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The Efficacy and Safety of Sildenafil Citrate Used in Combination With Intravenous Epoprostenol in PAH

This study has been completed.
Sponsor:
Information provided by:
Pfizer
ClinicalTrials.gov Identifier:
NCT00159861
First received: September 8, 2005
Last updated: December 20, 2013
Last verified: December 2013
Results First Received: April 2, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver);   Primary Purpose: Treatment
Condition: Pulmonary Hypertension
Intervention: Drug: Sildenafil citrate

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects were entered into the open-label extension study portion upon completion of the preceding 16-week, placebo controlled core study portion or, for subjects who required a change in epoprostenol dose due to clinical deterioration, after at least 4 weeks in the core study portion.

Reporting Groups
  Description
Placebo: Core Study / Sildenafil: Extension Study Core Study: Placebo (16 weeks, or at least 4 weeks for subjects who required a change in epoprostenol dose due to clinical deterioration); Extension Study: Sildenafil (until last enrolled subject completed 3 years of treatment) - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil: Core Study / Sildenafil: Extension Study Core Study (16 weeks, or at least 4 weeks for subjects who required a change in epoprostenol dose due to clinical deterioration): Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study (until last enrolled subject completed 3 years of treatment): Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Participant Flow for 2 periods

Period 1:   Core Study - 16 Weeks
    Placebo: Core Study / Sildenafil: Extension Study   Sildenafil: Core Study / Sildenafil: Extension Study
STARTED   133   134 
Treated   131   134 
COMPLETED   108 [1]   122 [2] 
NOT COMPLETED   25   12 
Death                3                0 
Adverse Event                12                6 
Lack of Efficacy                2                3 
Reason Unspecified                5                3 
Subject Defaulted                1                0 
Randomized but not Treated                2                0 
[1] Entered A1481153: 115; Did not enter A1481153: 16
[2] Entered A1481153: 127; Did not enter A1481153: 7

Period 2:   Extension Study - up to 3 Years
    Placebo: Core Study / Sildenafil: Extension Study   Sildenafil: Core Study / Sildenafil: Extension Study
STARTED   115 [1]   127 [1] 
Treated   115   127 
COMPLETED   53   56 
NOT COMPLETED   62   71 
Death                24                28 
Adverse Event                14                14 
Lack of Efficacy                5                1 
Reason Unspecified                12                19 
Withdrawal by Subject                7                9 
[1] Subjects may have entered extension study after 4 weeks in core study (prior to completion).



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Placebo/Sildenafil Core Study: Placebo; Extension Study: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil/Sildenafil Study A1481141: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study A1481153: Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Total Total of all reporting groups

Baseline Measures
   Placebo/Sildenafil   Sildenafil/Sildenafil   Total 
Overall Participants Analyzed 
[Units: Participants]
 131   134   265 
Age, Customized 
[Units: Participants]
     
18 to 44 years   47   54   101 
45 to 64 years   73   64   137 
>= 65 years   11   16   27 
Gender 
[Units: Participants]
     
Female   102   110   212 
Male   29   24   53 


  Outcome Measures
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1.  Primary:   Categorized Change From Baseline in 6-Minute Walking Distance   [ Time Frame: 1 Year, 2 Year, 3 Year ]

Measure Type Primary
Measure Title Categorized Change From Baseline in 6-Minute Walking Distance
Measure Description Number of subjects with categorized change in 6-minute walking distance. Distance that a subject could walk in 6-minutes at a comfortable pace with as many breaks as needed. Performed as close to trough levels of sildenafil as possible (just before dosing; at least 4 hours after the previous dose of study drug). Scores for categorized changes for missing visits were imputed as the worse score of its non-missing neighbors. If a visit was missing and there was no subsequent score, the score was coded to missing.
Time Frame 1 Year, 2 Year, 3 Year  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS. m = meters. N=number of subjects with evaluable data at core study Baseline. Treatment groups shown by core study randomization; includes subjects who were only treated in the core study and those who continued into the extension study.

Reporting Groups
  Description
Placebo/Sildenafil Core Study: Placebo; Extension Study: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil/Sildenafil Core Study: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study: Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   Placebo/Sildenafil   Sildenafil/Sildenafil 
Participants Analyzed 
[Units: Participants]
 131   134 
Categorized Change From Baseline in 6-Minute Walking Distance 
[Units: Participants]
   
1 Year: >= 60 m Improvement   27   46 
1 Year: 60 - 30 m Improvement   20   26 
1 Year: 30 - 0 m Improvement   23   15 
1 Year: 0 - 30 m Worsening   12   10 
1 Year: 30 - 60 m Worsening   6   6 
1 Year: > 60 m Worsening   6   6 
1 Year: Discontinued   22   14 
1 Year: Died   14   10 
1 Year: Missing   1   1 
2 Year: >= 60 m Improvement   23   44 
2 Year: 60 - 30 m Improvement   16   10 
2 Year: 30 - 0 m Improvement   15   8 
2 Year: 0 - 30 m Worsening   18   9 
2 Year: 30 - 60 m Worsening   2   7 
2 Year: > 60 m Worsening   7   7 
2 Year: Discontinued   25   23 
2 Year: Died   24   24 
2 Year: Missing   1   2 
3 Year: >= 60 m Improvement   22   29 
3 Year: 60 - 30 m Improvement   9   10 
3 Year: 30 - 0 m Improvement   10   8 
3 Year: 0 - 30 m Worsening   15   5 
3 Year: 30 - 60 m Worsening   3   7 
3 Year: > 60 m Worsening   5   8 
3 Year: Discontinued   35   33 
3 Year: Died   31   33 
3 Year: Missing   1   1 

No statistical analysis provided for Categorized Change From Baseline in 6-Minute Walking Distance



2.  Secondary:   Survival Status   [ Time Frame: 1, 2, 3, 4, and 5 years ]

Measure Type Secondary
Measure Title Survival Status
Measure Description Yearly survival status: number of subjects who survived, discontinued, and died. Analysis includes post-treatment visit data from subjects who discontinued study treatment. Time to death was taken relative to the first dose of study treatment in A1481141, and was censored on the last day the subject was known to be alive in A1481141 or A1481153.
Time Frame 1, 2, 3, 4, and 5 years  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set: all randomized and treated subjects recruited into core study. N=number of subjects with evaluable data at core study Baseline.

Reporting Groups
  Description
All Subjects Core Study A1481141: Placebo or Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study A1481153: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator.

Measured Values
   All Subjects 
Participants Analyzed 
[Units: Participants]
 265 
Survival Status 
[Units: Participants]
 
1 year: Deaths   24 
1 Year: Survived 1 Year of Study   205 
1 Year: Discontinued before 1 Year of Study   36 
2 Years: Deaths   48 
2 Years: Survived 2 Years of Study   169 
2 Years: Discontinued before 2 Years of Study   48 
3 Years: Deaths   64 
3 Years: Survived 3 Years of Study   133 
3 Years: Discontinued before 3 Years of Study   68 
4 Years: Deaths   71 
4 Years: Survived 4 Years of Study   88 
4 Years: Discontinued before 4 Years of Study   75 
4 Years: Ongoing for Less than Timepoint   26 
5 Years: Deaths   82 
5 Years: Survived 5 Years of Study   29 
5 Years: Discontinued before 5 Years of Study   74 
5 Years: Ongoing for Less than Timepoint   78 


Statistical Analysis 1 for Survival Status
Groups [1] All Subjects
Kaplan-Meier estimate [2] 0.095
95% Confidence Interval 0.059 to 0.132
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  1 Year: Proportion of participants who died.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Survival Status
Groups [1] All Subjects
Kaplan-Meier estimate [2] 0.194
95% Confidence Interval 0.144 to 0.243
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  2 Years: Proportion of participants who died.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Survival Status
Groups [1] All Subjects
Kaplan-Meier estimate [2] 0.260
95% Confidence Interval 0.205 to 0.315
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  3 Years: Proportion of participants who died.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Survival Status
Groups [1] All Subjects
Kaplan-Meier estimate [2] 0.291
95% Confidence Interval 0.234 to 0.348
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  4 Years: Proportion of participants who died.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Survival Status
Groups [1] All Subjects
Kaplan-Meier estimate [2] 0.369
95% Confidence Interval 0.302 to 0.437
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  5 Years: Proportion of participants who died.
[2] Other relevant estimation information:
  No text entered.



3.  Secondary:   Change in Pulmonary Hypertension Criteria for Functional Capacity and Therapeutic Class   [ Time Frame: 1 Year, 2 Year, 3 Year ]

Measure Type Secondary
Measure Title Change in Pulmonary Hypertension Criteria for Functional Capacity and Therapeutic Class
Measure Description Pulmonary hypertension (PH) criteria: Class I: PH without limitation of physical activity (PA) (no undue dyspnea, fatigue, chest pain, near syncope); Class II: PH with slight limitation in PA, comfortable at rest, ordinary PA causes undue dyspnea, fatigue, chest pain, near syncope; Class III: PH with marked limitation in PA, comfortable at rest, less than ordinary activity causes undue dyspnea, fatigue, chest pain or syncope; Class IV: PH with inability to carry out PA without symptoms, signs of right heart failure, dyspnea or fatigue may be present at rest, discomfort increased by any PA.
Time Frame 1 Year, 2 Year, 3 Year  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS; N=number of subjects with evaluable data at core study Baseline. Treatment groups shown by core study randomization; includes subjects in core study and in extension study. Scores for categorized changes for missing visits imputed as worse score of its non-missing neighbors; missing visits with no subsequent score: score coded to missing.

Reporting Groups
  Description
Placebo/Sildenafil Core Study: Placebo; Extension Study: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil/Sildenafil Core Study: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study: Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   Placebo/Sildenafil   Sildenafil/Sildenafil 
Participants Analyzed 
[Units: Participants]
 131   134 
Change in Pulmonary Hypertension Criteria for Functional Capacity and Therapeutic Class 
[Units: Participants]
   
1 Year: Improved 2 Classes   2   3 
1 Year: Improved 1 Class   27   46 
1 Year: No Change   59   57 
1 Year: Worsened 1 Class   7   3 
1 Year: Worsened 2 Classes   0   1 
1 Year: Discontinued   22   14 
1 Year: Died   14   10 
2 Year: Improved 2 Classes   1   4 
2 Year: Improved 1 Class   24   31 
2 Year: No Change   50   47 
2 Year: Worsened 1 Class   7   5 
2 Year: Worsened 2 Classes   0   0 
2 Year: Discontinued   25   23 
2 Year: Died   24   24 
3 Year: Improved 2 Classes   1   4 
3 Year: Improved 1 Class   21   21 
3 Year: No Change   39   37 
3 Year: Worsened 1 Class   3   6 
3 Year: Worsened 2 Classes   1   0 
3 Year: Discontinued   35   33 
3 Year: Died   31   33 

No statistical analysis provided for Change in Pulmonary Hypertension Criteria for Functional Capacity and Therapeutic Class



4.  Secondary:   Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36)   [ Time Frame: Baseline, Month 15, Month 27, Month 39 ]

Measure Type Secondary
Measure Title Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36)
Measure Description Subject-rated measure of health status comprised of 36 items: 8 subscale scores (physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health), 2 summary scores (physical component and mental component), and a self-evaluated change in health status. Subscale and summary scores range: 0-100. Higher subscale and summary scores = better health status. Change from baseline = score at observation minus score at baseline.
Time Frame Baseline, Month 15, Month 27, Month 39  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS. N=number of subjects with evaluable data at core study Baseline; n=number of subjects with SF-36 score at observation, Placebo, Sildenafil, respectively. Treatment groups shown by core study randomization; includes subjects who who were only treated in the core study and those who continued into the extension study. Phys = physical.

Reporting Groups
  Description
Placebo/Sildenafil Core Study: Placebo; Extension Study: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil/Sildenafil Core Study: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study: Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   Placebo/Sildenafil   Sildenafil/Sildenafil 
Participants Analyzed 
[Units: Participants]
 131   134 
Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36) 
[Units: Scores on scale]
Mean (95% Confidence Interval)
   
Month 15: Physical Functioning Score (n=59, 83)   10.5 
 (6.0 to 15.1) 
 14.8 
 (10.1 to 19.4) 
Month 27: Physical Functioning Score (n=60, 62)   9.7 
 (5.0 to 14.4) 
 12.5 
 (7.1 to 17.9) 
Month 39: Physical Functioning Score (n=42, 47)   8.9 
 (1.9 to 15.9) 
 14.0 
 (7.6 to 20.4) 
Month 15: Role Limitations (phys health)(n=59, 82)   15.7 
 (4.9 to 26.4) 
 14.2 
 (3.3 to 25.2) 
Month 27: Role Limitations (phys health)(n=60, 62)   4.6 
 (-8.3 to 17.5) 
 2.6 
 (-9.8 to 14.9) 
Month 39: Role Limitations (phys health)(n=42, 47)   4.2 
 (-11.0 to 19.4) 
 5.1 
 (-9.8 to 20.1) 
Month 15: Bodily Pain Score (n=59, 82)   10.4 
 (4.5 to 16.3) 
 5.9 
 (0.3 to 11.5) 
Month 27: Bodily Pain Score (n=60, 62)   -0.1 
 (-6.4 to 6.3) 
 4.0 
 (-1.8 to 9.9) 
Month 39: Bodily Pain Score (n=42, 46)   -4.9 
 (-13.2 to 3.4) 
 3.5 
 (-3.4 to 10.5) 
Month 15: General Health Score (n=59, 83)   -0.2 
 (-5.5 to 5.2) 
 10.1 
 (5.4 to 14.7) 
Month 27: General Health Score (n=60, 62)   2.7 
 (-2.6 to 8.1) 
 6.9 
 (2.0 to 11.7) 
Month 39: General Health Score (n=41, 47)   3.1 
 (-2.6 to 8.7) 
 3.4 
 (-2.8 to 9.7) 
Month 15: Vitality Score (n=59, 83)   5.0 
 (-0.3 to 10.4) 
 8.9 
 (3.7 to 14.0) 
Month 27: Vitality Score (n=60, 62)   5.7 
 (0.8 to 10.5) 
 7.2 
 (2.0 to 12.3) 
Month 39: Vitality Score (n=42, 47)   6.9 
 (0.3 to 13.6) 
 5.2 
 (-0.7 to 11.1) 
Month 15: Social Functioning Score (n=59, 83)   5.9 
 (-2.2 to 14.1) 
 5.1 
 (-1.2 to 11.5) 
Month 27: Social Functioning Score (n=60, 63)   6.7 
 (-0.6 to 13.9) 
 1.4 
 (-6.5 to 9.3) 
Month 39: Social Functioning Score (n=42, 47)   2.4 
 (-5.9 to 10.6) 
 -0.8 
 (-9.3 to 7.7) 
Month 15: Role Limitations (Emotional) (n=59, 82)   1.7 
 (-10.1 to 13.5) 
 1.2 
 (-8.8 to 11.3) 
Month 27: Role Limitations (Emotional) (n=60, 62)   -1.7 
 (-13.4 to 10.0) 
 -7.0 
 (-18.1 to 4.1) 
Month 39: Role Limitations (Emotional) (n=42, 47)   3.2 
 (-10.7 to 17.1) 
 2.1 
 (-7.5 to 11.8) 
Month 15: Mental Health Score (n=59, 83)   0.5 
 (-3.9 to 4.9) 
 3.3 
 (-1.1 to 7.7) 
Month 27: Mental Health Score (n=60, 62)   0.9 
 (-3.4 to 5.1) 
 0.1 
 (-4.6 to 4.8) 
Month 39: Mental Health Score (n=42, 47)   0.8 
 (-4.9 to 6.6) 
 3.7 
 (-1.9 to 9.3) 

No statistical analysis provided for Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36)



5.  Secondary:   Change From Baseline in European Quality of Life Scale (EuroQol) 5-Dimensions (EQ-5D): Utility Index Score   [ Time Frame: Baseline, Month 15, Month 27, Month 39 ]

Measure Type Secondary
Measure Title Change From Baseline in European Quality of Life Scale (EuroQol) 5-Dimensions (EQ-5D): Utility Index Score
Measure Description EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.
Time Frame Baseline, Month 15, Month 27, Month 39  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS. N=number of subjects with evaluable data at core study Baseline; n=number of subjects with evaluable data at observation, Placebo, Sildenafil, respectively. Treatment groups shown by core study randomization; includes subjects who who were only treated in the core study and those who continued into the extension study.

Reporting Groups
  Description
Placebo/Sildenafil Core Study: Placebo; Extension Study: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil/Sildenafil Core Study: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study: Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   Placebo/Sildenafil   Sildenafil/Sildenafil 
Participants Analyzed 
[Units: Participants]
 124   125 
Change From Baseline in European Quality of Life Scale (EuroQol) 5-Dimensions (EQ-5D): Utility Index Score 
[Units: Scores on scale]
Mean (95% Confidence Interval)
   
Month 15 (n=58, 78)   0.0505 
 (-0.0078 to 0.1087) 
 0.0473 
 (-0.0065 to 0.1012) 
Month 27 (n=56, 60)   0.0489 
 (-0.0146 to 0.1123) 
 0.0483 
 (-0.0272 to 0.1237) 
Month 39 (n=40, 43)   -0.0278 
 (-0.1253 to 0.0697) 
 0.0770 
 (0.0013 to 0.1526) 

No statistical analysis provided for Change From Baseline in European Quality of Life Scale (EuroQol) 5-Dimensions (EQ-5D): Utility Index Score



6.  Secondary:   Change From Baseline in European Quality of Life (EuroQol) Visual Analogue Scale (EQ-5D VAS): Current Health State Score   [ Time Frame: Baseline, Month 15, Month 27, Month 39 ]

Measure Type Secondary
Measure Title Change From Baseline in European Quality of Life (EuroQol) Visual Analogue Scale (EQ-5D VAS): Current Health State Score
Measure Description EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.
Time Frame Baseline, Month 15, Month 27, Month 39  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS. N=number of subjects with evaluable data at core study Baseline; n=number of subjects with evaluable data at observation, Placebo, Sildenafil, respectively. Treatment groups shown by core study randomization; includes subjects who who were only treated in the core study and those continued into the extension study.

Reporting Groups
  Description
Placebo/Sildenafil Core Study: Placebo; Extension Study: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil/Sildenafil Core Study: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study: Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   Placebo/Sildenafil   Sildenafil/Sildenafil 
Participants Analyzed 
[Units: Participants]
 125   126 
Change From Baseline in European Quality of Life (EuroQol) Visual Analogue Scale (EQ-5D VAS): Current Health State Score 
[Units: Scores on scale]
Mean (95% Confidence Interval)
   
Month 15 (n=57, 81)   6.8 
 (2.4 to 11.1) 
 12.8 
 (8.3 to 17.3) 
Month 27 (n=55, 60)   5.5 
 (1.7 to 9.3) 
 11.2 
 (5.9 to 16.4) 
Month 39 (n=40, 41)   4.7 
 (-0.2 to 9.5) 
 11.5 
 (5.5 to 17.5) 

No statistical analysis provided for Change From Baseline in European Quality of Life (EuroQol) Visual Analogue Scale (EQ-5D VAS): Current Health State Score



7.  Secondary:   Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36): Reported Health Transition Score   [ Time Frame: Baseline, Month 15, Month 27, Month 39 ]

Measure Type Secondary
Measure Title Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36): Reported Health Transition Score
Measure Description Subject-rated measure of health status (36 items): 8 subscale scores (physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, mental health), 2 summary scores (physical component, mental component), and a self-evaluated change in health status. Change from Baseline in SF-36 Health Transition score at each visit. I=much better than 1 year ago; II=somewhat better than 1 year ago; III=about the same as 1 year ago; IV=somewhat worse than 1 year ago; V=much worse than 1 year ago
Time Frame Baseline, Month 15, Month 27, Month 39  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS. N=number of subjects with evaluable data at core study Baseline. Treatment groups shown by core study randomization; includes subjects who who were only treated in the core study and those continued into the extension study. BL=Baseline.

Reporting Groups
  Description
Placebo/Sildenafil Core Study: Placebo; Extension Study: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sildenafil/Sildenafil Core Study: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study: Sildenafil - initial dose 20 mg TID, may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   Placebo/Sildenafil   Sildenafil/Sildenafil 
Participants Analyzed 
[Units: Participants]
 131   134 
Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36): Reported Health Transition Score 
[Units: Participants]
   
BL I; Month 15: I   2   9 
BL I; Month 15: II   5   4 
BL I; Month 15: III   5   2 
BL I; Month 15: IV   0   1 
BL I; Month 15: V   0   0 
BL II; Month 15: I   7   5 
BL II; Month 15: II   9   12 
BL II; Month 15: III   3   7 
BL II; Month 15: IV   1   2 
BL II; Month 15: V   0   0 
BL III; Month 15: I   3   4 
BL III; Month 15: II   6   8 
BL III; Month 15: III   11   7 
BL III; Month 15: IV   0   2 
BL III; Month 15: V   0   0 
BL IV; Month 15: I   2   5 
BL IV; Month 15: II   0   3 
BL IV; Month 15: III   2   3 
BL IV; Month 15: IV   1   4 
BL IV; Month 15: V   1   0 
BL V; Month 15: I   0   1 
BL V; Month 15: II   0   3 
BL V; Month 15: III   0   1 
BL V; Month 15: IV   0   0 
BL V; Month 15: V   0   0 
Month 15: Missing Data   73   51 
BL I; Month 27: I   4   2 
BL I; Month 27: II   2   6 
BL I; Month 27: III   2   2 
BL I; Month 27: IV   3   0 
BL I; Month 27: V   0   0 
BL II; Month 27: I   4   3 
BL II; Month 27: II   9   7 
BL II; Month 27: III   8   7 
BL II; Month 27: IV   1   3 
BL II; Month 27: V   0   0 
BL III; Month 27: I   3   5 
BL III; Month 27: II   7   6 
BL III; Month 27: III   9   7 
BL III; Month 27: IV   2   3 
BL III; Month 27: V   0   0 
BL IV; Month 27: I   1   1 
BL IV; Month 27: II   1   3 
BL IV; Month 27: III   1   3 
BL IV; Month 27: IV   1   3 
BL IV; Month 27: V   0   0 
BL V; Month 27: I   0   1 
BL V; Month 27: II   0   0 
BL V; Month 27: III   0   1 
BL V; Month 27: IV   0   0 
BL V; Month 27: V   0   0 
Month 27: Missing Data   73   71 
BL I; Month 39: I   1   2 
BL I; Month 39: II   2   4 
BL I; Month 39: III   3   4 
BL I; Month 39: IV   1   1 
BL I; Month 39: V   0   0 
BL II; Month 39: I   4   5 
BL II; Month 39: II   6   3 
BL II; Month 39: III   6   6 
BL II; Month 39: IV   3   1 
BL II; Month 39: V   0   0 
BL III; Month 39: I   2   3 
BL III; Month 39: II   3   3 
BL III; Month 39: III   8   6 
BL III; Month 39: IV   1   1 
BL III; Month 39: V   0   0 
BL IV; Month 39: I   0   0 
BL IV; Month 39: II   1   0 
BL IV; Month 39: III   0   2 
BL IV; Month 39: IV   1   4 
BL IV; Month 39: V   0   0 
BL V; Month 39: I   0   1 
BL V; Month 39: II   0   0 
BL V; Month 39: III   0   1 
BL V; Month 39: IV   0   0 
BL V; Month 39: V   0   0 
Month 39: Missing Data   89   87 

No statistical analysis provided for Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36): Reported Health Transition Score



8.  Secondary:   Change From Baseline in BORG Dyspnea Score   [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Month 9, Month 12, Month 15, Month 18, Month 21, Month 24, Month 27, Month 30, Month 33, Month 36 ]

Measure Type Secondary
Measure Title Change From Baseline in BORG Dyspnea Score
Measure Description BORG Dyspnea score: change from core study Baseline. Subject rating of maximum degree of dyspnea experienced at any time during the 6-Minute Walk Test. Range: 0 (no breathlessness at all) to 10 (maximum breathlessness).
Time Frame Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Month 9, Month 12, Month 15, Month 18, Month 21, Month 24, Month 27, Month 30, Month 33, Month 36  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS. N=number of subjects with evaluable data at core study Baseline; n=number of subjects with evaluable data at observation, Placebo, Sildenafil, respectively. Treatment groups shown by core study randomization; includes subjects who were only treated in the core study and those who continued into the extension study.

Reporting Groups
  Description
Placebo/Sildenafil Core Study A1481141: Placebo TID (3 times daily); Extension Study A1481153: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator
Sldenafil/Sildenafil Core Study A1481141: Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study A1481153: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   Placebo/Sildenafil   Sldenafil/Sildenafil 
Participants Analyzed 
[Units: Participants]
 115   123 
Change From Baseline in BORG Dyspnea Score 
[Units: Scores on scale]
Median (Full Range)
   
Week 4 (n=112, 120)   0.0 
 (-9.0 to 10.0) 
 0.0 
 (-6.0 to 4.0) 
Week 8 (n=106, 113)   0.0 
 (-8.0 to 9.0) 
 0.0 
 (-6.0 to 4.0) 
Week 12 (n=102, 108)   0.0 
 (-6.0 to 4.0) 
 0.0 
 (-7.0 to 4.0) 
Week 16 (n=95, 106)   0.0 
 (-6.0 to 9.0) 
 0.0 
 (-7.0 to 6.0) 
Week 20 (n=80, 96)   0.0 
 (-8.0 to 6.0) 
 0.0 
 (-7.0 to 4.0) 
Week 24 (n=91, 105)   0.0 
 (-7.0 to 4.0) 
 0.0 
 (-8.0 to 4.0) 
Month 9 (n=75, 98)   0.0 
 (-4.0 to 4.0) 
 0.0 
 (-8.0 to 5.0) 
Month 12 (n=72, 90)   0.0 
 (-6.0 to 4.0) 
 0.0 
 (-7.0 to 4.0) 
Month 15 (n=75, 91)   0.0 
 (-6.0 to 3.0) 
 0.0 
 (-9.0 to 4.0) 
Month 18 (n=67, 74)   0.0 
 (-7.0 to 3.0) 
 0.0 
 (-8.0 to 4.0) 
Month 21 (n=67, 79)   0.0 
 (-6.0 to 3.0) 
 0.0 
 (-7.0 to 4.0) 
Month 24 (n=68, 60)   0.0 
 (-6.0 to 7.0) 
 0.0 
 (-7.0 to 5.0) 
Month 27 (n=67, 69)   0.0 
 (-4.0 to 4.0) 
 0.0 
 (-7.0 to 3.0) 
Month 30 (n=55, 68)   0.0 
 (-7.0 to 7.0) 
 0.0 
 (-8.0 to 5.0) 
Month 33 (n=62, 65)   0.0 
 (-4.0 to 7.0) 
 0.0 
 (-7.0 to 6.0) 
Month 36 (n=51, 62)   0.0 
 (-7.0 to 5.0) 
 0.0 
 (-7.0 to 5.0) 

No statistical analysis provided for Change From Baseline in BORG Dyspnea Score



9.  Other Pre-specified:   Change in Epoprostenol Dose From Baseline Maintained for 6 Months   [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Month 9, and at 3-month intervals through Month 69 ]

Measure Type Other Pre-specified
Measure Title Change in Epoprostenol Dose From Baseline Maintained for 6 Months
Measure Description Number of subjects with changes in Epoprostenol dose from baseline maintained continuously for 6 months. Increased = Epoprostenol dose continuously more than 20% greater than core study Baseline for at least 6 months. Decrease = Epoprostenol dose continuously more than 20% less than core study Baseline for at least 6 months. No change = Epoprostenol dose change met neither Increase or Decrease criteria. Stopped = Epoprostenol dose stopped for at least 6 months.
Time Frame Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Month 9, and at 3-month intervals through Month 69  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety population: all subjects who took at least one dose of study medication in core study. N=number of subjects with evaluable data at core study Baseline. Includes subjects who were only treated in the core study and those who continued into the extension study.

Reporting Groups
  Description
All Subjects Core Study A1481141: Placebo or Sildenafil 20, 40, or 80 mg TID (3 times daily) based on toleration; Extension Study A1481153: Sildenafil - initial dose 20 mg TID (3 times daily), may have been increased to 40 mg TID or 80 mg TID at discretion of Investigator

Measured Values
   All Subjects 
Participants Analyzed 
[Units: Participants]
 265 
Change in Epoprostenol Dose From Baseline Maintained for 6 Months 
[Units: Participants]
 
Week 4: >20% Increase   0 
Week 4: No Change   0 
Week 4: >20% Decrease   0 
Week 4: Stopped   0 
Week 4: Missing   13 
Week 8: >20% Increase   0 
Week 8: No Change   0 
Week 8: >20% Decrease   0 
Week 8: Stopped   0 
Week 8: Missing   11 
Week 12: >20% Increase   0 
Week 12: No Change   0 
Week 12: >20% Decrease   0 
Week 12: Stopped   0 
Week 12: Missing   14 
Week 16: >20% Increase   0 
Week 16: No Change   0 
Week 16: >20% Decrease   0 
Week 16: Stopped   0 
Week 16: Missing   199 
Week 20: >20% Increase   0 
Week 20: No Change   0 
Week 20: >20% Decrease   0 
Week 20: Stopped   0 
Week 20: Missing   186 
Week 24: >20% Increase   0 
Week 24: No Change   0 
Week 24: >20% Decrease   0 
Week 24: Stopped   0 
Week 24: Missing   190 
Month 9: >20% Increase   0 
Month 9: No Change   0 
Month 9: >20% Decrease   0 
Month 9: Stopped   0 
Month 9: Missing   174 
Month 12: >20% Increase   4 
Month 12: No Change   162 
Month 12: >20% Decrease   9 
Month 12: Stopped   0 
Month 12: Missing   0 
Month 15: >20% Increase   5 
Month 15: No Change   130 
Month 15: >20% Decrease   20 
Month 15: Stopped   1 
Month 15: Missing   0 
Month 18: >20% Increase   10 
Month 18: No Change   109 
Month 18: >20% Decrease   27 
Month 18: Stopped   1 
Month 18: Missing   0 
Month 21: >20% Increase   10 
Month 21: No Change   105 
Month 21: >20% Decrease   27 
Month 21: Stopped   2 
Month 21: Missing   0 
Month 24: >20% Increase   15 
Month 24: No Change   93 
Month 24: >20% Decrease   24 
Month 24: Stopped   2 
Month 24: Missing   0 
Month 27: >20% Increase   18 
Month 27: No Change   87 
Month 27: >20% Decrease   23 
Month 27: Stopped   3 
Month 27: Missing   0 
Month 30: >20% Increase   19 
Month 30: No Change   78 
Month 30: >20% Decrease   23 
Month 30: Stopped   3 
Month 30: Missing   0 
Month 33: >20% Increase   18 
Month 33: No Change   76 
Month 33: >20% Decrease   22 
Month 33: Stopped   2 
Month 33: Missing   0 
Month 36: >20% Increase   20 
Month 36: No Change   66 
Month 36: >20% Decrease   19 
Month 36: Stopped   4 
Month 36: Missing   0 
Month 39: >20% Increase   19 
Month 39: No Change   55 
Month 39: >20% Decrease   19 
Month 39: Stopped   5 
Month 39: Missing   0 
Month 42: >20% Increase   19 
Month 42: No Change   55 
Month 42: >20% Decrease   18 
Month 42: Stopped   5 
Month 42: Missing   0 
Month 45: >20% Increase   24 
Month 45: No Change   51 
Month 45: >20% Decrease   15 
Month 45: Stopped   4 
Month 45: Missing   0 
Month 48: >20% Increase   23 
Month 48: No Change   38 
Month 48: >20% Decrease   17 
Month 48: Stopped   5 
Month 48: Missing   0 
Month 51: >20% Increase   17 
Month 51: No Change   33 
Month 51: >20% Decrease   14 
Month 51: Stopped   3 
Month 51: Missing   0 
Month 54: >20% Increase   14 
Month 54: No Change   31 
Month 54: >20% Decrease   14 
Month 54: Stopped   5 
Month 54: Missing   0 
Month 57: >20% Increase   12 
Month 57: No Change   27 
Month 57: >20% Decrease   12 
Month 57: Stopped   4 
Month 57: Missing   0 
Month 60: >20% Increase   12 
Month 60: No Change   22 
Month 60: >20% Decrease   11 
Month 60: Stopped   2 
Month 60: Missing   0 
Month 63: >20% Increase   6 
Month 63: No Change   21 
Month 63: >20% Decrease   4 
Month 63: Stopped   1 
Month 63: Missing   0 
Month 66: >20% Increase   4 
Month 66: No Change   15 
Month 66: >20% Decrease   2 
Month 66: Stopped   1 
Month 66: Missing   0 
Month 69: >20% Increase   4 
Month 69: No Change   9 
Month 69: >20% Decrease   1 
Month 69: Stopped   0 
Month 69: Missing   0 

No statistical analysis provided for Change in Epoprostenol Dose From Baseline Maintained for 6 Months




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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