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

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

Official Title
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A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil Citrate In The Treatment Of Subjects Who Have Completed Study A1481131

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Sildenafil citrate
* Drug: Sildenafil citrate
* Drug: Sildenafil citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must complete the 16 Week double-blind efficacy study A1481131. Exclusion Criteria: Any patient who did not complete Study A1481131.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil high dose<br>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<br>* 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)<br>|
| Experimental: Sildenafil Low dose<br> | Drug: Sildenafil citrate<br>* Oral,10 mg 3 times a day (tid), only subjects with body weight >20 kg<br>|
| Experimental: Sildenafil medium dose<br>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<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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. | 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. | 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. | 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. | Year 1 | 
| 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 | 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. | 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. | 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). | Baseline, Year 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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children