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

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00578786
• Collaborator: (none)
• Enrollment: 383
• Locations: 22
• Arm: 1
• Duration (Months): 72.9
• Patients Per Site: 17.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

AMB-320/321-E was designed to provide long-term, controlled monitoring of pulmonary arterial hypertension (PAH) patients treated with ambrisentan (AMB) in order to properly define the adverse event profile associated with this endothelin receptor antagonist (ERA), including the incidence and severity of elevated serum liver function tests (LFTs). In addition, this study continued the efficacy assessments of the previous studies, examined long-term AMB treatment success, and compared long-term survival of subjects treated with AMB to the NIH registry of patients with PAH.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: ambrisentan	Phase 3

Detailed Description

AMB-320 (ARIES-1; NCT00423748) and AMB-321 (ARIES-2; NCT00423202) were 12-week, Phase 3, randomized, double-blind, placebo-controlled, multicenter, efficacy studies of AMB in subjects with PAH. The objectives of these studies were to determine the effect of three doses of AMB (2.5, 5.0, and 10.0 mg) on exercise capacity, as well as several clinical measures of PAH. The current study (NCT00578786) was unblinded (by design) prior to completion. The ARIES studies were identical except for the dose groups assessed and the geographic locations where the studies were conducted. Both studies evaluated placebo and 5.0-mg AMB dose groups; however, AMB-320 (NCT00423748) also examined an AMB dose of 10.0 mg, while AMB-321 (NCT00423202) included an AMB dose of 2.5 mg. AMB-320/321-E was an optional study for subjects who had participated in AMB-320 (NCT00423748) or AMB-321 (NCT00423202) that allowed continued long-term treatment with AMB.

Study Design

• Study Type: Interventional
• Actual Enrollment: 383 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202)
• Study Start Date: Feb 1, 2004
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ambrisentan 2.5, 5 or 10 mg ambrisentan	Drug: ambrisentan; 2.5, 5.0 or 10.0 mg ambrisentan po, qd, long-term; Other Names: Letairis(TM)

Outcome Measures

Primary Outcome Measures

1. Frequently Reported (15% or More Overall) Adverse Events by Severity [Baseline to Week 295]

   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).

2. Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) [Baseline to Week 295]

   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.

Secondary Outcome Measures

1. Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test [Baseline]

   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.).

2. Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [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.

3. Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [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.

4. Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [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.

5. Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [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.

6. Baseline Borg Dyspnea Index [Baseline]

   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).

7. Change From Baseline to Year 1 in Borg Dyspnea Index [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.

8. Change From Baseline to Year 2 in Borg Dyspnea Index [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.

9. Change From Baseline to Year 3 in Borg Dyspnea Index [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.

10. Baseline World Health Organization (WHO) Functional Class [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.

11. Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class [Baseline to Year 1]

    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.

12. Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class [Baseline to Year 2]

    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.

13. Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class [Baseline to Year 3]

    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.

14. Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group [Baseline]

    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.

15. Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group [Baseline to Week 12]

    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.

16. Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group [Baseline to Week 24]

    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.

17. Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group [Baseline to Week 36]

    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.

18. Percentage of Participants With No Clinical Worsening of PAH [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.

19. Percentage of Participants With Failure-Free Treatment Status [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.

20. Long-term Survival [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject must have completed Week 12 of AMB-320 (NCT00423748) or AMB-321 (NCT00423202) or must have received placebo during AMB-320 (NCT00423748) or AMB-321 (NCT00423202) and met two or more early escape criteria;

2. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form and must sign the form prior to the initiation of any study procedures.

3. Female subject of childbearing potential must agree to use two reliable methods of contraception until study completion and for at least four weeks following their final study visit. Reliable methods include: birth control pills/implants/injections, intrauterine devices (IUDs), spermicide, diaphragms, or condoms.

Exclusion Criteria:

• Subjects must have met the exclusion criteria of the AMB-320 (NCT00423748) and AMB-321 (NCT00423202)studies. In addition, a subject who meets any one of the following criteria is ineligible for participation in the study:

1. Subject receiving bosentan, sildenafil, or iv inotropes at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit;

2. Subject receiving chronic prostanoid therapy (epoprostenol, treprostinil, iloprost, beraprost, or any other investigational prostacyclin derivative) within four weeks prior to the AMB-320/321-E Screening/RandomizationVisit;

3. Female subject who is pregnant or breastfeeding;

4. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject;

5. Subject who has demonstrated noncompliance with previous medical regimens;

6. Subject who has a recent history of abusing alcohol or illicit drugs;

7. Subject who has participated in a clinical study involving another investigational drug or device at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanatorio Otamendi	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1115AAB
2	Hospital Britanico-Buenos Aires	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1280AEB
3	Instituto del Corazon Denton A. Cooley	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1416A
4	UAI Hosp. Universitario	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1437BZL
5	HIGA Hospital Interzonal General de Agudos Oscar Allende	Mar del Plata	Buenos Aires	Argentina	07600
6	Clinica Independencia Munro	Munro	Buenos Aires	Argentina	01605
7	Hospital Italiano de Rosario	Rosario	Sante Fe	Argentina	02000
8	Sanatorio Allende	Cordoba		Argentina	X5000JHQ
9	Hospital Italiano de Cordoba	Cordoba		Argentina	X5004 FJE
10	Hospital Privado Centro Medico de Cordoba	Cordoba		Argentina	X5016KEH
11	Instituto de Cardiologia J.F. Cabral	Corrientes		Argentina	W3400AMZ
12	Hospital Universitario Clementino Fraga Filho	Ilha do Fundao	Rio de Janeiro	Brazil	21941-590
13	Hospital Madre Teresa	Belo Horizonte		Brazil	30380-090
14	Hospital San Lucas de Pontificia Universidade Catolica	Porto Alegre		Brazil	90610-000
15	Complexo Hospitalar Sanata Casa de Porto Alegre	Porto Alegre		Brazil	92020-090
16	Universidade do Estado de Sao Paulo - UNIFESP	Sao Paulo		Brazil	04023-062
17	Hospital das Clinicas da FMUSP	Sao Paulo		Brazil	05403-000
18	Hospital San Juan de Dios	Santiago	Santiago de Chile	Chile	CP 8330024
19	Hospital Clinico Universidad Catolica	Santiago	Santiago de Chile	Chile	CP 8350488
20	Instituto Nacional del Torax	Santiago	Santiago de Chile	Chile	CP7500691
21	Instituto Nacional de Cardiologia Ignacio Chavez	Mexico, DF	DF	Mexico	14080
22	Unidad De Investigacion Clinica en Medicina	Monterrey, Nuevo Leon	Nuevo Leon	Mexico	64718

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Chair: Chris Dufton, PhD, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00578786
• Other Study ID Numbers: AMB-320/321-E; ARIES-E
• First Posted: Dec 21, 2007
• Last Update Posted: Jan 15, 2013
• Last Verified: Jan 1, 2013

• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Ambrisentan

Study Results

Participant Flow

Recruitment Details	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).
Pre-assignment Detail	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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg
Arm/Group Description	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.	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.	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).
Period Title: Overall Study
STARTED	96	190	97
COMPLETED	57	124	67
NOT COMPLETED	39	66	30

Baseline Characteristics

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Total
Arm/Group Description	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.	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.	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 of all reporting groups
Overall Participants	96	190	97	383
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.27 (14.968)	51.46 (14.429)	49.09 (16.572)	51.06 (15.139)
Sex: Female, Male (Count of Participants)
Female	69 71.9%	154 81.1%	79 81.4%	302 78.9%
Male	27 28.1%	36 18.9%	18 18.6%	81 21.1%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	81 84.4%	148 77.9%	65 67%	294 76.8%
Black	0 0%	5 2.6%	6 6.2%	11 2.9%
Asian	1 1%	6 3.2%	2 2.1%	9 2.3%
Hispanic	14 14.6%	29 15.3%	22 22.7%	65 17%
Other	0 0%	2 1.1%	2 2.1%	4 1%
Pulmonary Arterial Hypertension Stratification (participants) [Number]
Idiopathic PAH (IPAH)	63 65.6%	119 62.6%	59 60.8%	241 62.9%
Non-IPAH	33 34.4%	71 37.4%	38 39.2%	142 37.1%
6-Minute Walk Distance (6MWD) (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	350.3 (86.640)	347.7 (87.333)	342.3 (80.840)	347.0 (85.389)
World Heath Organization (WHO) Class (participants) [Number]
WHO Class I	1 1%	7 3.7%	4 4.1%	12 3.1%
WHO Class II	51 53.1%	77 40.5%	35 36.1%	163 42.6%
WHO Class III	39 40.6%	91 47.9%	48 49.5%	178 46.5%
WHO Class IV	5 5.2%	15 7.9%	10 10.3%	30 7.8%
Borg Dyspnea Index (BDI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.14 (2.684)	3.80 (2.332)	3.78 (2.133)	3.88 (2.377)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.68 (5.038)	26.86 (5.632)	28.26 (7.212)	27.17 (5.958)

Outcome Measures

1. Secondary Outcome

Title	Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test
Description	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.).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
Mean (Standard Deviation) [Meters]	350.3 (86.64)	347.7 (87.33)	342.3 (80.84)	347.0 (85.39)

2. Primary Outcome

Title	Frequently Reported (15% or More Overall) Adverse Events by Severity
Description	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).
Time Frame	Baseline to Week 295

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg
Arm/Group Description	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.	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.	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.
Measure Participants	43	146	194
Headache - Mild	1 1%	20 10.5%	36 37.1%
Headache - Moderate	0 0%	14 7.4%	17 17.5%
Headache - Severe	0 0%	0 0%	8 8.2%
Pulmonary hypertension (worsening) - Mild	2 2.1%	2 1.1%	7 7.2%
Pulmonary hypertension (worsening) - Moderate	4 4.2%	10 5.3%	29 29.9%
Pulmonary hypertension (worsening) - Severe	6 6.3%	6 3.2%	19 19.6%
Right ventricular failure - Mild	0 0%	2 1.1%	6 6.2%
Right ventricular failure - Moderate	2 2.1%	7 3.7%	14 14.4%
Right ventricular failure - Severe	5 5.2%	12 6.3%	26 26.8%
Cough - Mild	1 1%	23 12.1%	24 24.7%
Cough - Moderate	1 1%	2 1.1%	22 22.7%
Cough - Severe	0 0%	1 0.5%	0 0%
Upper respiratory tract infection - Mild	3 3.1%	13 6.8%	23 23.7%
Upper respiratory tract infection - Moderate	2 2.1%	4 2.1%	26 26.8%
Upper respiratory tract infection - Severe	0 0%	0 0%	1 1%
Dizziness - Mild	1 1%	8 4.2%	31 32%
Dizziness - Moderate	2 2.1%	7 3.7%	14 14.4%
Dizziness - Severe	0 0%	0 0%	3 3.1%
Dyspnoea exacerbated - Mild	1 1%	4 2.1%	8 8.2%
Dyspnoea exacerbated - Moderate	3 3.1%	14 7.4%	22 22.7%
Dyspnoea exacerbated - Severe	1 1%	2 1.1%	7 7.2%
Arthralgia - Mild	1 1%	5 2.6%	19 19.6%
Arthralgia - Moderate	3 3.1%	11 5.8%	18 18.6%
Arthralgia - Severe	1 1%	2 1.1%	1 1%
Diarrhoea - Mild	2 2.1%	12 6.3%	17 17.5%
Diarrhoea - Moderate	1 1%	10 5.3%	15 15.5%
Diarrhoea - Severe	0 0%	2 1.1%	1 1%
Nasopharyngitis - Mild	1 1%	14 7.4%	19 19.6%
Nasopharyngitis - Moderate	1 1%	8 4.2%	15 15.5%
Nasopharyngitis - Severe	0 0%	0 0%	0 0%
Oedema peripheral - Mild	6 6.3%	31 16.3%	48 49.5%
Oedema peripheral - Moderate	6 6.3%	19 10%	50 51.5%
Oedema peripheral - Severe	1 1%	3 1.6%	4 4.1%

3. Secondary Outcome

Title	Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
Description	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.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	Participants were classified based on their randomized dose of ambrisentan in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Participants were classified based on their randomized dose of ambrisentan in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Participants were classified based on their randomized dose of ambrisentan in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	All dose groups combined.
Measure Participants	93	186	96	375
Mean (Standard Deviation) [Meters]	38.0 (74.28)	32.5 (78.55)	40.9 (72.85)	36.0 (75.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	38.0
	Confidence Interval	(2-Sided) 95%; 22.7 to 53.3
	Parameter Dispersion	Type: Standard Deviation; Value: 74.28
	Estimation Comments	Applies to Ambrisentan 2.5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	32.5
	Confidence Interval	(2-Sided) 95%; 21.1 to 43.8
	Parameter Dispersion	Type: Standard Deviation; Value: 78.55
	Estimation Comments	Applies to Ambrisentan 5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	40.9
	Confidence Interval	(2-Sided) 95%; 26.1 to 55.7
	Parameter Dispersion	Type: Standard Deviation; Value: 72.85
	Estimation Comments	Applies to Ambrisentan 10 mg group only. LOCF method of imputation. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Ambrisentan Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	36.0
	Confidence Interval	(2-Sided) 95%; 28.3 to 43.7
	Parameter Dispersion	Type: Standard Deviation; Value: 75.97
	Estimation Comments	Applies to Ambrisentan combined group only. LOCF method of imputation.

4. Secondary Outcome

Title	Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
Description	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.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Ambrisentan Combined Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	93	186	96	375
Mean (Standard Deviation) [Meters]	24.9 (96.14)	27.9 (94.50)	37.2 (72.97)	29.5 (89.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	24.9
	Confidence Interval	(2-Sided) 95%; 5.1 to 44.7
	Parameter Dispersion	Type: Standard Deviation; Value: 96.14
	Estimation Comments	Applies to Ambrisentan 2.5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	27.9
	Confidence Interval	(2-Sided) 95%; 14.2 to 41.6
	Parameter Dispersion	Type: Standard Deviation; Value: 94.50
	Estimation Comments	Applies to Ambrisentan 5.0 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	37.2
	Confidence Interval	(2-Sided) 95%; 22.4 to 52.0
	Parameter Dispersion	Type: Standard Deviation; Value: 72.97
	Estimation Comments	Applies to Ambrisentan 10 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Ambrisentan Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	29.5
	Confidence Interval	(2-Sided) 95%; 20.4 to 38.7
	Parameter Dispersion	Type: Standard Deviation; Value: 89.81
	Estimation Comments	Applies to Ambrisentan combined group only. LOCF method of imputation.

5. Secondary Outcome

Title	Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
Description	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.
Time Frame	Baseline to Year 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	93	186	96	375
Mean (Standard Deviation) [Meters]	6.7 (97.48)	23.2 (100.69)	28.0 (84.38)	20.3 (96.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; -13.4 to 26.8
	Parameter Dispersion	Type: Standard Deviation; Value: 97.48
	Estimation Comments	Applies to Ambrisentan 2.5 mg group only. LOCF method of imputation.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	23.2
	Confidence Interval	(2-Sided) 95%; 8.7 to 37.8
	Parameter Dispersion	Type: Standard Deviation; Value: 100.69
	Estimation Comments	Applies to Ambrisentan 5 mg group only. LOCF method of imputation.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	28.0
	Confidence Interval	(2-Sided) 95%; 10.9 to 45.1
	Parameter Dispersion	Type: Standard Deviation; Value: 84.38
	Estimation Comments	Applies to Ambrisentan 10 mg group only. LOCF method of imputation.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Ambrisentan Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	20.3
	Confidence Interval	(2-Sided) 95%; 10.6 to 30.1
	Parameter Dispersion	Type: Standard Deviation; Value: 96.05
	Estimation Comments	Applies to Ambrisentan combined group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

6. Secondary Outcome

Title	Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
Description	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.
Time Frame	Baseline to Year 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	93	186	96	375
Mean (Standard Deviation) [Meters]	0.7 (95.21)	18.8 (101.22)	27.8 (87.07)	16.6 (96.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -18.9 to 20.3
	Parameter Dispersion	Type: Standard Deviation; Value: 95.21
	Estimation Comments	Applies to Ambrisentan 2.5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	18.8
	Confidence Interval	(2-Sided) 95%; 4.2 to 33.5
	Parameter Dispersion	Type: Standard Deviation; Value: 101.22
	Estimation Comments	Applies to Ambrisentan 5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	27.8
	Confidence Interval	(2-Sided) 95%; 10.1 to 45.4
	Parameter Dispersion	Type: Standard Deviation; Value: 87.07
	Estimation Comments	Applies to Ambrisentan 10 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Ambrisentan Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	16.6
	Confidence Interval	(2-Sided) 95%; 6.8 to 26.4
	Parameter Dispersion	Type: Standard Deviation; Value: 96.54
	Estimation Comments	Applies to Ambrisentan combined group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

7. Secondary Outcome

Title	Baseline Borg Dyspnea Index
Description	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).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	189	97	382
Mean (Standard Deviation) [units on a scale]	4.14 (2.684)	3.80 (2.332)	3.78 (2.133)	3.88 (2.377)

8. Secondary Outcome

Title	Change From Baseline to Year 1 in Borg Dyspnea Index
Description	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.
Time Frame	Baseline to Year 1

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	93	185	96	374
Mean (Standard Deviation) [units on a scale]	-0.08 (2.254)	-0.59 (2.450)	-0.51 (2.400)	-0.44 (2.393)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.38
	Parameter Dispersion	Type: Standard Deviation; Value: 2.254
	Estimation Comments	Applies to Ambrisentan 2.5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.59
	Confidence Interval	(2-Sided) 95%; -0.94 to -0.23
	Parameter Dispersion	Type: Standard Deviation; Value: 2.450
	Estimation Comments	Applies to Ambrisentan 5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 95%; -1.00 to -0.03
	Parameter Dispersion	Type: Standard Deviation; Value: 2.400
	Estimation Comments	Applies to Ambrisentan 10 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Ambrisentan Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.20
	Parameter Dispersion	Type: Standard Deviation; Value: 2.393
	Estimation Comments	Applies to Ambrisentan combined group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

9. Secondary Outcome

Title	Change From Baseline to Year 2 in Borg Dyspnea Index
Description	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.
Time Frame	Baseline to Year 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	93	185	96	374
Mean (Standard Deviation) [units on a scale]	0.23 (2.603)	-0.33 (2.477)	-0.65 (2.305)	-0.27 (2.480)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.76
	Parameter Dispersion	Type: Standard Deviation; Value: 2.603
	Estimation Comments	Applies to Ambrisentan 2.5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.68 to 0.03
	Parameter Dispersion	Type: Standard Deviation; Value: 2.477
	Estimation Comments	Applies to Ambrisentan 5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 95%; -1.12 to -0.18
	Parameter Dispersion	Type: Standard Deviation; Value: 2.305
	Estimation Comments	Applies to Ambrisentan 10 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Ambrisentan Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.52 to -0.02
	Parameter Dispersion	Type: Standard Deviation; Value: 2.480
	Estimation Comments	Applies to Ambrisentan combined group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

10. Secondary Outcome

Title	Change From Baseline to Year 3 in Borg Dyspnea Index
Description	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.
Time Frame	Baseline to Year 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	93	185	96	374
Mean (Standard Deviation) [units on a scale]	0.20 (2.593)	-0.14 (2.514)	-0.48 (2.215)	-0.14 (2.467)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.74
	Parameter Dispersion	Type: Standard Deviation; Value: 2.593
	Estimation Comments	Applies to Ambrisentan 2.5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.22
	Parameter Dispersion	Type: Standard Deviation; Value: 2.514
	Estimation Comments	Applies to Ambrisentan 5 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.93 to -0.03
	Parameter Dispersion	Type: Standard Deviation; Value: 2.215
	Estimation Comments	Applies to Ambrisentan 10 mg group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Ambrisentan Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.11
	Parameter Dispersion	Type: Standard Deviation; Value: 2.467
	Estimation Comments	Applies to Ambrisentan combined group only. Missing values were imputed using last-observation-carried forward method (LOCF) based on post-baseline observations.

11. Secondary Outcome

Title	Baseline World Health Organization (WHO) Functional Class
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Ambrisentan Combined Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
WHO Functional Class I	1 1%	7 3.7%	4 4.1%	12 3.1%
WHO Functional Class II	51 53.1%	77 40.5%	35 36.1%	163 42.6%
WHO Functional Class III	39 40.6%	91 47.9%	48 49.5%	178 46.5%
WHO Functional Class IV	5 5.2%	15 7.9%	10 10.3%	30 7.8%

12. Secondary Outcome

Title	Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class
Description	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.
Time Frame	Baseline to Year 1

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Ambrisentan Combined Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
Improved	16 16.7%	56 29.5%	36 37.1%	108 28.2%
No Change	68 70.8%	122 64.2%	46 47.4%	236 61.6%
Deteriorated	10 10.4%	9 4.7%	14 14.4%	33 8.6%
Missing	2 2.1%	3 1.6%	1 1%	6 1.6%

13. Secondary Outcome

Title	Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class
Description	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.
Time Frame	Baseline to Year 2

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
Improved	16 16.7%	58 30.5%	39 40.2%	113 29.5%
No Change	58 60.4%	109 57.4%	43 44.3%	210 54.8%
Deteriorated	20 20.8%	20 10.5%	14 14.4%	54 14.1%
Missing	2 2.1%	3 1.6%	1 1%	6 1.6%

14. Secondary Outcome

Title	Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class
Description	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.
Time Frame	Baseline to Year 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Combined Ambrisentan Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
Improved	17 17.7%	61 32.1%	32 33%	110 28.7%
No Change	57 59.4%	109 57.4%	49 50.5%	215 56.1%
Deteriorated	20 20.8%	17 8.9%	15 15.5%	52 13.6%
Missing	2 2.1%	3 1.6%	1 1%	6 1.6%

15. Secondary Outcome

Title	Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group
Description	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.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Ambrisentan Group
Arm/Group Description	All dose groups combined.
Measure Participants	355
Physical Functioning	30.0 (9.02)
Role Physical	35.2 (10.21)
Bodily Pain	46.3 (11.93)
General Health	36.0 (8.65)
Vitality	42.1 (10.23)
Social Functioning	39.6 (11.8)
Role Emotional	39.2 (13.47)
Mental Health	43.3 (12.12)
Physical Component Summary	35.1 (8.52)
Mental Component Summary	44.5 (11.98)

16. Secondary Outcome

Title	Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
Description	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.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Ambrisentan Group
Arm/Group Description	All dose groups combined.
Measure Participants	303
Physical Functioning (n=299)	3.9 (7.40)
Role Physical (n=298)	5.6 (10.81)
Bodily Pain (n=303)	1.8 (11.27)
General Health (n=297)	3.1 (7.85)
Vitality (n=301)	4.6 (9.12)
Social Functioning (n=303)	3.9 (10.63)
Role Emotional (n=286)	3.9 (14.69)
Mental Health (n=301)	3.2 (9.72)
Physical Component Summary (n=276)	3.8 (7.59)
Mental Component Summary (n=276)	3.4 (10.77)

17. Secondary Outcome

Title	Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
Description	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.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Ambrisentan Group
Arm/Group Description	(All Doses)
Measure Participants	230
Physical Functioning (n=226)	4.7 (8.75)
Role Physical (n=227)	5.7 (13.37)
Bodily Pain (n=230)	1.0 (13.28)
General Health (n=223)	3.2 (8.11)
Vitality (n=227)	4.5 (9.55)
Social Functioning (n=230)	3.5 (11.50)
Role Emotional (n=220)	4.3 (14.45)
Mental Health (n=227)	2.6 (10.57)
Physical Component Summary (n=212)	3.8 (9.06)
Mental Component Summary (n=212)	3.2 (11.06)

18. Secondary Outcome

Title	Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
Description	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.
Time Frame	Baseline to Week 36

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Ambrisentan Group
Arm/Group Description	All dose groups combined.
Measure Participants	186
Physical Functioning (n=183)	4.9 (8.27)
Role Physical (n=181)	4.5 (12.34)
Bodily Pain (n=186)	1.9 (13.16)
General Health (n=181)	4.5 (12.34)
Vitality (n=185)	4.6 (9.16)
Social Functioning (n=186)	3.7 (12.26)
Role Emotional (n=178)	3.6 (15.17)
Mental Health (n=185)	2.9 (11.00)
Physical Component Summary (n=169)	3.9 (8.79)
Mental Component Summary (n=169)	2.9 (11.34)

19. Secondary Outcome

Title	Percentage of Participants With No Clinical Worsening of PAH
Description	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.
Time Frame	Baseline to Year 3

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Ambrisentan Combined Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
No clinical worsening after 1 year of treatment	80.4 (4.2)	83.9 (2.7)	82.8 (3.9)	82.7 (2.0)
No clinical worsening after 2 years of treatment	67.8 (4.9)	72.4 (3.4)	72.2 (4.8)	71.1 (2.4)
No clinical worsening after 3 years of treatment	60.7 (5.2)	67.4 (3.7)	59.9 (5.6)	63.8 (2.7)

20. Secondary Outcome

Title	Percentage of Participants With Failure-Free Treatment Status
Description	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.
Time Frame	Baseline to Year 4

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Ambrisentan Combined Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
No treatment failure after 1 year of treatment	86.8 (3.6)	89.0 (2.4)	90.1 (3.1)	88.7 (1.7)
No treatment failure after 2 years of treatment	77.6 (4.4)	79.8 (3.1)	81.4 (4.2)	79.6 (2.2)
No treatment failure after 3 years of treatment	69.1 (5.0)	73.8 (3.5)	67.9 (5.7)	71.3 (2.6)
No treatment failure after 4 years of treatment	60.8 (5.4)	69.0 (4.0)	63.2 (6.2)	66.4 (2.8)

21. Secondary Outcome

Title	Long-term Survival
Description	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.
Time Frame	Baseline to Year 4

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg	Ambrisentan Combined Group
Arm/Group Description	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.	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.	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.	All dose groups combined.
Measure Participants	96	190	97	383
Survival after 1 year of treatment	96.8 (1.8)	93.1 (1.9)	94.5 (2.4)	94.4 (1.2)
Survival after 2 years of treatment	84.7 (3.9)	87.3 (2.6)	90.7 (3.1)	87.5 (1.8)
Survival after 3 years of treatment	78.4 (4.5)	84.2 (2.9)	82.7 (4.5)	82.2 (2.2)
Survival After 4 Years of Treatment	71.1 (5.2)	78.1 (3.8)	82.7 (4.5)	76.5 (2.7)

22. Primary Outcome

Title	Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN)
Description	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.
Time Frame	Baseline to Week 295

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ambrisentan 2.5 mg	Ambrisentan 5 mg	Ambrisentan 10 mg
Arm/Group Description	Participants were classified based on the highest dose of AMB received at any time during the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Participants were classified based on the highest dose of AMB received at any time during the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.	Participants were classified based on the highest dose of AMB received at any time during the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.
Measure Participants	43	155	205
ALT >3.0 and </=5.0 x ULN	0 0%	2 1.1%	4 4.1%
ALT >5.0 and </= 8.0 x ULN	0 0%	1 0.5%	0 0%
ALT >8.0 x ULN	0 0%	3 1.6%	5 5.2%
Total ALT results >3.0 x ULN	0 0%	0 0%	1 1%
AST >3.0 and </=5.0 x ULN	1 1%	3 1.6%	7 7.2%
AST >5.0 and </= 8.0 x ULN	0 0%	1 0.5%	0 0%
AST >8.0 x ULN	0 0%	0 0%	1 1%
Total AST results >3.0 x ULN	1 1%	4 2.1%	8 8.2%

Adverse Events

Time Frame	Serious adverse event data collected through 288 weeks are presented.
Adverse Event Reporting Description	For the safety population, subjects were classified based on the highest dose of ambrisentan received at any time during the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.
Arm/Group Title	Ambrisentan 2.5 mg		Ambrisentan 5 mg		Ambrisentan 10 mg
Arm/Group Description	Participants were classified based on the highest dose of ambrisentan received at any time during the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.		Participants were classified based on the highest dose of ambrisentan received at any time during the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.		Participants were classified based on the highest dose of ambrisentan received at any time during the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Study drug was taken once daily.
All Cause Mortality
	Ambrisentan 2.5 mg		Ambrisentan 5 mg		Ambrisentan 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ambrisentan 2.5 mg		Ambrisentan 5 mg		Ambrisentan 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/43 (60.5%)		76/146 (52.1%)		103/194 (53.1%)
Blood and lymphatic system disorders
Anaemia	0/43 (0%)	0	2/146 (1.4%)	2	3/194 (1.5%)	3
Bone marrow depression	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Iron deficiency anaemia	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Lymphadenopathy	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Microcytic anaemia	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Thrombocytopenia	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Cardiac disorders
AV dissociation	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Acute coronary syndrome	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Acute myocardial infarction	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Angina pectoris	1/43 (2.3%)	1	2/146 (1.4%)	2	2/194 (1%)	2
Arrhythmia supraventricular	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Atrial fibrillation	1/43 (2.3%)	1	4/146 (2.7%)	4	2/194 (1%)	2
Atrial flutter	0/43 (0%)	0	1/146 (0.7%)	1	2/194 (1%)	2
Atrial tachycardia	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Cardiac arrest	1/43 (2.3%)	1	1/146 (0.7%)	1	2/194 (1%)	2
Cardiac failure congestive	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Cardio-respiratory arrest	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Cardiogenic shock	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Cor pulmonale	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Diastolic dysfunction	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Left ventricular failure	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Myocardial infarction	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Pericardial effusion	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Right ventricular failure	6/43 (14%)	6	14/146 (9.6%)	18	34/194 (17.5%)	55
Supraventricular tachycardia	1/43 (2.3%)	1	0/146 (0%)	0	3/194 (1.5%)	5
Tachyarrhthmia	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Tachycardia	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Ventricular fibrillation	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Congenital, familial and genetic disorders
Dermoid cyst of ovary	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Eye disorders
Cataract	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Gastrointestinal disorders
Abdominal distension	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Abdominal pain	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Abdominal pain upper	1/43 (2.3%)	1	0/146 (0%)	0	1/194 (0.5%)	1
Colonic polyp	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Diverticulum	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Duodenal ulcer haemorrhage	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Enteritis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Gastric haemorrhage	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Gastrointestinal haemorrhage	1/43 (2.3%)	1	2/146 (1.4%)	2	1/194 (0.5%)	1
Hypoaesthesia oral	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Inguinal hernia	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Intestinal functional disorder	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Mesenteric occlusion	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Oesophageal perforation	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Parotid gland enlargement	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Peritoneal hemorrhage	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Rectal haemorrhage	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Retroperitoneal haemorrhage	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
General disorders
Catheter related complication	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Chest discomfort	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Chest pain	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Microlithiasis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Multi-organ failure	0/43 (0%)	0	2/146 (1.4%)	2	1/194 (0.5%)	1
Noncardiac chest pain	0/43 (0%)	0	1/146 (0.7%)	1	4/194 (2.1%)	5
Oedema peripheral	1/43 (2.3%)	1	0/146 (0%)	0	2/194 (1%)	2
Pyrexia	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Sudden death	0/43 (0%)	0	2/146 (1.4%)	2	1/194 (0.5%)	1
Hepatobiliary disorders
Cholecystitis acute	0/43 (0%)	0	2/146 (1.4%)	4	1/194 (0.5%)	1
Cholelithiasis	0/43 (0%)	0	0/146 (0%)	0	4/194 (2.1%)	4
Immune system disorders
Drug hypersensitivity	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	3
Infections and infestations
Abdominal infection	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Arthritis bacterial	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Bone infection	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Bronchitis	0/43 (0%)	0	2/146 (1.4%)	3	1/194 (0.5%)	1
Bronchitis acute	1/43 (2.3%)	1	1/146 (0.7%)	2	0/194 (0%)	0
Bronchopneumonia	0/43 (0%)	0	0/146 (0%)	0	3/194 (1.5%)	3
Cellulitis	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Cytomegalovirus colitis	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Escherichia urinary tract infection	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Gastroenteritis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Gastrointestinal infection	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Haemophilus infection	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Lower respiratory tract infection	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	3
Lung infection	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Meningitis tuberculosis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Oral candidiasis	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Pneumonia	1/43 (2.3%)	1	5/146 (3.4%)	6	9/194 (4.6%)	13
Postoperative infection	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Pyelonephritis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Respiratory tract infection	0/43 (0%)	0	0/146 (0%)	0	3/194 (1.5%)	3
Respiratory tract infection bacterial	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Respiratory tract infection viral	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Sepsis	0/43 (0%)	0	2/146 (1.4%)	2	0/194 (0%)	0
Septic shock	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Sinusitis	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Streptococcal sepsis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Tracheobronchitis	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	2
Upper respiratory tract infection	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Urinary tract infection	0/43 (0%)	0	1/146 (0.7%)	1	2/194 (1%)	2
Injury, poisoning and procedural complications
Accidental overdose	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Chest injury	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	2
Fall	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	2
Femoral neck fracture	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Femur fracture	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Fractured coccyx	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Haemothorax	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Ligament injury	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Muscle strain	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Pacemaker complication	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Polytraumatism	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Post procedural haemorrhage	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Subdural haematoma	1/43 (2.3%)	1	1/146 (0.7%)	2	2/194 (1%)	2
Tendon rupture	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Investigations
Alanine aminotransferase increased	0/43 (0%)	0	3/146 (2.1%)	3	1/194 (0.5%)	1
Aspartate aminotransferase increased	0/43 (0%)	0	2/146 (1.4%)	2	0/194 (0%)	0
Exercise capacity descreased	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hepatic enzyme increased	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hysteroscopy	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Liver function test abnormal	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Platelet count decreased	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Metabolism and nutrition disorders
Dehydration	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Diabetes mellitus	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Fluid overload	0/43 (0%)	0	0/146 (0%)	0	3/194 (1.5%)	3
Hyperglycaemia	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Hypoglycaemia	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Hypokalaemia	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hyponatraemia	1/43 (2.3%)	1	0/146 (0%)	0	1/194 (0.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Back pain	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
CREST syndrome	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Connective tissue disorder	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Joint swelling	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Localised osteoarthritis	0/43 (0%)	0	1/146 (0.7%)	2	1/194 (0.5%)	1
Pain in extremity	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Polymyositis	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Scleroderma	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Systemic lupus erythematosus	0/43 (0%)	0	3/146 (2.1%)	5	1/194 (0.5%)	1
Systemic sclerosis	1/43 (2.3%)	1	1/146 (0.7%)	3	2/194 (1%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/43 (0%)	0	1/146 (0.7%)	2	0/194 (0%)	0
Breast cancer metastatic	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Colon neoplasm	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Endometrial cancer metastatic	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Fibroadenoma of the breast	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Gastric cancer	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Hepatic cancer metastatic	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Insulinoma	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Malignant soft tissue neoplasm	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Metastases to bone marrow	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Metastases to central nervous system	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Metastases to liver	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Metastases to lung	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Multiple myeloma	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Rectal cancer	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Squamous cell carcinoma	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Nervous system disorders
Cerebral haemorrhage	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Cervicobrachial syndrome	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Convulsion	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Dizziness	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Encephalitis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Haemorrhage intracranial	0/43 (0%)	0	0/146 (0%)	0	2/194 (1%)	2
Headache	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hypertensive encephalopathy	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hypoglycaemic coma	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Paraesthesia	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Syncope	3/43 (7%)	3	3/146 (2.1%)	3	5/194 (2.6%)	5
Syncope vasovagal	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Pregnancy, puerperium and perinatal conditions
Pregnancy	0/43 (0%)	0	5/146 (3.4%)	5	2/194 (1%)	2
Psychiatric disorders
Anxiety	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Depressed mood	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Depression	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	2
Neurosis	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Panic attack	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Panic reaction	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Suicide attempt	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Renal and urinary disorders
Haematuria	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Lupus nephritis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Nephrolithiasis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Oliguria	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Renal Failure Acute	0/43 (0%)	0	3/146 (2.1%)	3	1/194 (0.5%)	1
Renal impairment	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Renal insufficiency	0/43 (0%)	0	2/146 (1.4%)	2	2/194 (1%)	2
Urinary tract disorder	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Reproductive system and breast disorders
Dysfunctional uterine bleeding	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Menorrhagia	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Metrorrhagia	0/43 (0%)	0	2/146 (1.4%)	2	0/194 (0%)	0
Ovarian cyst	1/43 (2.3%)	1	0/146 (0%)	0	1/194 (0.5%)	1
Ovarian cyst ruptured	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Vaginal haemorrhage	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/43 (0%)	0	3/146 (2.1%)	3	2/194 (1%)	2
Aspiration	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Asthma	1/43 (2.3%)	1	0/146 (0%)	0	1/194 (0.5%)	1
Dyspnoea	0/43 (0%)	0	2/146 (1.4%)	3	2/194 (1%)	3
Dyspnoea at rest	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Dyspnoea exacerbated	2/43 (4.7%)	2	1/146 (0.7%)	1	4/194 (2.1%)	4
Haemoptysis	0/43 (0%)	0	1/146 (0.7%)	1	2/194 (1%)	2
Hydrothorax	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hypoxia	0/43 (0%)	0	1/146 (0.7%)	1	6/194 (3.1%)	8
Interstitial lung disease	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Pleural effusion	0/43 (0%)	0	1/146 (0.7%)	1	3/194 (1.5%)	7
Pleuritic pain	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Pneumomediastinum	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Pneumonia aspiration	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Pneumonitis	0/43 (0%)	0	2/146 (1.4%)	2	0/194 (0%)	0
Pulmonary alveolar haemorrhage	0/43 (0%)	0	1/146 (0.7%)	1	1/194 (0.5%)	1
Pulmonary embolism	1/43 (2.3%)	1	1/146 (0.7%)	1	1/194 (0.5%)	1
Pulmonary fibrosis	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Pulmonary haemorrhage	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Pulmonary hypertension	7/43 (16.3%)	8	10/146 (6.8%)	12	33/194 (17%)	48
Respiratory arrest	1/43 (2.3%)	1	1/146 (0.7%)	1	1/194 (0.5%)	1
Respiratory failure	1/43 (2.3%)	1	3/146 (2.1%)	3	2/194 (1%)	2
Skin and subcutaneous tissue disorders
Diabetic ulcer	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Stevens Johnson syndrome	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Toxic skin eruption	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Surgical and medical procedures
Heart and lung transplant	1/43 (2.3%)	1	0/146 (0%)	0	0/194 (0%)	0
Therapy regimen changed	0/43 (0%)	0	1/146 (0.7%)	1	2/194 (1%)	2
Vascular disorders
Aortic stenosis	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Deep vein thrombosis	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hypertensive crisis	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hypotension	0/43 (0%)	0	0/146 (0%)	0	1/194 (0.5%)	1
Hypovolaemic shock	0/43 (0%)	0	1/146 (0.7%)	1	0/194 (0%)	0
Other (Not Including Serious) Adverse Events
	Ambrisentan 2.5 mg		Ambrisentan 5 mg		Ambrisentan 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/43 (83.7%)		131/146 (89.7%)		190/194 (97.9%)
Blood and lymphatic system disorders
Anaemia	6/43 (14%)		19/146 (13%)		26/194 (13.4%)
Iron deficiency anaemia	2/43 (4.7%)		1/146 (0.7%)		12/194 (6.2%)
Cardiac disorders
Angina pectoris	1/43 (2.3%)		3/146 (2.1%)		12/194 (6.2%)
Cyanosis	0/43 (0%)		1/146 (0.7%)		14/194 (7.2%)
Palpitations	3/43 (7%)		12/146 (8.2%)		35/194 (18%)
Right ventricular failure	4/43 (9.3%)		15/146 (10.3%)		20/194 (10.3%)
Tachycardia	0/43 (0%)		3/146 (2.1%)		12/194 (6.2%)
Ear and labyrinth disorders
Vertigo	0/43 (0%)		5/146 (3.4%)		19/194 (9.8%)
Gastrointestinal disorders
Abdominal distension	0/43 (0%)		2/146 (1.4%)		15/194 (7.7%)
Abdominal pain	2/43 (4.7%)		11/146 (7.5%)		16/194 (8.2%)
Abdominal pain upper	2/43 (4.7%)		6/146 (4.1%)		21/194 (10.8%)
Constipation	0/43 (0%)		12/146 (8.2%)		21/194 (10.8%)
Diarrhoea	3/43 (7%)		24/146 (16.4%)		33/194 (17%)
Dyspepsia	1/43 (2.3%)		7/146 (4.8%)		14/194 (7.2%)
Gastritis	1/43 (2.3%)		13/146 (8.9%)		7/194 (3.6%)
Gastroesophageal reflux disease	0/43 (0%)		1/146 (0.7%)		12/194 (6.2%)
Nausea	3/43 (7%)		12/146 (8.2%)		38/194 (19.6%)
Vomiting	0/43 (0%)		7/146 (4.8%)		23/194 (11.9%)
General disorders
Asthenia	3/43 (7%)		8/146 (5.5%)		9/194 (4.6%)
Chest discomfort	1/43 (2.3%)		2/146 (1.4%)		25/194 (12.9%)
Chest pain	1/43 (2.3%)		6/146 (4.1%)		15/194 (7.7%)
Fatigue	3/43 (7%)		14/146 (9.6%)		30/194 (15.5%)
Non-cardiac chest pain	1/43 (2.3%)		10/146 (6.8%)		19/194 (9.8%)
Oedema peripheal	13/43 (30.2%)		53/146 (36.3%)		101/194 (52.1%)
Pyrexia	1/43 (2.3%)		11/146 (7.5%)		18/194 (9.3%)
Hepatobiliary disorders
Hepatomegaly	1/43 (2.3%)		7/146 (4.8%)		13/194 (6.7%)
Infections and infestations
Bronchitis	3/43 (7%)		13/146 (8.9%)		17/194 (8.8%)
Bronchitis acute	3/43 (7%)		4/146 (2.7%)		7/194 (3.6%)
Influenza	5/43 (11.6%)		13/146 (8.9%)		22/194 (11.3%)
Nasopharyngitis	2/43 (4.7%)		22/146 (15.1%)		34/194 (17.5%)
Respiratory tract infection	2/43 (4.7%)		6/146 (4.1%)		24/194 (12.4%)
Sinusitis	0/43 (0%)		15/146 (10.3%)		24/194 (12.4%)
Upper respiratory tract infection	5/43 (11.6%)		17/146 (11.6%)		50/194 (25.8%)
Urinary tract imfection	2/43 (4.7%)		7/146 (4.8%)		26/194 (13.4%)
Injury, poisoning and procedural complications
Contusion	0/43 (0%)		1/146 (0.7%)		13/194 (6.7%)
Fall	0/43 (0%)		1/146 (0.7%)		11/194 (5.7%)
Investigations
Blood alkaline phosphatase increased	4/43 (9.3%)		3/146 (2.1%)		6/194 (3.1%)
Cardiac murmur	2/43 (4.7%)		4/146 (2.7%)		10/194 (5.2%)
Gamma-glutamyltransferase increased	4/43 (9.3%)		9/146 (6.2%)		13/194 (6.7%)
Heart sounds abnormal	0/43 (0%)		4/146 (2.7%)		13/194 (6.7%)
International normalised ratio increased	0/43 (0%)		7/146 (4.8%)		14/194 (7.2%)
Metabolism and nutrition disorders
Fluid retention	0/43 (0%)		2/146 (1.4%)		10/194 (5.2%)
Hypercholesterolaemia	2/43 (4.7%)		9/146 (6.2%)		11/194 (5.7%)
Hypokalaemia	2/43 (4.7%)		13/146 (8.9%)		23/194 (11.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/43 (11.6%)		18/146 (12.3%)		38/194 (19.6%)
Back pain	1/43 (2.3%)		11/146 (7.5%)		36/194 (18.6%)
Muscle cramp	1/43 (2.3%)		9/146 (6.2%)		14/194 (7.2%)
Myalgia	1/43 (2.3%)		9/146 (6.2%)		18/194 (9.3%)
Pain in extremity	3/43 (7%)		7/146 (4.8%)		36/194 (18.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neck pain	2/43 (4.7%)		3/146 (2.1%)		10/194 (5.2%)
Nervous system disorders
Dizziness	3/43 (7%)		15/146 (10.3%)		47/194 (24.2%)
Headache	1/43 (2.3%)		34/146 (23.3%)		61/194 (31.4%)
Paraesthesia	0/43 (0%)		2/146 (1.4%)		11/194 (5.7%)
Syncope	2/43 (4.7%)		7/146 (4.8%)		19/194 (9.8%)
Psychiatric disorders
Anxiety	1/43 (2.3%)		10/146 (6.8%)		17/194 (8.8%)
Depression	1/43 (2.3%)		11/146 (7.5%)		25/194 (12.9%)
Insomnia	2/43 (4.7%)		13/146 (8.9%)		23/194 (11.9%)
Respiratory, thoracic and mediastinal disorders
Abnormal chest sound	0/43 (0%)		1/146 (0.7%)		10/194 (5.2%)
Cough	2/43 (4.7%)		26/146 (17.8%)		46/194 (23.7%)
Crackles lung	0/43 (0%)		5/146 (3.4%)		16/194 (8.2%)
Dyspnoea	3/43 (7%)		13/146 (8.9%)		29/194 (14.9%)
Dyspnoea exacerbated	4/43 (9.3%)		19/146 (13%)		35/194 (18%)
Dyspnoea exertional	0/43 (0%)		3/146 (2.1%)		17/194 (8.8%)
Epistaxis	3/43 (7%)		9/146 (6.2%)		31/194 (16%)
Hypoxia	0/43 (0%)		3/146 (2.1%)		10/194 (5.2%)
Nasal congestion	1/43 (2.3%)		19/146 (13%)		28/194 (14.4%)
Pharyngolaryngeal pain	0/43 (0%)		3/146 (2.1%)		15/194 (7.7%)
Rhinitis	2/43 (4.7%)		5/146 (3.4%)		12/194 (6.2%)
Pulmonary hypertension	7/43 (16.3%)		12/146 (8.2%)		32/194 (16.5%)
Skin and subcutaneous tissue disorders
Pruritis	1/43 (2.3%)		3/146 (2.1%)		12/194 (6.2%)
Rash	1/43 (2.3%)		5/146 (3.4%)		12/194 (6.2%)
Vascular disorders
Flushing	3/43 (7%)		9/146 (6.2%)		8/194 (4.1%)
Hypotension	5/43 (11.6%)		8/146 (5.5%)		16/194 (8.2%)
Jugular vein distension	0/43 (0%)		2/146 (1.4%)		17/194 (8.8%)

Limitations/Caveats

Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. At Year 3, almost half of those randomized to 2.5 mg were titrated to 5 mg and 10 mg; a third starting at 5 mg were titrated to 10 mg.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.