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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00159874

Enrollment

234

Registered

2005-09-12

Start date

2004-01-31

Completion date

2012-12-31

Last updated

2021-02-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Arterial Hypertension

Keywords

children

Brief summary

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

Interventions

DRUGSildenafil citrate

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)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

1 Years to 17 Years

Healthy volunteers

Inclusion criteria

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

Exclusion criteria

* Any patient who did not complete Study A1481131.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Reporting at Least One Adverse Event	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	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	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	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	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	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	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.	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	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.	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.	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.	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.	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	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.

Secondary

Measure	Time frame	Description
Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Physical Scale at Year 1.	Baseline, 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.
Peak Volume of Oxygen (VO2) Consumed at Year 1 Using a Bicycle Ergometry Cardiopulmonary Exercise Test (CPX)	1 year	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
Physician Global Assessment at Year 1	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.
Participant (Parent) Global Assessment at Year 1	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.
Percentage Change From Baseline in Percent Predicted Peak VO2 at Year 1.	Baseline, 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.
Percent Change From Baseline in Time to Maximum VO2 at Year 1	Baseline, 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.
Percent Change From Baseline in Respiratory Exchange Ratio at Year 1	Baseline, 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).
Percent Change From Start of Sildenafil in Total Ventilation (VE) to Year 1	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.
Percentage Change From Baseline in End Tidal Oxygen (O2) at Year 1.	Baseline, 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.
Percentage Change From Baseline in End Tidal Carbon Dioxide (CO2) at Year 1.	Baseline, 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.
Percentage Change From Baseline in Anaerobic Threshold at Year 1.	Baseline, 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.
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.	Baseline, 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.
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 2.	Baseline, 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.
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 3.	Baseline, 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.
Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 4.	Baseline, 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.
Additions From Baseline in Background Therapy up to the End of Study	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).
Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Psychosocial Scale at Year 1.	Baseline, 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.

Countries

Brazil, Chile, Colombia, Guatemala, Hungary, India, Italy, Japan, Malaysia, Mexico, Poland, Russia, Sweden, Taiwan, United States

Participant flow

Recruitment details

This extension study included 220 participants at 31 sites. 14 participants did not go from A1481131 (NCT00159913) to A1481156. Participants from one center in Canada participated in base study A1481131 (NCT00159913) but not in this extension study.

Pre-assignment details

Participants remained in the same dose group as in study A1481131 (NCT00159913). Participants randomized to placebo in NCT00159913 were rerandomized to sildenafil in A1481156. Placebo participants in low weight category were rerandomized to medium or high dose (1:2) and other weight categories were rerandomized to low, medium or high dose (1:1:1).

Participants by arm

Arm	Count
Sildenafil Low/Low Dose Participants randomized to sildenafil low dose in study A1481131 (NCT00159913) and in the extension study A1481156	42
Sildenafil Medium/ Medium Dose Participants randomized to sildenafil medium dose in study A1481131 (NCT00159913) and in the extension study A1481156	55
Sildenafil High/ High Dose Participants randomized to sildenafil high dose in study A1481131 (NCT00159913) and in the extension study A1481156	77
Placebo/ Low Dose Participants randomized to placebo in study A1481131 (NCT00159913) and randomized to sildenafil low dose in study A1481156	13
Placebo/ Medium Dose Participants randomized to placebo in study A1481131 (NCT00159913) and randomized to sildenafil medium dose in study A1481156	19
Placebo/ High Dose Participants randomized to placebo in study A1481131 (NCT00159913) and randomized to sildenafil high dose in study A1481156	23
Placebo Non-randomized This group comprised those placebo participants who either discontinued from base study A1481131 (NCT00159913) or chose not to enter study A1481156 and hence not randomly assigned to a sildenafil dose group at the start of study A1481156	5
Total	234

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Overall Study	Adverse Event	2	2	5	1	1	2	0
Overall Study	Death	3	8	15	0	1	2	0
Overall Study	Does Not Meet Entrance Criteria	1	0	1	0	0	0	0
Overall Study	Lack of Efficacy	2	0	1	1	0	3	0
Overall Study	Lost to Follow-up	1	0	3	0	1	2	1
Overall Study	Other	8	8	8	0	2	1	3
Overall Study	Pregnancy	1	1	0	0	0	0	0
Overall Study	Protocol Violation	0	5	2	0	0	0	0
Overall Study	Withdrawal by Subject	2	6	8	4	3	2	1

Baseline characteristics

Characteristic	Sildenafil Low/Low Dose	Total	Placebo Non-randomized	Placebo/ High Dose	Placebo/ Medium Dose	Placebo/ Low Dose	Sildenafil High/ High Dose	Sildenafil Medium/ Medium Dose
Age, Customized 13-17	17 Participants	73 Participants	2 Participants	7 Participants	6 Participants	1 Participants	22 Participants	18 Participants
Age, Customized 1-4	0 Participants	35 Participants	1 Participants	2 Participants	3 Participants	1 Participants	19 Participants	9 Participants
Age, Customized >=18	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Customized 5-12	25 Participants	126 Participants	2 Participants	14 Participants	10 Participants	11 Participants	36 Participants	28 Participants
Sex: Female, Male Female	25 Participants	145 Participants	3 Participants	15 Participants	11 Participants	9 Participants	51 Participants	31 Participants
Sex: Female, Male Male	17 Participants	89 Participants	2 Participants	8 Participants	8 Participants	4 Participants	26 Participants	24 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	51 / 55	70 / 74	87 / 100
serious Total, serious adverse events	14 / 55	37 / 74	48 / 100

Outcome results

Primary

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.

Time frame: Throughout the treatment duration (median treatment duration 1689 to 1744 days)

Population: Safety population included all randomly assigned participants who took at least 1 dose of study medication in Study A1481131 (NCT00159913).

Arm	Measure	Value (NUMBER)
Sildenafil Low/Low Dose	Discontinuation Due to Intolerability	2 Participants
Sildenafil Medium/ Medium Dose	Discontinuation Due to Intolerability	1 Participants
Sildenafil High/ High Dose	Discontinuation Due to Intolerability	3 Participants

Primary

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.

Time frame: Pre-DMC recomendation (04 August 2011)

Population: Safety population included all randomly assigned participants who took at least 1 dose of study medication in Study A1481131 (NCT00159913).

Arm	Measure	Value (NUMBER)
Sildenafil Low/Low Dose	Downtitration in Dose Due to Intolerability.	0 Participants
Sildenafil Medium/ Medium Dose	Downtitration in Dose Due to Intolerability.	0 Participants
Sildenafil High/ High Dose	Downtitration in Dose Due to Intolerability.	3 Participants
Placebo/ Low Dose	Downtitration in Dose Due to Intolerability.	0 Participants
Placebo/ Medium Dose	Downtitration in Dose Due to Intolerability.	2 Participants
Placebo/ High Dose	Downtitration in Dose Due to Intolerability.	1 Participants
Placebo Non-randomized	Downtitration in Dose Due to Intolerability.	0 Participants

Primary

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.

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