Open Label Study of Sildenafil in Patients With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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To assess the safety of sildenafil 20 mg TID orally given to Japanese pulmonary arterial hypertension patients (Part 1 and 2) To assess the efficacy after 12 weeks of treatment of sildenafil 20 mg TID orally given to Japanese pulmonary arterial hypertension patients (Part 1)

Official Title
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A Phase 3, Multi-Center, Open-Label Study to Assess Safety and Efficacy of Sildenafil Citrate 20 mg TID in Subjects With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: sildenafil citrate (UK-92,480)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged 16 and over, and classified as having pulmonary arterial hypertension Subjects who meet the following conditions on right heart catheterization at screening or baseline: mean pulmonary arterial pressure of ≥ 25mmHg and pulmonary capillary wedge pressure of ≤ 15mmHg at rest Subjects whose baseline 6-Minute Walk test distance is >100 m and <450 m Exclusion Criteria: Significant Hepatic and/or renal disorder Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic ischemic optic neuropathy (NAION) Subjects who are currently receiving nitrates or nitric oxide donors in any form, ritonavir, ketoconazole and itraconazole

Ages Eligible for Study
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Minimum Age: 16 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sildenafil citrate (UK-92,480)<br>sildenafil citrate 20 mg TID | Drug: sildenafil citrate (UK-92,480)<br>* sildenafil citrate (UK-92,480)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the 6-minute Walk Distance From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：6-minute walk distance at Week 12 minus 6-minute walk distance at baseline. The 6-minute walk distance:total distance walked during the 6-minute walk test. | Baseline, Week 12 | 
| Change in the Mean Pulmonary Arterial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change:Mean pulmonary arterial pressure at Week 12 minus mean pulmonary arterial pressure at baseline. | Baseline, Week 12 | 
| Change in the Pulmonary Vascular Resistance From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Pulmonary vascular resistance at Week 12 minus pulmonary vascular resistance at baseline | Baseline, Week 12 | 
| Change in the Cardiac Output From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Cardiac output at Week 12 minus cardiac output at baseline | Baseline, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the 6-minute Walk Distance From Baseline at Week 8 in Participants Who Entered the Study From Part I | Change：6-minute walk distance at Week 8 minus 6-minute walk distance at baseline. The 6-minute walk distance:Total distance walked during the 6- minute walk test. | Baseline, Week 8 | 
| Change in the Systolic Pulmonary Arterial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Systolic pulmonary arterial pressure at Week 12 minus Systolic pulmonary arterial pressure at baseline. | Baseline, Week 12 | 
| Change in the Diastolic Pulmonary Arterial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Diastolic pulmonary arterial pressure at Week 12 minus diastolic pulmonary arterial pressure at baseline. | Baseline, Week 12 | 
| Change in the Systolic Systemic Blood Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Systolic systemic blood pressure at Week 12 minus systolic systemic blood pressure at baseline. | Baseline, Week 12 | 
| Change in the Diastolic Systemic Blood Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Diastolic systemic blood pressure at Week 12 minus diastolic systemic blood pressure at baseline. | Baseline, Week 12 | 
| Change in the Mean Systemic Blood Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Mean systemic blood pressure:diastolic blood pressure+(systolic blood pressure-diastolic blood pressure)/3. Change：Mean systemic blood pressure at Week 12 minus mean systemic blood pressure at baseline. | Baseline, Week 12 | 
| Change in the Pulmonary Capillary Wedge Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Pulmonary capillary wedge pressure at Week 12 minus pulmonary capillary wedge pressure at baseline. | Baseline, Week 12 | 
| Change in the Right Atrial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Right atrial pressure at Week 12 minus right atrial pressure at baseline. | Baseline, Week 12 | 
| Change in the Cardiac Index From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Cardiac index at Week 12 minus cardiac index at baseline. | Baseline, Week 12 | 
| Change in the Heart Rate From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Heart rate at Week 12 minus heart rate at baseline. | Baseline, Week 12 | 
| Change in the Pulmonary Vascular Resistance Index From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change:Pulmonary vascular resistance index at Week 12 minus pulmonary vascular resistance index at baseline. | Baseline, Week 12 | 
| Change in the Systemic Vascular Resistance From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Systemic vascular resistance at Week 12 minus systemic vascular resistance at baseline. | Baseline, Week 12 | 
| Change in the Systemic Vascular Resistance Index From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Systemic vascular resistance index at Week 12 minus systemic vascular resistance index at baseline. | baseline, Week 12 | 
| Change in the Mixed Venous Oxygen Saturation From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Mixed venous oxygen saturation at Week 12 minus mixed venous oxygen saturation at baseline. | Baseline, Week 12 | 
| Change in the Arterial Oxygen Saturation From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Arterial oxygen saturation at Week 12 minus arterial oxygen saturation at baseline. | Baseline, Week 12 | 
| Change in the Arterial Oxygen Partial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Arterial oxygen partial pressure at Week 12 minus arterial oxygen partial pressure at baseline. | baseline, Week 12 | 
| Change in the Partial Pressure of Mixed Venous Oxygen From Baseline at Week 12 in Participants Who Entered the Study From Part I | Change：Partial pressure of mixed venous oxygen at Week 12 minus partial pressure of mixed venous oxygen at baseline. | Baseline, Week 12 | 
| Changes in the World Health Organization (WHO) Functional Class of Pulmonary Arterial Hypertension From Baseline at Weeks 12 in Participants Who Entered the Study From Part I | The cross-tabulation table on the WHO functional classes of pulmonary arterial hypertension at baseline and Week 12. The WHO functional classes of pulmonary arterial hypertension:Class I (pulmonary arterial hypertension patients with no limitation in physical activity) to Class IV (pulmonary arterial hypertension patients who can not perform a physical activity without any symptoms). | Baseline, Week 12 | 
| Changes in the BORG Dyspnoea Score From Baseline at Week 8 and Week 12 in Participants Who Entered the Study From Part I | Change：BORG dyspnoea score at Week 8 and Week 12 minus BORG dyspnoea score at baseline. BORG dyspnoea score:Scale 0 (no breathlessness at all) to 10 (maximum). The score reflected the maximum degree of dyspnoea that the participants experienced at any time during the 6-minute walk distance. | Baseline, Week 8, Week 12 | 
| Changes in the the Plasma Brain Natriuretic Peptide Level From Baseline at Week 4, Week 8 and Week 12 in Participants Who Entered the Study From Part I | Change：Plasma brain natriuretic peptide level at Week 4, Week 8 and Week 12 minus plasma brain natriuretic peptide level at baseline | Baseline, Week 4, Week 8, Week 12 | 
| Change in the 6-minute Walk Distance From Baseline at Week 12 in Participants Who Newly Entered the Study From Part II | Change：6-minute walk distance at Week 12 minus 6-minute walk distance at baseline. The 6-minute walk distance:Total distance walked during the 6- minute walk test. | Baseline, Week 12 | 
| Change in the World Health Organization (WHO) Functional Class From Baseline at Week 12 in Participants Who Newly Entered the Study From Part II | The cross-tabulation table on the WHO functional classes of pulmonary arterial hypertension at baseline and Week 12. The WHO functional classes of pulmonary arterial hypertension:Class I (pulmonary arterial hypertension patients with no limitation in physical activity) to Class IV (pulmonary arterial hypertension patients who can not perform a physical activity without any symptoms). | Baseline, Week 12 | 
| Changes in the BORG Dyspnoea Score From Baseline at Week 12 in Participants Who Newly Entered the Study From Part II | Change：BORG dyspnoea score at Week 12 minus BORG dyspnoea score at baseline. BORG dyspnoea score:Scale 0 (no breathlessness at all) to 10 (maximum). The score reflected the maximum degree of dyspnoea that the participants experienced at any time during the 6-minute walk distance. | Baseline, Week 12 | 
| Changes in the the Plasma Brain Natriuretic Peptide Level From Baseline at Week 12 in Participants Who Newly Enterd the Study From Part II | Change：Plasma brain natriuretic peptide level at Week 12 minus plasma brain natriuretic peptide level at baseline | Baseline, Week 12 | 
| Maximum Plasma Concentrations (Cmax) of Sildenafil and Sildenafil's Metabolite, UK-103,320 | Maximum plasma concentrations was calculated from the observed value of plasma concentrations in each participant | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing | 
| Time to First Occurrence of Maximum Plasma Concentrations (Tmax) of Sildenafil and Sildenafil's Metabolite, UK-103,320 | Time to first occurrence of maximum plasma concentrations were calculated from the observed value of plasma concentrations in each participant. | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing | 
| The Area Under the Curve (AUC) From Time 0 to Time 8 Hour of Sildenafil and Sildenafil's Metabolite, UK-103,320 | The area under the curve from time 0 to time 8 hour was calculated from area under the curve in each perticipant on the date of blood sampling using the linear/log trapezoidal rule | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing | 
| The Average Plasma Concentration (Css,av) of Sildenafil at Steady State | The average plasma concentration of sildenafil at steady state was calculated from the area under the curve from time 0 to 8 hour/dosing interval (8 hours). | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing | 
| The Average Plasma Trough Concentration (Ctrough) of Sildenafil | The average plasma trough concentration of sildenafil was calculated from the observed value before administration of the drug in each participants. | Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing | 
| Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | The total number of participants with laboratory test abnormalities without regard to baseline abnormality. | Baseline up to 1.3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension, PAH