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 ]

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

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

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 ]

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 ]

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 ]

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 ]

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 ]


  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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