A Study to Evaluate GSK1325760A - a Long-Term Extension Study

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the safety of long-term administration of GSK1325760A in patients with PAH. The secondary objectives of this study are to evaluate long-term administration of GSK1325760A on: Improvement in exercise capacity (six-minutes walk distance: 6MWD), change in WHO Functional Classification and time to clinical worsening of PAH Change in the Borg Dyspnea Index (assessed immediately following the six-minute walk test [6MWT]) Change in plasma brain natriuretic peptide (BNP) levels Cardiopulmonary hemodynamics parameters (as measured by echocardiography)

Official Title
-----------------
Study AMB107818, Clinical Evaluation of GSK1325760A in the Treatment of Pulmonary Arterial Hypertension (PAH)- An Open Label Study of GSK1325760A to Evaluate the Safety and Efficacy of GSK1325760A - a Long-term Extension Study -

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

Intervention / Treatment
-----------------
* Drug: GSK1325760A


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who complete the 24-week administration of the Phase II/III study (Study No.AMB107816) Subjects who are assessed that the long-term extension administration of GSK1325760A is appropriate in the judgement of the investigator or subinvestigator Subjects who request the long-term extension administration of GSK1325760A, and agree to newly sign the informed consent form Exclusion Criteria: Subjects who have been withdrawn from the Phase II/III study. Female subjects who wish to become pregnant. Treatment with other PAH medication is needed. A worsening of 2 or more levels of the WHO Functional Classification (see Appendix 2.1) comparing with the baseline of Phase II/III study (Study No.AMB107816). Worsening of right ventricular failure (e.g. as indicated by increased jugular venous pressure, new/worsened hepatomegaly, ascites, or peripheral edema) during Phase II/III study (Study No.AMB107816). Rapidly progressing cardiac, hepatic or renal failure during Phase II/III study (Study No.AMB107816). Participation to the long-term extension study is considered as inappropriate in the judgment of the investigator or subinvestigator.
Sexes Eligible for Study
-----------------
All

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

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

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: GSK1325760A<br> | Drug: GSK1325760A<br>* 2.5mg, 5mg or 10mg/day, po, GSK1325760A treatment will be continued until its approval by the MHLW.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event | An adverse event was defined as any untoward medical occurrence in a participant, temporally associated with the use of an investigational product, whether or not considered related to the investigational product. | For 140.57 weeks at maximum, starting from Week 24 | 
| Number of Participants With Adverse Events Categorized by Severity | The severity of adverse events was assessed by the investigator; events were assigned to one of the following categories: mild, an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; moderate, an event that was sufficiently discomforting to interfere with normal everyday activities; and severe, an event that prevented normal everyday activities. | For 140.57 weeks at maximum, starting from Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 | Change from baseline was calculated as each value at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 minus the baseline value. 6MWD was measured by a 6-minute walk test. This test measures the distance that a participant can walk in a period of 6 minutes. Imputation technique was last observation carried forward, which was used in an attempt to compensate for missing data. For each participant, missing values were replaced with the last observed value. | Baseline and Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 | 
| Mean Change From Baseline in the Borg Dyspnea Index (BDI) at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion | The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum) and indicates the degree of breathlessness after completion of the 6-minute walk test. The BDI scale was assessed by each participant. Change from baseline was calculated as each value at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion minus the baseline value. Observed data analysis (no imputation technique). | Baseline and Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion (up to Week 159.85) | 
| Number of Participants With the Indicated Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion | There are four grades for the WHO FC (Class I = none, Class IV = most severe). The WHO FC indicates the severity of Pulmonary Arterial Hypertension and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. Observed data analysis (no imputation technique). | Baseline and Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion (up to Week 164.14) | 
| Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH), Assessed as the First Occurrence of a Particular Event | Time to clinical worsening was defined as the time from baseline to the first occurrence of death, lung transplantation, hospitalization for PAH treatment, atrial septostomy (a surgical procedure in which a small hole is made in the wall between the left and right atria of the heart), or study discontinuation due to change to other PAH treatment. Time to clinical worsening was measured as the number of participants who experienced these events up to 164.14 weeks. | Up to 164.14 weeks | 
| Mean Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion | mPAP is a measure of cardiopulmonary hemodynamics (echocardiography). Change from baseline was calculated as each value at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion minus the baseline value. Observed data analysis (no imputation technique). | Baseline and Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion (up to Week 153) | 
| Mean Change From Baseline in Cardiac Output (CO) at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion | CO is a measure of cardiopulmonary hemodynamics (echocardiography). Change from baseline was calculated as each value at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion minus the baseline value. Observed data analysis (no imputation technique). | Baseline and Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion (up to Week 156.14) | 
| Mean Change From Baseline in B-type Natriuretic Peptide (BNP) Values at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion | Change from baseline was calculated as each value at Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion minus the baseline value. BNP is a surrogate marker of heart failure and was measured by a central laboratory. Observed data analysis (no imputation techniques). | Baseline and Weeks 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, and Withdrawal/Completion (up to Week 164.14) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ambrisentan, Pulmonary Arterial Hypertension