Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease

This study has been terminated.
(Subjects on drug were more likely to have severe pain crises requiring hospitalization.)
Sponsor:
Information provided by:
National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:
NCT00492531
First received: June 26, 2007
Last updated: June 3, 2011
Last verified: June 2011
Results First Received: April 28, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Sickle Cell Disease
Pulmonary Hypertension
Interventions: Drug: Sildenafil
Drug: Placebo

  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
Subjects with Sickle cell hemoglobinopathy were recruited from 10 centers(9 in United States and 1 in United Kingdom)

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Sildenafil Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Placebo Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).

Participant Flow:   Overall Study
    Sildenafil     Placebo  
STARTED     37     37  
COMPLETED     15 [1]   14 [2]
NOT COMPLETED     22     23  
Withdrawn(More than one reason selected)                 22                 23  
[1] Of 15 subjects who completed study, 13 were enrolled in Open label.
[2] Of 14 subjects who completed study, 13 were enrolled in Open label.



  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
Sildenafil Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Placebo Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Total Total of all reporting groups

Baseline Measures
    Sildenafil     Placebo     Total  
Number of Participants  
[units: participants]
  37     37     74  
Age  
[units: years]
Mean ± Standard Deviation
  47  ± 13     44  ± 14     45  ± 13  
Gender  
[units: participants]
     
Female     23     23     46  
Male     14     14     28  
Ethnicity (NIH/OMB)  
[units: Participants]
     
Not Hispanic or Latino     32     37     69  
Unknown or Not Reported     5     0     5  
Race (NIH/OMB)  
[units: participants]
     
Black or African American     36     37     73  
Unknown or Not Reported     1     0     1  
6 minute walk [1]
[units: Meters]
Mean ± Standard Deviation
  381  ± 75     386  ± 75     383  ± 75  
Tricuspid regurgitant jet velocity (TRV) [2]
[units: m/s]
Mean ± Standard Deviation
  3.0  ± 0.5     3.0  ± 0.3     3.0  ± 0.3  
[1] The distance walked in six minute was used to assess the exercise capacity of the patient at baseline.
[2] Tricuspid regurgitant jet velocity was measured by transthoracic Doppler Echocardiography.



  Outcome Measures
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1.  Primary:   Change in Exercise Capacity as Assessed by 6 Minute Walk.   [ Time Frame: Baseline to week 16/Imputed last visit. ]
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Measure Type Primary
Measure Title Change in Exercise Capacity as Assessed by 6 Minute Walk.
Measure Description The primary outcome measure was change in exercise capacity assessed by 6 minute walk distance in meters from baseline to 16 weeks. Subjects without a week 16 assessment had their last observation carried forward.
Time Frame Baseline to week 16/Imputed last visit.  
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.
All efficacy and safety analyses were conducted on the intent-to-treat (ITT) population, defined as all randomized subjects, regardless of therapy received. Pre-defined imputation rules:A value of 0 meters was imputed for subjects who died during the MIT.Subjects without a week 16 assessment had their last observation carried forward (LOCF).

Reporting Groups
  Description
Sildenafil Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Placebo Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).

Measured Values
    Sildenafil     Placebo  
Number of Participants Analyzed  
[units: participants]
  37     37  
Change in Exercise Capacity as Assessed by 6 Minute Walk.  
[units: meters]
Mean ± Standard Deviation
  -16  ± 20     -7  ± 20  


Statistical Analysis 1 for Change in Exercise Capacity as Assessed by 6 Minute Walk.
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.70
Mean Difference (Net) [4] -9
95% Confidence Interval ( -56 to 38 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  6 minute walk was based on ANCOVA model with treatment as a fixed effect and 6 minute walk distance, TRV stratum and study site as covariate.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity   [ Time Frame: 16 weeks ]
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Measure Type Secondary
Measure Title Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity
Measure Description Secondary outcome measure was change from baseline in Pulmonary hypertension at week 16 as assessed by Tricuspid regurgitant jet velocity(TRV). Tricuspid regurgitant jet velocity was measured by transthoracic Doppler Echocardiography.
Time Frame 16 weeks  
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.
No text entered.

Reporting Groups
  Description
Sildenafil Subjects received oral sildenafil 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).
Placebo Subjects received matching oral dose of placebo 20 mg three times daily for six weeks, followed by 40 mg three times daily for four weeks, followed by 80 mg three times daily for six weeks (as tolerated).

Measured Values
    Sildenafil     Placebo  
Number of Participants Analyzed  
[units: participants]
  37     37  
Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity  
[units: meters/second]
Mean ± Standard Deviation
   
Baseline     3.1  ± 0.5     3.0  ± 0.3  
Week 6     3.2  ± 0.7     2.9  ± 0.3  
Week 16     2.9  ± 0.5     2.9  ± 0.3  

No statistical analysis provided for Change From Baseline in Pulmonary Hypertension at Week 16 as Assessed by Tricuspid Regurgitant Jet Velocity



3.  Secondary:   Borg Dyspnea Score   [ Time Frame: baseline to 16 weeks ]

4.  Secondary:   Brain Natriuretic Peptide(BNP)Levels.   [ Time Frame: 16 weeks ]


  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
As a result of early termination due to safety findings, the study was underpowered to assess the effects of sildenafil therapy on the predetermined efficacy endpoints.


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