatment, dose-blinded extension study evaluating the safety and long term efficacy of sildenafil citrate in children with PAH. Read more about this study
- Who is it for?
- Ages 1 year to 17 years
- Conditions the study is for
- Pulmonary Arterial Hypertension
- What is being tested?
- Sildenafil citrate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 234 participants
- Where
- 39 sitesin 15 countries
- Study dates
- Jan 2004to Dec 2012
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Patients must complete the 16 Week double-blind efficacy study A1481131.
Who cannot join
- Any patient who did not complete Study A1481131.
Trial locations and contacts
39 sites in 15 countries.
39 sites in 15 countries
United States11 sites
Pfizer Investigational Site
Ann Arbor, Michigan, 48109
Pfizer Investigational Site
Aurora, Colorado, 80045
Pfizer Investigational Site
Boston, Massachusetts, 02115
Pfizer Investigational Site
Charleston, South Carolina, 29425
Pfizer Investigational Site
Columbus, Ohio, 43205
Pfizer Investigational Site
New York, New York, 10032
Pfizer Investigational Site
Palo Alto, California, 34304
Pfizer Investigational Site
Palo Alto, California, 94305
Pfizer Investigational Site
Seattle, Washington, 98105
Pfizer Investigational Site
St Louis, Missouri, 63110
Pfizer Investigational Site
Stanford, California, 94305
Poland4 sites
Pfizer Investigational Site
Krakow, 30-663
Pfizer Investigational Site
Ruda Śląska, 41-703
Pfizer Investigational Site
Warsaw, 04-730
Pfizer Investigational Site
Zabrze, 41-800
Hungary3 sites
Pfizer Investigational Site
Budapest, 1083
Pfizer Investigational Site
Budapest, 1096
Pfizer Investigational Site
Szeged, 6720
India3 sites
Pfizer Investigational Site
Hyderabad, Andhra Pradesh, 500 001
Pfizer Investigational Site
Hyderabad, Andhra Pradesh, 500 073
Pfizer Investigational Site
Kochi, Kerala, 682 041
Malaysia3 sites
Pfizer Investigational Site
George Town, Pulau Pinang, 10050
Pfizer Investigational Site
George Town, Pulau Pinang, 10900
Pfizer Investigational Site
George Town, Pulau Pinang, 11600
Taiwan3 sites
Pfizer Investigational Site
Kaohsiung City, 81346
Pfizer Investigational Site
Taipei, 100
Pfizer Investigational Site
Taipei, 11217
Brazil2 sites
Pfizer Investigational Site
São Paulo, São Paulo, 04012-909
Pfizer Investigational Site
São Paulo, São Paulo, 04023-062
Colombia2 sites
Pfizer Investigational Site
Bogota, Cundinamarca
Pfizer Investigational Site
Medellín, Antioquia
Russia2 sites
Pfizer Investigational Site
Moscow, 115478
Pfizer Investigational Site
Moscow, 125412
About this study
Official title: A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil Citrate In The Treatment Of Subjects Who Have Completed Study A1481131
Active treatment, dose-blinded extension study evaluating the safety and long term efficacy of sildenafil citrate in children with PAH.
- Conditions
- Pulmonary Arterial Hypertension
- Being tested
- Sildenafil citrate
- Keywords
- children
- Medical subject headings
- Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sildenafil citrateDrug
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 citrateDrug
Oral,10 mg 3 times a day (tid), only subjects with body weight >20 kg
Sildenafil citrateDrug
Oral, subjects with body weight ≥8 - 20 kg: 10 mg 3 times a day (tid); subjects with body weight >20 - 45 kg: 20 mg 3 times a day (tid); subjects with body weight >45 kg: 40 mg 3 times a day (tid)
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Sildenafil citrate |
| Sildenafil Low dose | Experimental | Not described Receives: 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. Receives: Drug: Sildenafil citrate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Week 52
Secondary outcomes (17)
Peak Volume of Oxygen (VO2) Consumed at Year 1 Using a Bicycle Ergometry Cardiopulmonary Exercise Test (CPX)
Exercise Tolerance Test (CPX test) was performed on developmentally able participants to determine the peak volume of VO2 consumed. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant
Measured: 1 year
Percentage Change From Baseline in Percent Predicted Peak VO2 at Year 1.
Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the percent predicted peak VO2 at Week 16 and Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.
Measured: Baseline, Year 1
Percent Change From Baseline in Time to Maximum VO2 at Year 1
Exercise Tolerance Test (CPX test) was performed on developmentally able participants to determine the time to maximum VO2. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.
Measured: Baseline, Year 1
Percent Change From Baseline in Respiratory Exchange Ratio at Year 1
This is the ratio of carbon dioxide (CO2) produced to O2 consumed [VCO2/VO2]. Exercise Tolerance Test was performed on developmentally able participants to determine the respiratory exchange ratio on week 16 and Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913).
Measured: Baseline, Year 1
Percent Change From Start of Sildenafil in Total Ventilation (VE) to Year 1
Exercise Tolerance Test (CPX test) was performed on developmentally able participants to determine the total ventilation. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.
Measured: Year 1
Percentage Change From Baseline in End Tidal Oxygen (O2) at Year 1.
Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the End Tidal O2 at Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.
Measured: Baseline, Year 1
Percentage Change From Baseline in End Tidal Carbon Dioxide (CO2) at Year 1.
Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the End Tidal CO2 at Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.
Measured: Baseline, Year 1
Percentage Change From Baseline in Anaerobic Threshold at Year 1.
Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the anaerobic threshold at Week 16 and Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.
Measured: Baseline, Year 1
Summary of Shift in Changes From Start of Sildenafil in World Health Organization Pulmonary Hypertension (WHO PH) Functional Class by A1481156 Treatment Group at Year 1.
The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarized at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated.
Measured: Baseline, Year 1
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 2.
The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated.
Measured: Baseline, Year 2
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 3.
The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 (NCT00159913) baseline at Years 1, 2, 3 and 4 were evaluated.
Measured: Baseline, Year 3
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 4.
The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated.
Measured: Baseline, Year 4
Additions From Baseline in Background Therapy up to the End of Study
This was defined as an addition or discontinuation in the class(es) of drugs used as background medication (e.g., anticoagulants, oxygen, diuretics, calcium channel blockers, and digoxin) compared to baseline of Study A1481131 (NCT00159913).
Measured: Up to the end of study
Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Psychosocial Scale at Year 1.
CHQ: 50-item, 15 subscale parent or legal guardian assessed instrument of child's physical, emotional, social well-being, and relative burden of disease on the parents; rated on Likert-type scale: range 0 to 100; higher scores indicate a more positive health status. Global indicators for Physical Health and Psychosocial Health are weighted composites derived from subscale items using scoring algorithms (transformed scores); range 0 to 100: higher scores indicate more positive health status.
Measured: Baseline, Year 1
Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Physical Scale at Year 1.
CHQ: 50-item, 15 subscale parent or legal guardian assessed instrument of child's physical, emotional, social well-being, and relative burden of disease on the parents; rated on Likert-type scale: range 0 to 100; higher scores indicate a more positive health status. Global indicators for Physical Health and Psychosocial Health are weighted composites derived from subscale items using scoring algorithms (transformed scores); range 0 to 100: higher scores indicate more positive health status.
Measured: Baseline, Year 1
Participant (Parent) Global Assessment at Year 1
The participant (parent) global assessment of disease severity was assessed at Year 1 in this extension study. The number and percentage of participants markedly improved, moderately improved, mild improvement, no change, slightly worse, moderately worse, markedly worse were evaluated. Participants who withdrew from study treatment after at least 10 weeks of treatment were requested to perform the global assessments.
Measured: Year 1
Physician Global Assessment at Year 1
The physician global assessment of disease severity was assessed at Year 1 in this extension study. The number and percentage of participants with markedly improved, moderately improved, mild improvement, no change, slightly worse, moderately worse, markedly worse were evaluated. Participants who withdrew from study treatment after at least 10 weeks of treatment were requested to perform the global assessments.
Measured: Year 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Sep 2005 (estimated)
- Study startJan 2004
- Primary completionDec 2012
- Study completionDec 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Arterial HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 234 participants (actual)
Sponsor and investigators
- Lead sponsor
- Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Pfizer CT.gov Call Center, Study director, Pfizer
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00159874
- Sponsor's protocol ID
- A1481156
- Status last verified
- Jan 2021
- First submitted
- 8 Sep 2005
- Last updated
- 1 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 31908813Chanu 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.
PubMed 31538282Barst 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.
PubMed 24637559
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil Citrate In The Treatment Of Subjects Who Have Completed Study A1481131
- ClinicalTrials.gov ID
- NCT00159874
- Acronym / sponsor ID
- A1481156
- Conditions
- Pulmonary Arterial Hypertension
- Keywords
- children
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 234 participants (actual)
- Lead sponsor
- Pfizer's Upjohn has merged with Mylan to form Viatris Inc.Industry (pharma, biotech, devices)
- Study start
- Jan 2004
- Primary completion
- Dec 2012 (actual)
- Study completion
- Dec 2012 (actual)
- First posted
- 12 Sep 2005 (estimated)
- Results
- Posted 11 Aug 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Active treatment, dose-blinded extension study evaluating the safety and long term efficacy of sildenafil citrate in children with PAH.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Sildenafil high dose | Experimental | Drug: Sildenafil citrateAs 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. |
| Sildenafil Low dose | Experimental | Drug: Sildenafil citrate |
| Sildenafil medium dose | Experimental | Drug: Sildenafil citrateAs 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. |
Who may qualify
- Ages
- 1 year to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- Patients must complete the 16 Week double-blind efficacy study A1481131.
Key exclusion criteria (1 listed)
- Any patient who did not complete Study A1481131.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sildenafil citrateOral, 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) | Drug | Sildenafil high dose |
| Sildenafil citrateOral,10 mg 3 times a day (tid), only subjects with body weight >20 kg | Drug | Sildenafil Low dose |
| Sildenafil citrateOral, subjects with body weight ≥8 - 20 kg: 10 mg 3 times a day (tid); subjects with body weight >20 - 45 kg: 20 mg 3 times a day (tid); subjects with body weight >45 kg: 40 mg 3 times a day (tid) | Drug | Sildenafil medium dose |
Primary outcome
Number of Participants Reporting at Least One Adverse Event
Time frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
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.
Number of Participants Reporting Treatment-related Adverse Events
Time frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
Safety was measured according to standard adverse event collection as described in the adverse event section of the results.
Number of Participants Reporting at Least One Serious Adverse Event
Time frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
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.
Number of Participants Reporting Treatment-related Serious Adverse Events
Time frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
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.
Number of Deaths Reported in the Study Prior to the Data Monitoring Committee (DMC) Recommendation of Dose Down Titration
Time frame: Pre-DMC Recommendation dose down titration (04 August 2011)
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.
Number of Deaths Reported During This Study
Time frame: Last follow-up visit or 30 days after the last administration of study drug
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.
Discontinuation Due to Intolerability
Time frame: Throughout the treatment duration (median treatment duration 1689 to 1744 days)
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.
Downtitration in Dose Due to Intolerability.
Time frame: Pre-DMC recomendation (04 August 2011)
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.
Number of Participants With Deterioration Post Baseline in Visual Acuity Safety Tests
Time frame: Week 36
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.
Number of Participants With Deterioration Post Baseline in Color Vision Monitoring Safety Tests.
Time frame: Week 36
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.
Pediatric Cognitive Development Status at Week 16.
Time frame: 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.
Pediatric Cognitive Development Status at Week 52.
Time frame: 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.
Pediatric Motor Development Status at Week 16.
Time frame: 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.
Pediatric Motor Development Status at Week 52
Time frame: 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.
17 secondary outcomes
Peak Volume of Oxygen (VO2) Consumed at Year 1 Using a Bicycle Ergometry Cardiopulmonary Exercise Test (CPX)
Time frame: 1 year
Percentage Change From Baseline in Percent Predicted Peak VO2 at Year 1.
Time frame: Baseline, Year 1
Percent Change From Baseline in Time to Maximum VO2 at Year 1
Time frame: Baseline, Year 1
Percent Change From Baseline in Respiratory Exchange Ratio at Year 1
Time frame: Baseline, Year 1
Percent Change From Start of Sildenafil in Total Ventilation (VE) to Year 1
Time frame: Year 1
Percentage Change From Baseline in End Tidal Oxygen (O2) at Year 1.
Time frame: Baseline, Year 1
Percentage Change From Baseline in End Tidal Carbon Dioxide (CO2) at Year 1.
Time frame: Baseline, Year 1
Percentage Change From Baseline in Anaerobic Threshold at Year 1.
Time frame: Baseline, Year 1
Summary of Shift in Changes From Start of Sildenafil in World Health Organization Pulmonary Hypertension (WHO PH) Functional Class by A1481156 Treatment Group at Year 1.
Time frame: Baseline, Year 1
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 2.
Time frame: Baseline, Year 2
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 3.
Time frame: Baseline, Year 3
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 4.
Time frame: Baseline, Year 4
Additions From Baseline in Background Therapy up to the End of Study
Time frame: Up to the end of study
Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Psychosocial Scale at Year 1.
Time frame: Baseline, Year 1
Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Physical Scale at Year 1.
Time frame: Baseline, Year 1
Participant (Parent) Global Assessment at Year 1
Time frame: Year 1
Physician Global Assessment at Year 1
Time frame: Year 1
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31908813Russell 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.
- Derived from this study: PubMed 31538282Chanu 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.
- Derived from this study: PubMed 24637559Barst 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.
- To obtain contact information for a study center near you, click here.Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pfizer CT.gov Call Center study director
Pfizer
39 sites in 15 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Sildenafil citrate in people with Pulmonary Arterial Hypertension, run by Pfizer's Upjohn has merged with Mylan to form Viatris Inc. at 39 sites in 15 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 39 sites in United States, Poland, Hungary, India, Malaysia and 10 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Reporting at Least One Adverse Event (time frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00159874, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2021.