Phase 2 Extension Study of Ambrisentan in Pulmonary Arterial Hypertension

Study Overview
=================
Brief Summary
-----------------
AMB-220-E is an international, multicenter, open-label study examining the long-term safety of ambrisentan (BSF 208075) in subjects who have previously completed Myogen study NCT00046319, A Phase II, Randomized, Double-Blind, Dose-Controlled, Dose-Ranging, Multicenter Study of BSF 208075 Evaluating Exercise Capacity in Subjects with Moderate to Severe Pulmonary Arterial Hypertension.

Official Title
-----------------
An Open-Label, Long-Term Study of Ambrisentan in Pulmonary Hypertension Subjects Having Completed Myogen Study AMB-220

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

Intervention / Treatment
-----------------
* Drug: ambrisentan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have completed Visit 14/Week 24 of the NCT00046319 study. Women of childbearing potential must have a negative urine pregnancy test at the Screening/Enrollment Visit and agree to use a reliable double barrier method of contraception until study completion and for >=4 weeks following their final study visit. Must have completed the Down-titration Period of NCT00046319 prior to enrollment in AMB-220-E and will meet the following additional criteria: Subjects with a diagnosis of HIV must have stable disease status at the time of Screening/Enrollment. Must be stable on conventional therapy for PAH for >=4 weeks prior to the Screening Visit. Exclusion Criteria: Chronic prostanoid therapy, or other investigational prostacyclin derivative within 4 weeks prior to the Screening Visit. Intravenous inotrope use within 2 weeks prior to the Screening Visit. Females who are pregnant or breastfeeding. Contraindication to treatment with an endothelin receptor antagonist (ERA).

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

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

| Intervention/Treatment |
| --- |
|Drug: ambrisentan|1, 2.5, 5, and 10 mg ambrisentan given orally once daily|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pulmonary Arterial Hypertension (PAH) Who Completed the Phase II NCT00046319 Study and Who Experienced Severe Adverse Events (AEs) During Long-term Ambrisentan Exposure | The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of severe severity (ie, made it impossible to perform routine activities and the subject may have experienced intolerable discomfort or pain) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study. | Week 24 (AMB-220-E baseline) to Week 334 | 
| Number of Participants With PAH Who Completed the Phase II NCT00046319 Study and Who Experienced AEs of Moderate Severity During Long-term Ambrisentan Exposure | The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of moderate severity (ie, interfered with routine activities and subject may have experienced significant discomfort) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study. | Week 24 (AMB-220-E baseline) to Week 329.3 | 
| Number of Participants With PAH Who Completed the Phase II NCT00046319 Study and Who Experienced AEs of Mild Severity During Long-term Ambrisentan Exposure | The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of mild severity (ie, did not interfere with routine activities and the subject may have experienced slight discomfort) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study. | Week 24 (AMB-220-E baseline) to Week 329.3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline Measurement in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (Baseline [Week 24]) | The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). | Week 24 (AMB-220-E baseline) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (Last Observation Carried Forward [LOCF]) (Week 48) | The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). | 24 weeks (Week 24 to Week 48) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 108) | The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). | 84 weeks (Week 24 to Week 108) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 156) | The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). | 132 weeks (Week 24 to Week 156) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 204) | The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). | 180 weeks (Week 24 to Week 204) | 
| Baseline Measurement in Exercise Capacity as Measured by the Borg Dyspnea Index (BDI) (Baseline [Week 24]) | Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). | Week 24 (AMB-220-E baseline) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 48) | Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). | 24 weeks (Week 24 to Week 48) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 108) | Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). | 84 weeks (Week 24 to Week 108) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 156) | Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). | 132 weeks (Week 24 to Week 156) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 204) | Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). | 180 weeks (Week 24 to Week 204) | 
| Baseline Measurement in Exercise Capacity as Measured by the World Health Organization (WHO) Functional Classification (Baseline [Week 24]) | Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest. | Week 24 (AMB-220-E baseline) | 
| Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 24 Weeks of Treatment in AMB-220-E | Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest. | 24 weeks (Week 24 [baseline of AMB-220-E] to Week 48) | 
| Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 84 Weeks of Treatment in AMB-220-E | Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest. | 84 weeks (Week 24 of NCT00046319 to Week 108) | 
| Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 132 Weeks of Treatment in AMB-220-E | Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest. | 132 weeks (Week 24 of NCT00046319 to Week 156) | 
| Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 180 Weeks of Treatment in AMB-220-E | Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest. | 180 weeks (Week 24 of NCT00046319 to Week 204) | 
| Baseline Measurement in Exercise Capacity as Measured by the Subject Global Assessment (SGA) (Baseline [Week 24]) | The SGA was determined using a visual-analog scale. Subjects were asked the question, How are you feeling today? and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented very poor and 100 represented excellent. | Week 24 (AMB-220-E baseline) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 48) | The SGA was determined using a visual-analog scale. Subjects were asked the question, How are you feeling today? and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented very poor and 100 represented excellent. | 24 weeks (Week 24 to Week 48) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 108) | The SGA was determined using a visual-analog scale. Subjects were asked the question, How are you feeling today? and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented very poor and 100 represented excellent. | 84 weeks (Week 24 to Week 108) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 156) | The SGA was determined using a visual-analog scale. Subjects were asked the question, How are you feeling today? and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented very poor and 100 represented excellent. | 132 weeks (Week 24 to Week 156) | 
| Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 204) | The SGA was determined using a visual-analog scale. Subjects were asked the question, How are you feeling today? and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented very poor and 100 represented excellent. | 180 weeks (Week 24 to Week 204) | 
| Time to Clinical Worsening of PAH | Clinical worsening of PAH was defined as death, lung transplantation, hospitalization for PAH, atrial septostomy, the addition of approved prostanoid therapy, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents. Sildenafil, a type 5 phosphodiesterase (PDE-5) inhibitor, had not received regulatory approval for the treatment of PAH until late in the conduct of AMB 220 and AMB 220-E, and did not count toward clinical worsening. Results are presented as the Kaplan-Meier estimate (% probability) of not having clinical worsening after a given time. | Week 0 (NCT00046319 baseline) to Week 360 | 
| Failure-free Treatment Status | Failure-free treatment status was defined as the time from initiation of active treatment to the first occurrence of death, lung transplantation, the addition of approved prostanoid therapy, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents. Results are presented as the Kaplan-Meier estimate (% probability) of not having treatment failure after a given time. | Week 0 (NCT00046319 baseline) to Week 360 | 
| Long-term Survival | Long-term survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of survival after a given time. | Week 24 (AMB-220-E baseline) to Week 329.3 |