Effects of Oral Sildenafil on Mortality in Adults With PAH

Study Overview
=================
Brief Summary
-----------------
This is a blinded study in adult patients with PAH evaluating the relative effects of sildenafil on mortality when administered at the three doses (80 mg, 20 mg or 5 mg, all three times per day [TID]). In addition, the relative effects on clinical worsening and 6-minute walking distance (6MWD) will be assessed.

Official Title
-----------------
A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH)

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: sildenafil citrate
* Drug: sildenafil citrate
* Drug: sildenafil citrate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects ≥ 18 <75 years of age with any of the following conditions: Idiopathic Primary Pulmonary Arterial Hypertension (IPAH) PAH secondary to connective tissue disease PAH with surgical repair (at least 5 years previously) of atrial septal defect (ASD),ventricular septal defect (VSD), patent ductus arteriosus (PDA) and aorto-pulmonary window PAH diagnosis confirmed by right heart catheterization performed within 12 months prior to randomization Functional Class II-IV; Baseline 6MWD ≥ 50 m. Exclusion Criteria: Significant (ie, >2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation History of cardiac arrest, respiratory arrest, hemodynamic collapse, CPR, ventricular tachycardia, ventricular fibrillation, or uncontrolled atrial fibrillation History of pulmonary embolism; History of chronic lung disease / restrictive lung disease (eg, chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function No prior long term treatment with PDE-5 inhibitors Treatment with bosentan OR riociguat within 3 months of randomization Current treatment with nitrates or nitric oxide

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose<br> | Drug: sildenafil citrate<br>* sildenafil citrate (PDE-5 inhibitor) 5 mg tablet TID until study treatment discontinued or end of study<br>* Other names: Revatio;|
| Experimental: Medium dose<br> | Drug: sildenafil citrate<br>* sildenafil citrate (PDE-5 inhibitor) 20 mg tablet TID until study treatment discontinued or end of study<br>* Other names: Revatio;|
| Experimental: High dose<br> | Drug: sildenafil citrate<br>* sildenafil citrate (PDE-5 inhibitor) 80 mg tablet TID until study treatment discontinued or end of study<br>* Other names: Revatio;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | In this outcome measure number of deaths during the study were reported. | Day 1 of study treatment up to date of death (within a maximum duration of 2102 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Worsening Events | Clinical worsening was defined as all-cause mortality, non-elective hospital stay for worsening pulmonary arterial hypertension (PAH) (including but not limited to right heart failure [RHF], initiation of intravenous (IV) prostanoids, lung transplantation, or septostomy) or disease progression. Disease progression was defined as a reduction from baseline in the 6-Minute Walk Distance (6MWD) test by 15% and worsening functional class from baseline, both confirmed by second test within 2 weeks of study treatment. | Day 1 of study treatment up to date of clinical worsening event (within a maximum duration of 2080 days) | 
| Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 6 | 6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH. | Baseline, Month 6 | 
| Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 12 | 6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH. | Baseline, Month 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pulmonary arterial hypertension, pulmonary hypertension, PAH, sildenafil, revatio