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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:
ClinicalTrials.gov Identifier:
NCT00492531
First Posted: June 27, 2007
Last Update Posted: January 6, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Mark Gladwin, National Heart, Lung, and Blood Institute (NHLBI)
Results First Submitted: April 28, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions: Sickle Cell Disease
Pulmonary Hypertension
Interventions: Drug: Sildenafil
Drug: Placebo

  Participant Flow
  Hide Participant Flow

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Withdrawn(More than one reason selected)                22                23 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 
Overall Participants Analyzed 
[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]
     
Hispanic or Latino   0   0   0 
Not Hispanic or Latino   32   37   69 
Unknown or Not Reported   5   0   5 
Race (NIH/OMB) 
[Units: Participants]
     
American Indian or Alaska Native   0   0   0 
Asian   0   0   0 
Native Hawaiian or Other Pacific Islander   0   0   0 
Black or African American   36   37   73 
White   0   0   0 
More than one race   0   0   0 
Unknown or Not Reported   1   0   1 
6 minute walk [1] 
[Units: Meters]
Mean (Standard Deviation)
 381  (75)   386  (75)   383  (75) 
[1] The distance walked in six minute was used to assess the exercise capacity of the patient at baseline.
Tricuspid regurgitant jet velocity (TRV) [1] 
[Units: M/s]
Mean (Standard Deviation)
 3.0  (0.5)   3.0  (0.3)   3.0  (0.3) 
[1] Tricuspid regurgitant jet velocity was measured by transthoracic Doppler Echocardiography.


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Change in Exercise Capacity as Assessed by 6 Minute Walk.   [ Time Frame: Baseline to week 16/Imputed last visit. ]

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.  

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 
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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] ANCOVA
P Value [4] 0.70
Mean Difference (Net) [5] -9
95% Confidence Interval -56 to 38
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] 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.
[4] 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.
[5] 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 ]

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  

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 
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 ]

Measure Type Secondary
Measure Title Borg Dyspnea Score
Measure Description Borg dyspnea score was used to measure the level of severity of breathlessness perceived by the patient before and after 6 minute walk. The severity is measured on a 10 point scale with 0= nothing at all and 10=maximum severity of breathlessness.
Time Frame baseline to 16 weeks  

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 
Participants Analyzed 
[Units: Participants]
 37   37 
Borg Dyspnea Score 
[Units: Score on a scale]
Mean (Standard Deviation)
   
Baseline   2.5  (2.1)   2.1  (2.0) 
Week 6   3.4  (2.3)   1.8  (1.3) 
Week 10   2.7  (2.0)   2.7  (1.7) 
Week 16   2.0  (1.6)   2.8  (2.4) 

No statistical analysis provided for Borg Dyspnea Score



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

Measure Type Secondary
Measure Title Brain Natriuretic Peptide(BNP)Levels.
Measure Description No text entered.
Time Frame 16 weeks  

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 
Participants Analyzed 
[Units: Participants]
 35   35 
Brain Natriuretic Peptide(BNP)Levels. 
[Units: Pg/dl]
Mean (Standard Deviation)
   
Baseline   2.3  (0.6)   2.0  (0.6) 
Week 6   2.4  (0.4)   2.0  (0.7) 
Week 10   2.3  (0.5)   2.2  (0.6) 
Week 16   2.5  (0.7)   2.3  (0.6) 

No statistical analysis provided for Brain Natriuretic Peptide(BNP)Levels.




  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
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.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Mark Gladwin
Organization: Professor of Medicine: Chief, Pulmonary, Allergy and Critical Care Medicine: Director, Hemostasis and Vascular Biology Research Institute; University of Pittsburgh School of Medicine
phone: 412-692-2117
e-mail: gladwinmt@upmc.edu


Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):


Responsible Party: Mark Gladwin, National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT00492531     History of Changes
Other Study ID Numbers: 070177
07-H-0177 ( Other Identifier: IRB Approval number , NHLBI )
First Submitted: June 26, 2007
First Posted: June 27, 2007
Results First Submitted: April 28, 2011
Results First Posted: June 6, 2011
Last Update Posted: January 6, 2016