Trial Outcomes & Findings for A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202) (NCT NCT00578786)

Last Updated: 2013-01-15

Results Overview

The primary endpoint of this study is the incidence and severity of adverse events associated with long-term exposure to AMB in participants with PAH. The most frequently occurring adverse events (occurring in 15% or more of the participants in the combined group) are presented, by severity, that began after entering this extension study. Adverse events that were serious are included. Adverse events are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 6.1 and are presented by MedDRA preferred term. Severity was graded as follows: mild (AE did not interfere with routine activities; subject may have experienced slight discomfort), moderate (AE interfered with routine activities; subject may have experienced significant discomfort), and severe (AE made it impossible to perform routine activities; subject may have experienced intolerable discomfort or pain).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

383 participants

Primary outcome timeframe

Baseline to Week 295

Results posted on

2013-01-15

Participant Flow

Participants completing Week 12 of NCT00423748 or NCT00423202 could enroll in extension (E) study. Participants on placebo in parent study and d/c treatment due to \>/=2 early escape criteria were eligible. Total randomized: 361 (completed/early escape in prior study), 19 (d/c prior study), and 3 (completed prior study, did not enroll in E study).

Participants on active treatment in NCT00423748 or NCT00423202 continued to receive their last assigned blinded ambrisentan (AMB) dose from the prior study. Those on placebo in NCT00423748 were randomized to receive either 5 or 10 mg of AMB in the extension study. Those on placebo in NCT00423202 were randomized to either 2.5 or 5 mg of AMB.

Participant milestones

Participant milestones
Measure	Ambrisentan 2.5 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, almost half of those randomized to AMB 2.5 mg were titrated to 5 mg and 10 mg.	Ambrisentan 5 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, a third starting at 5 mg were titrated to 10 mg.	Ambrisentan 10 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies).
Overall Study STARTED	96	190	97
Overall Study COMPLETED	57	124	67
Overall Study NOT COMPLETED	39	66	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Ambrisentan 2.5 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, almost half of those randomized to AMB 2.5 mg were titrated to 5 mg and 10 mg.	Ambrisentan 5 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, a third starting at 5 mg were titrated to 10 mg.	Ambrisentan 10 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies).
Overall Study Adverse Event	27	37	17
Overall Study Lack of Efficacy	2	5	2
Overall Study Early Escape from Prior Study	2	1	2
Overall Study Withdrawal by Subject	7	8	5
Overall Study Protocol Violation	0	3	1
Overall Study Physician Decision	1	0	1
Overall Study Sponsor Decision	0	0	1
Overall Study Lost to Follow-up	0	4	0
Overall Study Pregnancy	0	1	0
Overall Study Not Otherwise Specified	0	4	1
Overall Study Qualified but Not Enrolled in Extension	0	3	0

Baseline Characteristics

A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ambrisentan 2.5 mg n=96 Participants Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, almost half of those randomized to AMB 2.5 mg were titrated to 5 mg and 10 mg.	Ambrisentan 5 mg n=190 Participants Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, a third starting at 5 mg were titrated to 10 mg.	Ambrisentan 10 mg n=97 Participants Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies).	Total n=383 Participants Total of all reporting groups
Age Continuous	52.27 years STANDARD_DEVIATION 14.968 • n=93 Participants	51.46 years STANDARD_DEVIATION 14.429 • n=4 Participants	49.09 years STANDARD_DEVIATION 16.572 • n=27 Participants	51.06 years STANDARD_DEVIATION 15.139 • n=483 Participants
Sex: Female, Male Female	69 Participants n=93 Participants	154 Participants n=4 Participants	79 Participants n=27 Participants	302 Participants n=483 Participants
Sex: Female, Male Male	27 Participants n=93 Participants	36 Participants n=4 Participants	18 Participants n=27 Participants	81 Participants n=483 Participants
Race/Ethnicity, Customized Caucasian	81 participants n=93 Participants	148 participants n=4 Participants	65 participants n=27 Participants	294 participants n=483 Participants
Race/Ethnicity, Customized Black	0 participants n=93 Participants	5 participants n=4 Participants	6 participants n=27 Participants	11 participants n=483 Participants
Race/Ethnicity, Customized Asian	1 participants n=93 Participants	6 participants n=4 Participants	2 participants n=27 Participants	9 participants n=483 Participants
Race/Ethnicity, Customized Hispanic	14 participants n=93 Participants	29 participants n=4 Participants	22 participants n=27 Participants	65 participants n=483 Participants
Race/Ethnicity, Customized Other	0 participants n=93 Participants	2 participants n=4 Participants	2 participants n=27 Participants	4 participants n=483 Participants
Pulmonary Arterial Hypertension Stratification Idiopathic PAH (IPAH)	63 participants n=93 Participants	119 participants n=4 Participants	59 participants n=27 Participants	241 participants n=483 Participants
Pulmonary Arterial Hypertension Stratification Non-IPAH	33 participants n=93 Participants	71 participants n=4 Participants	38 participants n=27 Participants	142 participants n=483 Participants
6-Minute Walk Distance (6MWD)	350.3 meters STANDARD_DEVIATION 86.640 • n=93 Participants	347.7 meters STANDARD_DEVIATION 87.333 • n=4 Participants	342.3 meters STANDARD_DEVIATION 80.840 • n=27 Participants	347.0 meters STANDARD_DEVIATION 85.389 • n=483 Participants
World Heath Organization (WHO) Class WHO Class I	1 participants n=93 Participants	7 participants n=4 Participants	4 participants n=27 Participants	12 participants n=483 Participants
World Heath Organization (WHO) Class WHO Class II	51 participants n=93 Participants	77 participants n=4 Participants	35 participants n=27 Participants	163 participants n=483 Participants
World Heath Organization (WHO) Class WHO Class III	39 participants n=93 Participants	91 participants n=4 Participants	48 participants n=27 Participants	178 participants n=483 Participants
World Heath Organization (WHO) Class WHO Class IV	5 participants n=93 Participants	15 participants n=4 Participants	10 participants n=27 Participants	30 participants n=483 Participants
Borg Dyspnea Index (BDI)	4.14 units on a scale STANDARD_DEVIATION 2.684 • n=93 Participants	3.80 units on a scale STANDARD_DEVIATION 2.332 • n=4 Participants	3.78 units on a scale STANDARD_DEVIATION 2.133 • n=27 Participants	3.88 units on a scale STANDARD_DEVIATION 2.377 • n=483 Participants
Body Mass Index (BMI)	26.68 kg/m^2 STANDARD_DEVIATION 5.038 • n=93 Participants	26.86 kg/m^2 STANDARD_DEVIATION 5.632 • n=4 Participants	28.26 kg/m^2 STANDARD_DEVIATION 7.212 • n=27 Participants	27.17 kg/m^2 STANDARD_DEVIATION 5.958 • n=483 Participants

PRIMARY outcome

Timeframe: Baseline to Week 295

Population: Safety Analysis Set: Includes all participants who received at least 1 dose of AMB in one of the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Treatment group assignments for the safety analysis set were based upon the highest dose of AMB received at any time during the parent or extension studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=43 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=146 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=194 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group All dose groups combined.
Frequently Reported (15% or More Overall) Adverse Events by Severity Headache - Mild	1 participants	20 participants	36 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Headache - Moderate	0 participants	14 participants	17 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Headache - Severe	0 participants	0 participants	8 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Pulmonary hypertension (worsening) - Mild	2 participants	2 participants	7 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Pulmonary hypertension (worsening) - Moderate	4 participants	10 participants	29 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Pulmonary hypertension (worsening) - Severe	6 participants	6 participants	19 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Right ventricular failure - Mild	0 participants	2 participants	6 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Right ventricular failure - Moderate	2 participants	7 participants	14 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Right ventricular failure - Severe	5 participants	12 participants	26 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Cough - Mild	1 participants	23 participants	24 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Cough - Moderate	1 participants	2 participants	22 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Cough - Severe	0 participants	1 participants	0 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Upper respiratory tract infection - Mild	3 participants	13 participants	23 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Upper respiratory tract infection - Moderate	2 participants	4 participants	26 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Upper respiratory tract infection - Severe	0 participants	0 participants	1 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Dizziness - Mild	1 participants	8 participants	31 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Dizziness - Moderate	2 participants	7 participants	14 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Dizziness - Severe	0 participants	0 participants	3 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Dyspnoea exacerbated - Mild	1 participants	4 participants	8 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Dyspnoea exacerbated - Moderate	3 participants	14 participants	22 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Dyspnoea exacerbated - Severe	1 participants	2 participants	7 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Arthralgia - Mild	1 participants	5 participants	19 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Arthralgia - Moderate	3 participants	11 participants	18 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Arthralgia - Severe	1 participants	2 participants	1 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Diarrhoea - Mild	2 participants	12 participants	17 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Diarrhoea - Moderate	1 participants	10 participants	15 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Diarrhoea - Severe	0 participants	2 participants	1 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Nasopharyngitis - Mild	1 participants	14 participants	19 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Nasopharyngitis - Moderate	1 participants	8 participants	15 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Nasopharyngitis - Severe	0 participants	0 participants	0 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Oedema peripheral - Mild	6 participants	31 participants	48 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Oedema peripheral - Moderate	6 participants	19 participants	50 participants	—
Frequently Reported (15% or More Overall) Adverse Events by Severity Oedema peripheral - Severe	1 participants	3 participants	4 participants	—

PRIMARY outcome

Timeframe: Baseline to Week 295

Population: Safety Analysis Set: Includes all participants who received at least 1 blinded dose of AMB in one of the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.

The number of participants with serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) falling into the following categories: \>3.0 and \</= 5.0 x ULN, \>5.0 and \</= 8.0 x ULN, and \>8.0 x ULN. Includes the highest value per participant across all visits as well as values from early termination visits.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=43 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=155 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=205 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group All dose groups combined.
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) ALT >3.0 and </=5.0 x ULN	0 participants	2 participants	4 participants	—
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) ALT >5.0 and </= 8.0 x ULN	0 participants	1 participants	0 participants	—
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) ALT >8.0 x ULN	0 participants	3 participants	5 participants	—
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) Total ALT results >3.0 x ULN	0 participants	0 participants	1 participants	—
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) AST >3.0 and </=5.0 x ULN	1 participants	3 participants	7 participants	—
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) AST >5.0 and </= 8.0 x ULN	0 participants	1 participants	0 participants	—
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) AST >8.0 x ULN	0 participants	0 participants	1 participants	—
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) Total AST results >3.0 x ULN	1 participants	4 participants	8 participants	—

SECONDARY outcome

Timeframe: Baseline

Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test	350.3 Meters Standard Deviation 86.64	347.7 Meters Standard Deviation 87.33	342.3 Meters Standard Deviation 80.84	347.0 Meters Standard Deviation 85.39

SECONDARY outcome

Timeframe: Baseline to Week 24

The 6-minute walk distance (6MWD) test 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.). Missing values were imputed using LOCF method based on post-baseline observations. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=93 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=186 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=375 Participants All dose groups combined.
Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	38.0 Meters Standard Deviation 74.28	32.5 Meters Standard Deviation 78.55	40.9 Meters Standard Deviation 72.85	36.0 Meters Standard Deviation 75.97

SECONDARY outcome

Timeframe: Baseline to Week 48

The 6-minute walk distance (6MWD) test 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.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=93 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=186 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=375 Participants All dose groups combined.
Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	24.9 Meters Standard Deviation 96.14	27.9 Meters Standard Deviation 94.50	37.2 Meters Standard Deviation 72.97	29.5 Meters Standard Deviation 89.81

SECONDARY outcome

Timeframe: Baseline to Year 2

The 6-minute walk distance (6MWD) test 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.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=93 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=186 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=375 Participants All dose groups combined.
Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	6.7 Meters Standard Deviation 97.48	23.2 Meters Standard Deviation 100.69	28.0 Meters Standard Deviation 84.38	20.3 Meters Standard Deviation 96.05

SECONDARY outcome

Timeframe: Baseline to Year 3

Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=93 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=186 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=375 Participants All dose groups combined.
Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	0.7 Meters Standard Deviation 95.21	18.8 Meters Standard Deviation 101.22	27.8 Meters Standard Deviation 87.07	16.6 Meters Standard Deviation 96.54

SECONDARY outcome

Timeframe: Baseline

Population: All assessments of efficacy were performed using the randomized analysis set, such that subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.

Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=189 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=382 Participants All dose groups combined.
Baseline Borg Dyspnea Index	4.14 units on a scale Standard Deviation 2.684	3.80 units on a scale Standard Deviation 2.332	3.78 units on a scale Standard Deviation 2.133	3.88 units on a scale Standard Deviation 2.377

SECONDARY outcome

Timeframe: Baseline to Year 1

Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=93 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=185 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=374 Participants All dose groups combined.
Change From Baseline to Year 1 in Borg Dyspnea Index	-0.08 units on a scale Standard Deviation 2.254	-0.59 units on a scale Standard Deviation 2.450	-0.51 units on a scale Standard Deviation 2.400	-0.44 units on a scale Standard Deviation 2.393

SECONDARY outcome

Timeframe: Baseline to Year 2

Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=93 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=185 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=374 Participants All dose groups combined.
Change From Baseline to Year 2 in Borg Dyspnea Index	0.23 units on a scale Standard Deviation 2.603	-0.33 units on a scale Standard Deviation 2.477	-0.65 units on a scale Standard Deviation 2.305	-0.27 units on a scale Standard Deviation 2.480

SECONDARY outcome

Timeframe: Baseline to Year 3

Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=93 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=185 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=374 Participants All dose groups combined.
Change From Baseline to Year 3 in Borg Dyspnea Index	0.20 units on a scale Standard Deviation 2.593	-0.14 units on a scale Standard Deviation 2.514	-0.48 units on a scale Standard Deviation 2.215	-0.14 units on a scale Standard Deviation 2.467

SECONDARY outcome

Timeframe: Baseline

WHO 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 possible at rest.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Baseline World Health Organization (WHO) Functional Class WHO Functional Class I	1 participants	7 participants	4 participants	12 participants
Baseline World Health Organization (WHO) Functional Class WHO Functional Class II	51 participants	77 participants	35 participants	163 participants
Baseline World Health Organization (WHO) Functional Class WHO Functional Class III	39 participants	91 participants	48 participants	178 participants
Baseline World Health Organization (WHO) Functional Class WHO Functional Class IV	5 participants	15 participants	10 participants	30 participants

SECONDARY outcome

Timeframe: Baseline to Year 1

Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in extension study. Missing values imputed using LOCF based on post-baseline observations.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class Improved	16 participants	56 participants	36 participants	108 participants
Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class No Change	68 participants	122 participants	46 participants	236 participants
Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class Deteriorated	10 participants	9 participants	14 participants	33 participants
Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class Missing	2 participants	3 participants	1 participants	6 participants

SECONDARY outcome

Timeframe: Baseline to Year 2

Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in extension study. Missing values were imputed using LOCF based on post-baseline observations.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class Improved	16 participants	58 participants	39 participants	113 participants
Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class No Change	58 participants	109 participants	43 participants	210 participants
Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class Deteriorated	20 participants	20 participants	14 participants	54 participants
Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class Missing	2 participants	3 participants	1 participants	6 participants

SECONDARY outcome

Timeframe: Baseline to Year 3

Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. Missing values were imputed using LOCF based on post-baseline observations.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class Improved	17 participants	61 participants	32 participants	110 participants
Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class No Change	57 participants	109 participants	49 participants	215 participants
Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class Deteriorated	20 participants	17 participants	15 participants	52 participants
Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class Missing	2 participants	3 participants	1 participants	6 participants

SECONDARY outcome

Timeframe: Baseline

Population: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.

The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=355 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group All dose groups combined.
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Functioning	30.0 units on a scale Standard Deviation 9.02	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Physical	35.2 units on a scale Standard Deviation 10.21	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Bodily Pain	46.3 units on a scale Standard Deviation 11.93	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group General Health	36.0 units on a scale Standard Deviation 8.65	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Vitality	42.1 units on a scale Standard Deviation 10.23	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Social Functioning	39.6 units on a scale Standard Deviation 11.8	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Emotional	39.2 units on a scale Standard Deviation 13.47	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Health	43.3 units on a scale Standard Deviation 12.12	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Component Summary	35.1 units on a scale Standard Deviation 8.52	—	—	—
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Component Summary	44.5 units on a scale Standard Deviation 11.98	—	—	—

SECONDARY outcome

Timeframe: Baseline to Week 12

Population: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.

The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and SD. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=303 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group All dose groups combined.
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Functioning (n=299)	3.9 units on a scale Standard Deviation 7.40	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Physical (n=298)	5.6 units on a scale Standard Deviation 10.81	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Bodily Pain (n=303)	1.8 units on a scale Standard Deviation 11.27	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group General Health (n=297)	3.1 units on a scale Standard Deviation 7.85	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Vitality (n=301)	4.6 units on a scale Standard Deviation 9.12	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Social Functioning (n=303)	3.9 units on a scale Standard Deviation 10.63	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Emotional (n=286)	3.9 units on a scale Standard Deviation 14.69	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Health (n=301)	3.2 units on a scale Standard Deviation 9.72	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Component Summary (n=276)	3.8 units on a scale Standard Deviation 7.59	—	—	—
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Component Summary (n=276)	3.4 units on a scale Standard Deviation 10.77	—	—	—

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.

The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and SD. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=230 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group All dose groups combined.
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Functioning (n=226)	4.7 units on a scale Standard Deviation 8.75	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Physical (n=227)	5.7 units on a scale Standard Deviation 13.37	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Bodily Pain (n=230)	1.0 units on a scale Standard Deviation 13.28	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group General Health (n=223)	3.2 units on a scale Standard Deviation 8.11	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Vitality (n=227)	4.5 units on a scale Standard Deviation 9.55	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Social Functioning (n=230)	3.5 units on a scale Standard Deviation 11.50	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Emotional (n=220)	4.3 units on a scale Standard Deviation 14.45	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Health (n=227)	2.6 units on a scale Standard Deviation 10.57	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Component Summary (n=212)	3.8 units on a scale Standard Deviation 9.06	—	—	—
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Component Summary (n=212)	3.2 units on a scale Standard Deviation 11.06	—	—	—

SECONDARY outcome

Timeframe: Baseline to Week 36

Population: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.

The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and SD. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=186 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group All dose groups combined.
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Functioning (n=183)	4.9 units on a scale Standard Deviation 8.27	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Physical (n=181)	4.5 units on a scale Standard Deviation 12.34	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Bodily Pain (n=186)	1.9 units on a scale Standard Deviation 13.16	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group General Health (n=181)	4.5 units on a scale Standard Deviation 12.34	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Vitality (n=185)	4.6 units on a scale Standard Deviation 9.16	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Social Functioning (n=186)	3.7 units on a scale Standard Deviation 12.26	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Role Emotional (n=178)	3.6 units on a scale Standard Deviation 15.17	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Health (n=185)	2.9 units on a scale Standard Deviation 11.00	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Physical Component Summary (n=169)	3.9 units on a scale Standard Deviation 8.79	—	—	—
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group Mental Component Summary (n=169)	2.9 units on a scale Standard Deviation 11.34	—	—	—

SECONDARY outcome

Timeframe: Baseline to Year 3

Clinical worsening of PAH was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to AMB in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having clinical worsening after a given time.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Percentage of Participants With No Clinical Worsening of PAH No clinical worsening after 1 year of treatment	80.4 percent probability (KM estimate) 95% Confidence Interval 4.2 • Interval 70.7 to 87.2	83.9 percent probability (KM estimate) 95% Confidence Interval 2.7 • Interval 77.7 to 88.5	82.8 percent probability (KM estimate) 95% Confidence Interval 3.9 • Interval 73.5 to 89.1	82.7 percent probability (KM estimate) 95% Confidence Interval 2.0 • Interval 78.4 to 86.2
Percentage of Participants With No Clinical Worsening of PAH No clinical worsening after 2 years of treatment	67.8 percent probability (KM estimate) 95% Confidence Interval 4.9 • Interval 57.0 to 76.4	72.4 percent probability (KM estimate) 95% Confidence Interval 3.4 • Interval 65.1 to 78.5	72.2 percent probability (KM estimate) 95% Confidence Interval 4.8 • Interval 61.7 to 80.3	71.1 percent probability (KM estimate) 95% Confidence Interval 2.4 • Interval 66.1 to 75.6
Percentage of Participants With No Clinical Worsening of PAH No clinical worsening after 3 years of treatment	60.7 percent probability (KM estimate) 95% Confidence Interval 5.2 • Interval 49.7 to 70.0	67.4 percent probability (KM estimate) 95% Confidence Interval 3.7 • Interval 59.7 to 74.0	59.9 percent probability (KM estimate) 95% Confidence Interval 5.6 • Interval 48.0 to 69.9	63.8 percent probability (KM estimate) 95% Confidence Interval 2.7 • Interval 58.4 to 68.8

SECONDARY outcome

Timeframe: Baseline to Year 4

Treatment failure was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to ambrisentan in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having treatment failure after a given time.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Percentage of Participants With Failure-Free Treatment Status No treatment failure after 1 year of treatment	86.8 percent probability (KM estimate) 95% Confidence Interval 3.6 • Interval 77.9 to 92.3	89.0 percent probability (KM estimate) 95% Confidence Interval 2.4 • Interval 83.3 to 92.9	90.1 percent probability (KM estimate) 95% Confidence Interval 3.1 • Interval 81.8 to 94.7	88.7 percent probability (KM estimate) 95% Confidence Interval 1.7 • Interval 85.0 to 91.6
Percentage of Participants With Failure-Free Treatment Status No treatment failure after 2 years of treatment	77.6 percent probability (KM estimate) 95% Confidence Interval 4.4 • Interval 67.4 to 84.9	79.8 percent probability (KM estimate) 95% Confidence Interval 3.1 • Interval 72.8 to 85.1	81.4 percent probability (KM estimate) 95% Confidence Interval 4.2 • Interval 71.4 to 88.2	79.6 percent probability (KM estimate) 95% Confidence Interval 2.2 • Interval 75.0 to 83.5
Percentage of Participants With Failure-Free Treatment Status No treatment failure after 3 years of treatment	69.1 percent probability (KM estimate) 95% Confidence Interval 5.0 • Interval 58.3 to 77.7	73.8 percent probability (KM estimate) 95% Confidence Interval 3.5 • Interval 66.2 to 80.0	67.9 percent probability (KM estimate) 95% Confidence Interval 5.7 • Interval 55.5 to 77.6	71.3 percent probability (KM estimate) 95% Confidence Interval 2.6 • Interval 65.9 to 76.0
Percentage of Participants With Failure-Free Treatment Status No treatment failure after 4 years of treatment	60.8 percent probability (KM estimate) 95% Confidence Interval 5.4 • Interval 49.4 to 70.5	69.0 percent probability (KM estimate) 95% Confidence Interval 4.0 • Interval 60.3 to 76.2	63.2 percent probability (KM estimate) 95% Confidence Interval 6.2 • Interval 49.9 to 73.9	66.4 percent probability (KM estimate) 95% Confidence Interval 2.8 • Interval 59.0 to 70.4

SECONDARY outcome

Timeframe: Baseline to Year 4

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.

Outcome measures

Outcome measures
Measure	Ambrisentan 2.5 mg n=96 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 5 mg n=190 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Ambrisentan 10 mg n=97 Participants Participants were classified based on their randomized dose of AMB in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Combined Ambrisentan Group n=383 Participants All dose groups combined.
Long-term Survival Survival after 1 year of treatment	96.8 percent probability (KM estimate) 95% Confidence Interval 1.8 • Interval 90.4 to 99.0	93.1 percent probability (KM estimate) 95% Confidence Interval 1.9 • Interval 88.1 to 96.0	94.5 percent probability (KM estimate) 95% Confidence Interval 2.4 • Interval 87.2 to 97.7	94.4 percent probability (KM estimate) 95% Confidence Interval 1.2 • Interval 91.4 to 96.3
Long-term Survival Survival after 2 years of treatment	84.7 percent probability (KM estimate) 95% Confidence Interval 3.9 • Interval 75.1 to 90.8	87.3 percent probability (KM estimate) 95% Confidence Interval 2.6 • Interval 81.2 to 91.6	90.7 percent probability (KM estimate) 95% Confidence Interval 3.1 • Interval 82.3 to 95.3	87.5 percent probability (KM estimate) 95% Confidence Interval 1.8 • Interval 83.5 to 90.6
Long-term Survival Survival after 3 years of treatment	78.4 percent probability (KM estimate) 95% Confidence Interval 4.5 • Interval 67.9 to 85.8	84.2 percent probability (KM estimate) 95% Confidence Interval 2.9 • Interval 77.4 to 89.1	82.7 percent probability (KM estimate) 95% Confidence Interval 4.5 • Interval 71.7 to 89.7	82.2 percent probability (KM estimate) 95% Confidence Interval 2.2 • Interval 77.5 to 86.1
Long-term Survival Survival After 4 Years of Treatment	71.1 percent probability (KM estimate) 95% Confidence Interval 5.2 • Interval 59.6 to 79.9	78.1 percent probability (KM estimate) 95% Confidence Interval 3.8 • Interval 69.5 to 84.6	82.7 percent probability (KM estimate) 95% Confidence Interval 4.5 • Interval 71.7 to 89.7	76.5 percent probability (KM estimate) 95% Confidence Interval 2.7 • Interval 70.7 to 81.3

Adverse Events

Ambrisentan 2.5 mg

Serious events: 26 serious events

Other events: 36 other events

Deaths: 0 deaths

Ambrisentan 5 mg

Serious events: 76 serious events

Other events: 131 other events

Deaths: 0 deaths

Ambrisentan 10 mg

Serious events: 103 serious events

Other events: 190 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Hunter Gillies, MD, DSEM

Gilead Sciences, Inc.

Phone: 650-522-1214

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place