Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00617305
• Collaborator: (none)
• Enrollment: 38
• Locations: 30
• Arms: 2
• Duration (Months): 39
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To evaluate the change from baseline in pulmonary vascular resistance (PVR), and other hemodynamic parameters, following the addition of ambrisentan to background phosphodiesterase type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial hypertension (PAH) who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The study was originally designed as a 2-arm, double-blind, randomized study in which patients received ambrisentan or placebo for 24 weeks, and then received ambrisentan blinded to dose for 24 weeks. With Protocol Amendment 2 (12 June, 2009), the study was switched to single-arm, open-label treatment, and all patients remaining in the placebo arm were switched to open-label ambrisentan treatment. Patients who enrolled after Amendment 2 all received open-label ambrisentan.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Ambrisentan; Drug: Placebo; Drug: Sildenafil; Drug: Tadalafil	Phase 4

Detailed Description

The primary objective of this study is to evaluate the change from baseline in pulmonary vascular resistance (PVR), and other hemodynamic parameters, following the addition of ambrisentan to background phosphodiesterase type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial hypertension (PAH) who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The secondary objectives of this study are to evaluate the change from baseline in other clinical measures of PAH following the addition of ambrisentan to background PDE-5i therapy in subjects with PAH who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The safety and tolerability of ambrisentan/PDE-5i combination therapy will be evaluated throughout the study. In addition, long-term efficacy will be examined.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter Study of Ambrisentan and a Phosphodiesterase Type-5 Inhibitor Combination Therapy in Subjects With Pulmonary Arterial Hypertension Who Have Demonstrated a Sub-Optimal Response to a Phosphodiesterase Type-5 Inhibitor
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ambrisentan Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i; sildenafil or tadalafil).	Drug: Ambrisentan; Ambrisentan was administered orally once daily; dose level was 5 mg for the first 4 weeks, followed by 10 mg for the remainder of the study; ambrisentan was supplied as 5-mg and 10-mg tablets.; Other Names: Letairis ; Drug: Sildenafil; Sildenafil was administered at the dose previously established for each subject (20-100 mg) orally three times daily. Sildenafil was supplied as 20-mg tablets, or formulated as sildenafil citrate in 25-, 50-, or 100-mg tablets.; Other Names: Revatio Viagra ; Drug: Tadalafil; Tadalafil was administered at the dose previously established for each subject (not to exceed 40 mg per day) orally once daily. Tadalafil was supplied as 20-mg tablets.; Other Names: Cialis Adcirca
Active Comparator: Placebo Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (sildenafil or tadalafil).	Drug: Placebo; Placebo to match ambrisentan was administered orally once daily.; Drug: Sildenafil; Sildenafil was administered at the dose previously established for each subject (20-100 mg) orally three times daily. Sildenafil was supplied as 20-mg tablets, or formulated as sildenafil citrate in 25-, 50-, or 100-mg tablets.; Other Names: Revatio Viagra ; Drug: Tadalafil; Tadalafil was administered at the dose previously established for each subject (not to exceed 40 mg per day) orally once daily. Tadalafil was supplied as 20-mg tablets.; Other Names: Cialis Adcirca

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Pulmonary Vascular Resistance (PVR), Last Observation Carried Forward (LOCF) [Baseline to Week 24]

   The primary objective of this study is to evaluate the change from baseline in PVR, and other hemodynamic parameters, following the addition of ambrisentan to background PDE-5i therapy in subjects with PAH who have demonstrated a sub-optimal response to PDE-5i monotherapy. A decrease in measurement value (dynes sec/cm^5) indicates improvement for this patient population.

Secondary Outcome Measures

1. Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) (LOCF) [Baseline to Week 24]

   This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.

2. Change From Baseline in Mean Right Atrial Pressure (mRAP) (LOCF) [Baseline to Week 24]

   This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.

3. Change From Baseline in Cardiac Output (LOCF) [Baseline to Week 24]

   This secondary hemodynamic outcome is supportive of the primary outcome. An increase in measurement value (L/min) indicates improvement for this patient population.

4. Change From Baseline in Six Minute Walk Distance (6MWD) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) [Baseline to Week 48]

   The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. An increase in measurement value (meters walked) indicates improvement for this patient population.

5. Change in Dyspnea Index Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) [Baseline to Week 48]

   The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. The dyspnea index measures the degree of breathlessness after completion of the 6MWT using a scale of 0 to 10, with 0 indicating no breathlessness and 10 indicating maximum breathlessness.

6. Change From Baseline in the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Quality of Life (QOL) Survey Overall Score Measured at Weeks 12, 24, 36 and 48 (LOCF) [Baseline to Week 48]

   The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 12, 36, and 48 were also evaluated. Lower scores and decreases from baseline represent improved functioning and QOL. The CAMPHOR survey was not assessed at Week 4. The total CAMPHOR score scale ranges from 0 (good) to 25 (poor). A reduction in score over time represents improvement in this patient population.

7. Change From Baseline in World Health Organization (WHO) Functional Class (LOCF) Measured at Weeks 4, 12, 24, 36 and 48. [Baseline to Week 48]

   The primary analysis of this secondary outcome measure is change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. WHO categories are 1 to 4 with the worst category being 4. Improvement is represented by a change in category to a lower number (for example, change from category 3 to 2), and deterioration is represented by a change in category to a higher number (for example, change from category 2 to 4). No change is represented by no change in category (for example, category 2 which remains 2).

8. Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) [Baseline to Week 48]

   The primary analysis of this secondary outcome measure is mean percent change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. A decrease in log-transformed measurement value (pg/mL) indicates improvement for this patient population.

9. Time to Clinical Worsening of PAH, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48 [Baseline to Week 48+]

   The time to clinical worsening was defined as the time from enrollment to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, or initiation of chronic parenteral prostanoid therapy. Results are presented as the Kaplan-Meier estimate (% probability) of having clinical worsening after a given time.

10. Overall Survival, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48 [Baseline to Week 48+]

    Overall survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of death after a given time.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Selected Inclusion Criteria

• Must be between 16 and 75 years of age;

• Must weigh at least 40 kg;

• Have a current diagnosis of idiopathic PAH, familial PAH, or PAH that is primarily due to connective tissue disease, congenital heart defects, drug or toxin use, or human immunodeficiency virus (HIV);

• Have WHO functional class III symptoms;

• Be receiving sildenafil or tadalafil monotherapy for the treatment of PAH for at least the past 12 weeks and at a stable dose for at least 8 consecutive weeks;

• Meet all of the following hemodynamic criteria by means of a right heart catheterization: mPAP of at least 25 mmHg; PVR of at least 400 dyne*sec/cm5; pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of not more than 15 mmHg;

• Meet all of the following pulmonary function test criteria no more than 12 weeks before the screening visit: total lung capacity at least 60% of predicted normal and forced expiratory volume in 1 second of at least 65% of predicted normal;

• Able to walk at least 150 meters during the screening 6-minute walk test (6MWT);

• If receiving calcium channel blockers or 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks;

• If diagnosed with HIV, must have stable disease status.

Selected Exclusion Criteria:

• Have a current pulmonary hypertension diagnosis other than idiopathic PAH, familial PAH, or PAH that is primarily due to connective tissue disease, congenital heart defects, drug or toxin use, or HIV;

• Have left ventricular ejection fraction (LVEF) ≤40% or clinically significant ischemic, valvular, or constrictive heart disease;

• Have received chronic prostanoid or endothelin receptor antagonist (ERA) therapy (eg, bosentan, sitaxsentan) within the past 12 weeks;

• Have discontinued ERA treatment for any adverse reaction other than those associated with liver function test abnormalities;

• Have received IV inotropes within 2 weeks;

• Have a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is greater than 2.0x the upper limit of normal.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama	Mobile	Alabama	United States	36617
2	Arizona Pulmonary Specialists	Phoenix	Arizona	United States	85013
3	West Los Angeles Healthcare Center	Los Angeles	California	United States	90073
4	Harbor - UCLA	Torrance	California	United States	90502
5	Cleveland Clinic	Ft. Lauderdale	Florida	United States	33331
6	University of Florida	Gainesville	Florida	United States	32610
7	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
8	Orlando Heart Center	Orlando	Florida	United States	32806
9	Emory University	Atlanta	Georgia	United States	30322
10	Atlanta Institute for Medical Research	Decatur	Georgia	United States	30030
11	University of Iowa	Iowa City	Iowa	United States	52242
12	University of Maryland	Baltimore	Maryland	United States	21201
13	BACH Cardiology	Boston	Massachusetts	United States	02115
14	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
15	Wayne State University	Detroit	Michigan	United States	48201
16	Mayo Clinic	Rochester	Minnesota	United States	55905
17	Weill Cornell Medical Center	New York	New York	United States	10021
18	Asheville Cardiology Associates	Asheville	North Carolina	United States	28803
19	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
20	The Lindner Clinical Trial Center	Cincinnati	Ohio	United States	45219
21	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
22	Ohio State University	Columbus	Ohio	United States	43210
23	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
24	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
25	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
26	Rhode Island Hospital	Providence	Rhode Island	United States	02903
27	UT Southwestern Medical Center	Dallas	Texas	United States	75235
28	Baylor College of Medicine	Houston	Texas	United States	77030
29	Scott & White Memorial Hospital	Temple	Texas	United States	76508
30	Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507

Sponsors and Collaborators

• Gilead Sciences

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00617305
• Other Study ID Numbers: GS-US-300-0117
• First Posted: Feb 18, 2008
• Last Update Posted: Jul 30, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by Gilead Sciences: ambrisentan; PAH; combination therapy; phosphodiesterase type-5 inhibitor (PDE-5i); cardiovascular; endothelin receptor antagonist; ERA
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Ambrisentan; Sildenafil Citrate; Tadalafil

Study Results

Participant Flow

Recruitment Details	Patients were enrolled in 16 study sites in the US. The first patient was screened on 09 April 2008, and the last patient was enrolled on 28 July 2010. The last patient observation was on 25 July 2011. Originally a double-blind, placebo-controlled study, it was changed to open label on 12 June 2009 due to slow enrollment.
Pre-assignment Detail	65 patients were screened; 8 were randomized (3 to ambrisentan and 5 to placebo) prior to study conversion to open label. The remaining patients were assigned to ambrisentan treatment.

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i
Period Title: Overall Study
STARTED	33	4	1
Completed 24-week Primary Analysis	31	4	0
COMPLETED	25	4	0
NOT COMPLETED	8	0	1

Baseline Characteristics

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Total
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i	Total of all reporting groups
Overall Participants	33	4	1	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	29 87.9%	4 100%	1 100%	34 89.5%
>=65 years	4 12.1%	0 0%	0 0%	4 10.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.2 (13.72)	43.5 (14.89)	49.0 (0)	47.8 (13.52)
Sex: Female, Male (Count of Participants)
Female	26 78.8%	2 50%	0 0%	28 73.7%
Male	7 21.2%	2 50%	1 100%	10 26.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 24.2%	0 0%	0 0%	8 21.1%
Not Hispanic or Latino	25 75.8%	4 100%	1 100%	30 78.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Asian	2 6.1%	0 0%	0 0%	2 5.3%
Black or African American	2 6.1%	0 0%	0 0%	2 5.3%
Hispanic	1 3%	0 0%	0 0%	1 2.6%
More than one race	1 3%	0 0%	0 0%	1 2.6%
White	27 81.8%	4 100%	1 100%	32 84.2%
Region of Enrollment (participants) [Number]
United States	33 100%	4 100%	1 100%	38 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Pulmonary Vascular Resistance (PVR), Last Observation Carried Forward (LOCF)
Description	The primary objective of this study is to evaluate the change from baseline in PVR, and other hemodynamic parameters, following the addition of ambrisentan to background PDE-5i therapy in subjects with PAH who have demonstrated a sub-optimal response to PDE-5i monotherapy. A decrease in measurement value (dynes sec/cm^5) indicates improvement for this patient population.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Patients with measurements at Baseline and Week 24 were evaluated

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	31	4	0	35	4
Baseline	761.2 (306.57)	731.6 (278.02)	758.0 (300.12)	703.6 (248.73)
Week 24	518.8 (196.35)	439.8 (130.34)	509.8 (190.18)	439.8 (130.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24
	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	-248.93
	Confidence Interval	(2-Sided) 95%; -337.7 to -160.2
	Parameter Dispersion	Type: Standard Deviation; Value: 241.978
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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	-291.80
	Confidence Interval	(2-Sided) 95%; -619.4 to 35.78
	Parameter Dispersion	Type: Standard Deviation; Value: 205.864
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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	-253.83
	Confidence Interval	(2-Sided) 95%; -334.8 to -172.8
	Parameter Dispersion	Type: Standard Deviation; Value: 235.787
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24
	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	-291.80
	Confidence Interval	(2-Sided) 95%; -619.4 to 35.78
	Parameter Dispersion	Type: Standard Deviation; Value: 205.864
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) (LOCF)
Description	This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Patients with measurements at Baseline and Week 24 were evaluated

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	31	4	0	35	4
Baseline	49.9 (9.75)	54.5 (12.50)	50.4 (9.98)	52.8 (11.48)
Week 24	44.4 (10.95)	38.8 (9.60)	43.8 (10.83)	38.8 (9.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24
	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	-5.38
	Confidence Interval	(2-Sided) 95%; -8.29 to -2.46
	Parameter Dispersion	Type: Standard Deviation; Value: 7.954
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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	-15.75
	Confidence Interval	(2-Sided) 95%; -29.64 to -1.86
	Parameter Dispersion	Type: Standard Deviation; Value: 8.732
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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	-6.56
	Confidence Interval	(2-Sided) 95%; -9.51 to -3.61
	Parameter Dispersion	Type: Standard Deviation; Value: 8.589
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24
	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	-15.75
	Confidence Interval	(2-Sided) 95%; -29.64 to -1.86
	Parameter Dispersion	Type: Standard Deviation; Value: 8.732
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Mean Right Atrial Pressure (mRAP) (LOCF)
Description	This secondary hemodynamic outcome is supportive of the primary outcome. A decrease in measurement value (mmHg) indicates improvement for this patient population.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Patients with measurements at Baseline and Week 24 were evaluated

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	31	4	0	35	4
Baseline	8.5 (4.82)	10.3 (2.63)	8.7 (4.64)	11.1 (2.97)
Week 24	8.4 (4.88)	6.3 (1.71)	8.1 (4.66)	6.3 (1.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24
	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	-0.06
	Confidence Interval	(2-Sided) 95%; -1.69 to 1.56
	Parameter Dispersion	Type: Standard Deviation; Value: 4.442
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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	-4.00
	Confidence Interval	(2-Sided) 95%; -10.50 to 2.50
	Parameter Dispersion	Type: Standard Deviation; Value: 4.082
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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%; -2.07 to 1.04
	Parameter Dispersion	Type: Standard Deviation; Value: 4.527
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24
	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	-4.00
	Confidence Interval	(2-Sided) 95%; -10.50 to 2.50
	Parameter Dispersion	Type: Standard Deviation; Value: 4.082
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Cardiac Output (LOCF)
Description	This secondary hemodynamic outcome is supportive of the primary outcome. An increase in measurement value (L/min) indicates improvement for this patient population.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Patients with measurements at Baseline and Week 24 were evaluated

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	28	4	0	32	4
Baseline	4.4 (1.22)	4.8 (0.81)	4.4 (1.17)	4.8 (0.71)
Week 24	5.2 (1.27)	5.2 (1.22)	5.2 (1.24)	5.2 (1.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24
	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	0.84
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.25
	Parameter Dispersion	Type: Standard Deviation; Value: 1.053
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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%; -0.77 to 1.42
	Parameter Dispersion	Type: Standard Deviation; Value: 0.685
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24
	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	0.78
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.15
	Parameter Dispersion	Type: Standard Deviation; Value: 1.021
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24
	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%; -0.77 to 1.42
	Parameter Dispersion	Type: Standard Deviation; Value: 0.685
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Six Minute Walk Distance (6MWD) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)
Description	The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. An increase in measurement value (meters walked) indicates improvement for this patient population.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All enrolled Population

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	33	4	1	37	5
Baseline	361.9 (98.74)	433.3 (80.77)	335.0 (0.0)	369.6 (98.56)	413.6 (82.61)
Week 4	376.5 (106.08)	441.0 (83.88)	442.0 (0.0)	383.7 (104.85)	441.2 (72.65)
Week 12	377.9 (109.61)	435.8 (134.61)	422.0 (0.0)	384.3 (111.96)	433.0 (116.74)
Week 24	382.4 (104.96)	423.8 (110.05)	422.0 (0.0)	387.0 (104.73)	423.4 (95.31)
Week 36	366.5 (127.62)	399.3 (152.93)	402.0 (0.0)	370.2 (128.61)	399.8 (132.45)
Week 48	378.9 (124.18)	383.5 (192.47)	402.0 (0.0)	379.4 (129.75)	387.2 (166.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	12.2
	Confidence Interval	(2-Sided) 95%; -3.9 to 28.4
	Parameter Dispersion	Type: Standard Deviation; Value: 44.84
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	7.8
	Confidence Interval	(2-Sided) 95%; -26.0 to 41.5
	Parameter Dispersion	Type: Standard Deviation; Value: 21.19
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	107.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	11.7
	Confidence Interval	(2-Sided) 95%; -2.7 to 26.2
	Parameter Dispersion	Type: Standard Deviation; Value: 42.68
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	27.6
	Confidence Interval	(2-Sided) 95%; -32.0 to 87.2
	Parameter Dispersion	Type: Standard Deviation; Value: 48.03
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	13.6
	Confidence Interval	(2-Sided) 95%; -1.4 to 28.5
	Parameter Dispersion	Type: Standard Deviation; Value: 41.46
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	2.5
	Confidence Interval	(2-Sided) 95%; -91.5 to 96.5
	Parameter Dispersion	Type: Standard Deviation; Value: 59.09
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	87.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	12.4
	Confidence Interval	(2-Sided) 95%; -2.1 to 26.9
	Parameter Dispersion	Type: Standard Deviation; Value: 42.83
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	19.4
	Confidence Interval	(2-Sided) 95%; -59.6 to 98.4
	Parameter Dispersion	Type: Standard Deviation; Value: 63.61
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	18.1
	Confidence Interval	(2-Sided) 95%; 0.5 to 35.6
	Parameter Dispersion	Type: Standard Deviation; Value: 48.67
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-9.5
	Confidence Interval	(2-Sided) 95%; -56.5 to 37.5
	Parameter Dispersion	Type: Standard Deviation; Value: 29.56
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	87.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	15.0
	Confidence Interval	(2-Sided) 95%; -1.0 to 31.1
	Parameter Dispersion	Type: Standard Deviation; Value: 47.44
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	9.8
	Confidence Interval	(2-Sided) 95%; -52.5 to 72.1
	Parameter Dispersion	Type: Standard Deviation; Value: 50.18
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	2.2
	Confidence Interval	(2-Sided) 95%; -25.6 to 30.1
	Parameter Dispersion	Type: Standard Deviation; Value: 77.24
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-34.0
	Confidence Interval	(2-Sided) 95%; -182.2 to 114.2
	Parameter Dispersion	Type: Standard Deviation; Value: 93.16
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	67.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-1.8
	Confidence Interval	(2-Sided) 95%; -28.4 to 24.8
	Parameter Dispersion	Type: Standard Deviation; Value: 78.50
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-13.8
	Confidence Interval	(2-Sided) 95%; -128.6 to 101.0
	Parameter Dispersion	Type: Standard Deviation; Value: 92.46
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	14.6
	Confidence Interval	(2-Sided) 95%; -15.0 to 44.2
	Parameter Dispersion	Type: Standard Deviation; Value: 82.07
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-49.8
	Confidence Interval	(2-Sided) 95%; -251.4 to 151.9
	Parameter Dispersion	Type: Standard Deviation; Value: 126.75
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	67.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	7.4
	Confidence Interval	(2-Sided) 95%; -22.4 to 37.3
	Parameter Dispersion	Type: Standard Deviation; Value: 88.11
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-26.4
	Confidence Interval	(2-Sided) 95%; -177.3 to 124.5
	Parameter Dispersion	Type: Standard Deviation; Value: 121.55
	Estimation Comments

6. Secondary Outcome

Title	Change in Dyspnea Index Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)
Description	The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. The dyspnea index measures the degree of breathlessness after completion of the 6MWT using a scale of 0 to 10, with 0 indicating no breathlessness and 10 indicating maximum breathlessness.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All enrolled Population

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	33	4	1	37	5
Baseline	3.7 (2.07)	2.5 (1.29)	3.0 (0.0)	3.6 (2.03)	2.6 (1.14)
Week 4	3.2 (1.68)	3.3 (2.22)	2.0 (0.0)	3.2 (1.71)	3.0 (2.00)
Week 12	3.2 (1.94)	4.0 (2.83)	3.0 (0.0)	3.3 (2.02)	3.8 (2.49)
Week 24	2.9 (1.96)	1.9 (1.31)	3.0 (0.0)	2.8 (1.91)	2.1 (1.24)
Week 36	3.2 (2.29)	3.5 (2.65)	3.0 (0.0)	3.2 (2.29)	3.4 (2.30)
Week 48	3.1 (2.32)	3.5 (4.04)	3.0 (0.0)	3.1 (2.49)	3.4 (3.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	-0.5
	Confidence Interval	(2-Sided) 95%; -1.1 to 0.0
	Parameter Dispersion	Type: Standard Deviation; Value: 1.50
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	0.8
	Confidence Interval	(2-Sided) 95%; -1.6 to 3.1
	Parameter Dispersion	Type: Standard Deviation; Value: 1.50
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	-1.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	-0.4
	Confidence Interval	(2-Sided) 95%; -0.9 to 0.1
	Parameter Dispersion	Type: Standard Deviation; Value: 1.54
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	0.4
	Confidence Interval	(2-Sided) 95%; -1.5 to 2.3
	Parameter Dispersion	Type: Standard Deviation; Value: 1.52
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-0.6
	Confidence Interval	(2-Sided) 95%; -1.1 to 0.0
	Parameter Dispersion	Type: Standard Deviation; Value: 1.45
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	1.5
	Confidence Interval	(2-Sided) 95%; -2.3 to 5.3
	Parameter Dispersion	Type: Standard Deviation; Value: 2.38
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	0.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-0.3
	Confidence Interval	(2-Sided) 95%; -0.9 to 0.2
	Parameter Dispersion	Type: Standard Deviation; Value: 1.67
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	1.2
	Confidence Interval	(2-Sided) 95%; -1.5 to 3.9
	Parameter Dispersion	Type: Standard Deviation; Value: 2.17
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.9
	Confidence Interval	(2-Sided) 95%; -1.5 to -0.2
	Parameter Dispersion	Type: Standard Deviation; Value: 1.81
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.6
	Confidence Interval	(2-Sided) 95%; -1.8 to 0.6
	Parameter Dispersion	Type: Standard Deviation; Value: 0.75
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	0.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.8
	Confidence Interval	(2-Sided) 95%; -1.4 to -0.3
	Parameter Dispersion	Type: Standard Deviation; Value: 1.72
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.5
	Confidence Interval	(2-Sided) 95%; -1.4 to 0.4
	Parameter Dispersion	Type: Standard Deviation; Value: 0.71
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.6
	Confidence Interval	(2-Sided) 95%; -1.2 to 0.1
	Parameter Dispersion	Type: Standard Deviation; Value: 1.79
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	1.0
	Confidence Interval	(2-Sided) 95%; -2.2 to 4.2
	Parameter Dispersion	Type: Standard Deviation; Value: 2.00
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	0.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.4
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.2
	Parameter Dispersion	Type: Standard Deviation; Value: 1.85
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	0.8
	Confidence Interval	(2-Sided) 95%; -1.4 to 3.0
	Parameter Dispersion	Type: Standard Deviation; Value: 1.79
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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%; -1.4 to 0.1
	Parameter Dispersion	Type: Standard Deviation; Value: 2.12
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	1.0
	Confidence Interval	(2-Sided) 95%; -4.5 to 6.5
	Parameter Dispersion	Type: Standard Deviation; Value: 3.46
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	0.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.5
	Confidence Interval	(2-Sided) 95%; -1.3 to 0.3
	Parameter Dispersion	Type: Standard Deviation; Value: 2.30
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	0.8
	Confidence Interval	(2-Sided) 95%; -3.0 to 4.6
	Parameter Dispersion	Type: Standard Deviation; Value: 3.03
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Quality of Life (QOL) Survey Overall Score Measured at Weeks 12, 24, 36 and 48 (LOCF)
Description	The primary analysis of this secondary outcome measure is mean change from Baseline to Week 24. The changes from Baseline to Weeks 12, 36, and 48 were also evaluated. Lower scores and decreases from baseline represent improved functioning and QOL. The CAMPHOR survey was not assessed at Week 4. The total CAMPHOR score scale ranges from 0 (good) to 25 (poor). A reduction in score over time represents improvement in this patient population.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All enrolled Population

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	33	4	1	37	5
Baseline	8.2 (6.14)	4.3 (5.44)	4.0 (0.0)	7.7 (6.12)	4.2 (4.71)
Week 12	6.8 (5.59)	5.5 (3.11)	2.0 (0.0)	6.7 (5.32)	4.8 (3.11)
Week 24	7.2 (5.82)	3.0 (2.94)	2.0 (0.0)	6.7 (5.69)	2.8 (2.59)
Week 36	7.7 (6.10)	3.5 (3.70)	3.0 (0.0)	7.2 (5.98)	3.4 (3.21)
Week48	7.6 (6.87)	3.8 (3.50)	3.0 (0.0)	7.1 (6.63)	3.6 (3.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-1.1
	Confidence Interval	(2-Sided) 95%; -2.7 to 0.4
	Parameter Dispersion	Type: Standard Deviation; Value: 3.98
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	1.3
	Confidence Interval	(2-Sided) 95%; -6.5 to 9.0
	Parameter Dispersion	Type: Standard Deviation; Value: 4.86
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-2.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-0.8
	Confidence Interval	(2-Sided) 95%; -2.3 to 0.6
	Parameter Dispersion	Type: Standard Deviation; Value: 4.09
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	0.6
	Confidence Interval	(2-Sided) 95%; -4.9 to 6.1
	Parameter Dispersion	Type: Standard Deviation; Value: 4.45
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.8
	Confidence Interval	(2-Sided) 95%; -2.7 to 1.1
	Parameter Dispersion	Type: Standard Deviation; Value: 5.00
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-1.3
	Confidence Interval	(2-Sided) 95%; -7.7 to 5.2
	Parameter Dispersion	Type: Standard Deviation; Value: 4.03
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-2.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.9
	Confidence Interval	(2-Sided) 95%; -2.6 to 0.9
	Parameter Dispersion	Type: Standard Deviation; Value: 4.84
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-1.4
	Confidence Interval	(2-Sided) 95%; -5.8 to 3.0
	Parameter Dispersion	Type: Standard Deviation; Value: 3.51
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.3
	Confidence Interval	(2-Sided) 95%; -2.3 to 1.7
	Parameter Dispersion	Type: Standard Deviation; Value: 5.20
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.8
	Confidence Interval	(2-Sided) 95%; -8.1 to 6.6
	Parameter Dispersion	Type: Standard Deviation; Value: 4.65
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-1.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.3
	Confidence Interval	(2-Sided) 95%; -2.2 to 1.5
	Parameter Dispersion	Type: Standard Deviation; Value: 5.07
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.8
	Confidence Interval	(2-Sided) 95%; -5.8 to 4.2
	Parameter Dispersion	Type: Standard Deviation; Value: 4.02
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.4
	Confidence Interval	(2-Sided) 95%; -2.8 to 2.1
	Parameter Dispersion	Type: Standard Deviation; Value: 6.33
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.5
	Confidence Interval	(2-Sided) 95%; -11.4 to 10.4
	Parameter Dispersion	Type: Standard Deviation; Value: 6.86
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo Only
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-1.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.4
	Confidence Interval	(2-Sided) 95%; -2.7 to 1.9
	Parameter Dispersion	Type: Standard Deviation; Value: 6.28
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.6
	Confidence Interval	(2-Sided) 95%; -8.0 to 6.8
	Parameter Dispersion	Type: Standard Deviation; Value: 5.94
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in World Health Organization (WHO) Functional Class (LOCF) Measured at Weeks 4, 12, 24, 36 and 48.
Description	The primary analysis of this secondary outcome measure is change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. WHO categories are 1 to 4 with the worst category being 4. Improvement is represented by a change in category to a lower number (for example, change from category 3 to 2), and deterioration is represented by a change in category to a higher number (for example, change from category 2 to 4). No change is represented by no change in category (for example, category 2 which remains 2).
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All enrolled Population

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	33	4	1	37	5
Week 4 - Improvement	3 9.1%	0 0%	1 100%	3 7.9%	1 NaN
Week 4 - No Change	29 87.9%	4 100%	0 0%	33 86.8%	4 NaN
Week 4 - Deterioration	0 0%	0 0%	0 0%	0 0%	0 NaN
Week 4 - Missing Data	1 3%	0 0%	0 0%	1 2.6%	0 NaN
Week 12 - Improvement	8 24.2%	1 25%	1 100%	9 23.7%	2 NaN
Week 12 - No Change	24 72.7%	3 75%	0 0%	27 71.1%	3 NaN
Week 12 - Deterioration	0 0%	0 0%	0 0%	0 0%	0 NaN
Week 12 - Missing Data	1 3%	0 0%	0 0%	1 2.6%	0 NaN
Week 24 - Improvement	12 36.4%	2 50%	1 100%	14 36.8%	3 NaN
Week 24 - No Change	19 57.6%	2 50%	0 0%	21 55.3%	2 NaN
Week 24 - Deterioration	1 3%	0 0%	0 0%	1 2.6%	0 NaN
Week 24 - Missing Data	1 3%	0 0%	0 0%	1 2.6%	0 NaN
Week 36 - Improvement	17 51.5%	2 50%	1 100%	19 50%	3 NaN
Week 36 - No Change	14 42.4%	2 50%	0 0%	16 42.1%	2 NaN
Week 36 - Deterioration	1 3%	0 0%	0 0%	1 2.6%	0 NaN
Week 36 - Missing Data	1 3%	0 0%	0 0%	1 2.6%	0 NaN
Week 48 - Improvement	14 42.4%	1 25%	1 100%	15 39.5%	2 NaN
Week 48 - No Change	17 51.5%	3 75%	0 0%	20 52.6%	3 NaN
Week 48 - Deterioration	1 3%	0 0%	0 0%	1 2.6%	0 NaN
Week 48 - Missing Data	1 3%	0 0%	0 0%	1 2.6%	0 NaN

9. Secondary Outcome

Title	Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF)
Description	The primary analysis of this secondary outcome measure is mean percent change from Baseline to Week 24. The changes from Baseline to Weeks 4, 12, 36, and 48 were also evaluated. A decrease in log-transformed measurement value (pg/mL) indicates improvement for this patient population.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

One patient (Any Placebo) was not evaluated for NT-proBNP. One patient (Placebo Only) had no baseline measurement, so no statistical analyses for change from baseline are given for the placebo only group (patient was only subject in this group).

Arm/Group Title	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Any Ambrisentan	Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i (4 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i and did not receive ambrisentan (1 patient had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i (5 patients had baseline measurements in this group)
Measure Participants	33	4	1	37	4
Baseline	6.1 (1.10)	6.7 (1.02)	0.0 (0.0)	6.2 (1.10)	6.7 (1.02)
Week 4	5.7 (1.02)	6.2 (1.80)	7.5 (0.0)	5.7 (1.05)	6.7 (1.46)
Week 12	5.7 (1.01)	6.3 (0.45)	7.6 (0.0)	5.8 (0.99)	6.8 (0.80)
Week 24	5.7 (1.03)	6.0 (0.98)	7.6 (0.0)	5.7 (1.02)	6.4 (1.12)
Week 36	5.7 (1.19)	5.9 (0.64)	8.0 (0.0)	5.7 (1.14)	6.3 (1.08)
Week 48	5.6 (1.16)	6.4 (0.82)	8.0 (0.0)	5.7 (1.14)	6.7 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.50
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	-0.2
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.28
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.49
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 4 (LOCF)
	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	-0.2
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.28
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-0.3
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.63
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-0.1
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 1.07
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-0.3
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.64
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 12 (LOCF)
	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	-0.1
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 1.07
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.83
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.34
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.81
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 24 (LOCF)
	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	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.34
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.92
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.8
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.90
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.91
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 36 (LOCF)
	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	-0.8
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.90
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan Only
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.91
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo/Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.3
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.77
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Any Ambrisentan
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.4
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.88
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Any Placebo
	Comments	Mean change from Baseline to Week 48 (LOCF)
	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	-0.3
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Deviation; Value: 0.77
	Estimation Comments

10. Secondary Outcome

Title	Time to Clinical Worsening of PAH, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48
Description	The time to clinical worsening was defined as the time from enrollment to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, or initiation of chronic parenteral prostanoid therapy. Results are presented as the Kaplan-Meier estimate (% probability) of having clinical worsening after a given time.
Time Frame	Baseline to Week 48+

Outcome Measure Data

Analysis Population Description

The Ambrisentan Only and Any Ambrisentan Groups were analyzed for Time to Clinical Worsening

Arm/Group Title	Ambrisentan Only	Any Ambrisentan
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)
Measure Participants	33	37
At Week 4	0	0
At Week 8	0	0
At Week 12	0	0
At Week 16	0	0
At Week 20	3	3
At Week 24	3	3
At Week 28	6	6
At Week 32	16	14
At Week 36	16	14
At Week 40	20	17
At Week 44	20	17
At Week 48	20	17
After Week 48	20	17

11. Secondary Outcome

Title	Overall Survival, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48
Description	Overall survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of death after a given time.
Time Frame	Baseline to Week 48+

Outcome Measure Data

Analysis Population Description

The Ambrisentan Only and Any Ambrisentan Groups were analyzed for Overall Survival

Arm/Group Title	Ambrisentan Only	Any Ambrisentan
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i) (33 patients had baseline measurements in this group)	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i (37 patients had baseline measurements in this group)
Measure Participants	33	37
At Week 4	0	0
At Week 8	0	0
At Week 12	0	0
At Week 16	0	0
At Week 20	0	0
At Week 24	0	0
At Week 28	0	0
At Week 32	0	0
At Week 36	0	0
At Week 40	4	3
At Week 44	4	3
At Week 48	4	3
After Week 48	4	3

Adverse Events

Time Frame	Adverse events (AEs) and serious adverse events (SAEs) were reported through Week 48.
Adverse Event Reporting Description	AEs/SAEs were analyzed for patients who: received ambrisentan but not placebo ("Ambrisentan Only"); received ambrisentan and did or did not receive placebo ("Any Ambrisentan"); received placebo and did or did not receive ambrisentan ("Any Placebo"). Safety analysis was not done for the "Ambrisentan/Placebo" or "Placebo Only" groups.
Arm/Group Title	Ambrisentan Only		Any Ambrisentan		Any Placebo
Arm/Group Description	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i)		Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i		Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i
All Cause Mortality
	Ambrisentan Only		Any Ambrisentan		Any Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ambrisentan Only		Any Ambrisentan		Any Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/33 (30.3%)		11/37 (29.7%)		1/5 (20%)
Blood and lymphatic system disorders
Anaemia	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Pancytopenia	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Cardiac disorders
Atrial Flutter	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Right ventricular failure	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Myocardial infarction	0/33 (0%)		1/37 (2.7%)		0/5 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrage	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Oesophageal splasm	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Abdominal pain	0/33 (0%)		0/37 (0%)		1/5 (20%)
General disorders
Chest discomfort	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Chest pain	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Infections and infestations
Cellulitis	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Diverticulitis	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Enterocolitis infectious	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Urinary tract infection	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Metabolism and nutrition disorders
Iron deficiency	1/33 (3%)		1/37 (2.7%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Hypoxia	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Pulmonary arterial hypertension	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Pneumonitis	0/33 (0%)		1/37 (2.7%)		0/5 (0%)
Respiratory failure	0/33 (0%)		1/37 (2.7%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Ambrisentan Only		Any Ambrisentan		Any Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/33 (97%)		36/37 (97.3%)		4/5 (80%)
Blood and lymphatic system disorders
Anaemia	3/33 (9.1%)		3/37 (8.1%)		0/5 (0%)
Cardiac disorders
Tachycardia	2/33 (6.1%)		3/37 (8.1%)		0/5 (0%)
Ear and labyrinth disorders
Deafness neurosensory	1/33 (3%)		2/37 (5.4%)		0/5 (0%)
Gastrointestinal disorders
Abdominal pain	3/33 (9.1%)		3/37 (8.1%)		1/5 (20%)
Gastrooesophageal reflux disease	3/33 (9.1%)		3/37 (8.1%)		0/5 (0%)
Constipation	2/33 (6.1%)		2/37 (5.4%)		1/5 (20%)
Abdominal discomfort	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Diarrhoea	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Haemorrhoids	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Nausea	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Toothache	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
General disorders
Oedema peripheral	7/33 (21.2%)		7/37 (18.9%)		0/5 (0%)
Fatigue	5/33 (15.2%)		5/37 (13.5%)		1/5 (20%)
Chest pain	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Infections and infestations
Upper respiratory tract infection	8/33 (24.2%)		8/37 (21.6%)		0/5 (0%)
Urinary tract infection	5/33 (15.2%)		5/37 (13.5%)		0/5 (0%)
Nasopharyngitis	3/33 (9.1%)		4/37 (10.8%)		1/5 (20%)
Lower respiratory tract infection	3/33 (9.1%)		3/37 (8.1%)		0/5 (0%)
Sinusitis	2/33 (6.1%)		3/37 (8.1%)		0/5 (0%)
Cellulitis	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Viral infection	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Bronchitis	1/33 (3%)		2/37 (5.4%)		0/5 (0%)
Investigations
Brain natriuretic peptide increased	3/33 (9.1%)		3/37 (8.1%)		0/5 (0%)
Blood uric acid increased	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Protein total increased	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Urine leukocyte esterase positive	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Blood creatinine increased	1/33 (3%)		1/37 (2.7%)		1/5 (20%)
Metabolism and nutrition disorders
Fluid overload	5/33 (15.2%)		7/37 (18.9%)		1/5 (20%)
Hypokalaemia	3/33 (9.1%)		3/37 (8.1%)		1/5 (20%)
Fluid retention	3/33 (9.1%)		3/37 (8.1%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Musculoskeletal pain	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Pain in extremity	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Nervous system disorders
Headache	7/33 (21.2%)		7/37 (18.9%)		1/5 (20%)
Dizziness	5/33 (15.2%)		5/37 (13.5%)		1/5 (20%)
Carpal tunnel syndrome	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Psychiatric disorders
Anxiety	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Depression	1/33 (3%)		1/37 (2.7%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	10/33 (30.3%)		10/37 (27%)		0/5 (0%)
Dyspnoea	4/33 (12.1%)		4/37 (10.8%)		0/5 (0%)
Epistaxis	4/33 (12.1%)		4/37 (10.8%)		0/5 (0%)
Oropharyngeal pain	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)
Pulmonary arterial hypertension	2/33 (6.1%)		2/37 (5.4%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years