Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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  
Number of Participants  
[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  
Number of 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  
Number of 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  
Number of 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  
Number of 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  
Number of 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  
Number of 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  
Number of 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  
Number of 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  
Number of 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
  Hide Limitations and Caveats

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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