A Study to Assess the Efficacy and Safety of 20, 40, and 80mg of Sildenafil Three Times a Day in the Treatment of Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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To evaluate the effect of three doses of oral sildenafil (20, 40 and 80 mg three times a day [TID]) on exercise capacity, as measured by the 6-Minute Walk test, as well as the safety and tolerability, after 12 weeks of treatment in subjects with pulmonary arterial hypertension who are aged 18 years and over. To investigate the plasma concentration-effect relationship and to determine the population pharmacokinetic (PK) parameters.

Official Title
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A Multinational, Multi-centre, Randomised, Double-blind, Double-dummy, Placebo-controlled Study to Assess the Efficacy and Safety of 20, 40, and 80mg TID Sildenafil in the Treatment of Pulmonary Arterial Hypertension in Subjects Aged 18 Years and Over

Conditions
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Hypertension, Pulmonary

Intervention / Treatment
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* Drug: sildenafil
* Drug: sildenafil
* Drug: placebo
* Drug: sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Included patients had primary pulmonary arterial hypertension, pulmonary hypertension secondary to connective tissue disease, or pulmonary hypertension with surgical repair at least 5 years previously; a mean pulmonary artery pressure greater than or equal to 25 mmHg and a pulmonary artery wedge pressure of less than or equal to 15 mmHg at rest, via right heart catheterisation within 21 days prior to randomisation; and a baseline 6-Minute Walk test distance of 100 m to 450 m. Exclusion Criteria: Subjects with congenital heart disease, pulmonary hypertension due to thromboembolism, HIV, chronic obstructive airway disease, congestive heart failure or schistosomiasis; subjects with significant (ie > 2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation; and acutely decompensated heart failure within the previous 30 days; subjects with pulmonary hypertension secondary to any other etiology other than those specified in the inclusion criteria.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br> | Drug: sildenafil<br>* sildenafil 20 mg by mouth three times daily (TID), with doses at least 6 hours apart, for 12 weeks<br>|
| Active Comparator: Arm 2<br> | Drug: sildenafil<br>* sildenafil 40 mg by mouth three times daily (TID), with doses at least 6 hours apart, for 12 weeks<br>|
| Active Comparator: Arm 3<br> | Drug: sildenafil<br>* sildenafil 80 mg by mouth three times daily (TID), with doses at least 6 hours apart, for 12 weeks; initially, patients received 40mg TID for one week and were then up-titrated to 80mg TID<br>|
| Placebo Comparator: Arm 4<br> | Drug: placebo<br>* placebo by mouth three times daily (TID), with doses at least 6 hours apart, for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in exercise capacity, as measured by distance walked in six minutes (6-Minute Walk test). |  | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in mean pulmonary arterial pressure |  | Week 12 | 
| Time from randomisation to the first occurrence of clinical worsening (death or lung transplantation or hospitalisation due to pulmonary hypertension or initiation of prostacyclin therapy or initiation of bosentan therapy) |  | Week 0 to 12 | 
| Change from baseline in the BORG dyspnoea score |  | Week 12 | 
| Change from baseline in pulmonary hypertension criteria for functional capacity and therapeutic class |  | Week 12 | 
| Change from baseline in the 8 dimensions of SF-36 (Physical functioning, Role functioning, Bodily pain, General health, Vitality, Social functioning, Mental health and Reported health transition) |  | Week 4 and Week 12 | 
| Change from baseline at Weeks 4 and 12 in the 5 dimensions of ED5Q (Mobility, Self care, Usual Activities, Pain/Discomfort and Anxiety/Depression) |  | Week 4 and Week 12 | 
| Patient overall preference assessment |  | Week 12 | 
| Change in Chronic Use of Background Therapy for Pulmonary Arterial Hypertension |  | throughout the study | 
| Change from baseline in hemodynamic parameters |  | Week 12 |