Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00380068
• Collaborator: (none)
• Enrollment: 224
• Locations: 39
• Arm: 1
• Duration (Months): 33
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of this study was to evaluate the safety and efficacy of ambrisentan in a broad population of participants with pulmonary hypertension (PH). Secondary objectives of this study were to evaluate the effects of ambrisentan on other clinical measures of pulmonary arterial hypertension (PAH), long-term treatment success, and survival.

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

Detailed Description

This study was to enroll up to 200 participants with PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1); 2) PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5). Participants with left heart disease or left heart failure were excluded (WHO Group 2). Participants could be receiving prostacyclin or sildenafil therapy at baseline, and participants who previously discontinued either bosentan, sitaxsentan, or both, due to liver function test abnormalities were eligible.

Study Design

• Study Type: Interventional
• Actual Enrollment: 224 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: ARIES-3: A Phase 3, Long-Term, Open-Label, Multicenter Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ambrisentan	Drug: Ambrisentan; Oral tablets taken once daily.; Other Names: Letairis Volibris

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD) [Baseline to Week 24]

Secondary Outcome Measures

1. Change From Baseline to Week 24 in Borg Dyspnea Index [Baseline to Week 24]

   Change from Baseline to Week 24 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.

2. Change From Baseline to Week 48 in Borg Dyspnea Index [Baseline to Week 48]

   Change from Baseline to Week 48 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.

3. Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP) [Baseline to Week 24]

4. Percent Change From Baseline to Week 48 in BNP [Baseline to Week 48]

5. Change From Baseline to Week 24 in WHO Functional Class [Baseline to Week 24]

   Change from baseline in World Health Organization functional class (WHO) at Week 24 is the incidence of participants that improved, had no change, or worsened. WHO categories are 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.

6. Change From Baseline to Week 48 in WHO Functional Class [Baseline to Week 48]

   Change from baseline in WHO at Week 48 is expressed as the incidence of participants that improved, had no change or worsened. WHO categories range from 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.

7. Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale [Baseline to Week 24]

   Change from baseline to Week 24 in the SF-36 health survey physical functioning scale. 10 activities rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

8. Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale [Baseline to Week 48]

   Change from baseline to Week 48 in the SF-36 health survey physical functioning scale. 10 activities are rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General US population mean and standard deviation. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and standard deviation of 10.

9. Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24 [Baseline to Week 24]

   Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents

10. Percent of Participants With no Clinical Worsening of PH at Week 48 [Baseline to Week 48]

    Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents

11. Failure-free Treatment Status [Baseline to Week 24]

    Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents

12. Failure-free Treatment Status [Baseline to Week 48]

    Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents

13. Monotherapy Treatment Status [Baseline to Week 24]

    Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment

14. Monotherapy Treatment Status [Baseline to Week 48]

    Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment

15. Long-term Survival [Baseline to Week 24]

    Defined as not dying during study participation

16. Long-term Survival [Baseline to Week 48]

    Defined as not dying during study participation

Eligibility Criteria

Criteria

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

Summarized Inclusion Criteria:

1. 18 years of age or older

2. Current diagnosis of PH associated with an acceptable etiology as outlined in the protocol, including: PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1);

1. PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5).

1. Stable regimen (within four weeks) of chronic prostanoid, PDE-5 inhibitor, calcium channel blocker, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor therapy

2. Right heart catheterization completed prior to screening must meet pre-specified criteria

3. Female participants of childbearing potential must have a negative serum pregnancy test and must agree to use a reliable double method of contraception until study completion and for at least four weeks following their final study visit.

4. Male participants must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking ambrisentan and queried regarding his understanding of the potential risks as described in the Informed Consent Form.

Summarized Exclusion Criteria:

1. Participation in a previous clinical study with ambrisentan

2. Bosentan or sitaxsentan use within four weeks prior to the screening visit

3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is greater than 3 times the upper limit of normal at the screening visit

4. Pulmonary function tests not meeting the following pre-specified criteria: 1) mean pulmonary arterial pressure (PAP) >= 25 mm Hg; 2) PVR > 3 mm Hg/L/min; 3) pulmonary capillary wedge pressure (PCWP) or left ventricle end diastolic pressure (LVEDP) < 15 mm Hg; 4) total lung capacity (TLC) >= 70% of predicted normal for participants without ILD or >= 60% of predicted normal in participants with ILD; forced expiratory volume in 1 second (FEV1) >= 65% of predicted normal in participants without COPD or

= 50% of predicted normal in participants with COPD

1. Contraindication to treatment with endothelin receptor antagonist (ERA)

2. History of malignancies other than basal cell carcinoma of the skin or in situ carcinoma of the cervix within the past five years

3. Female participant who is pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Arizona Pulmonary Specialists, Ltd	Phoenix	Arizona	United States	85013
3	UCSD Medical Center, Thornton Hospital	La Jolla	California	United States	92037
4	Greater Los Angeles, VA Medical Center	Los Angeles	California	United States	90073
5	Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center	Torrance	California	United States	90502
6	University of Colorado Health Sciences Center	Aurora	Colorado	United States	80045
7	University of Connecticut Health Center	Farmington	Connecticut	United States	06030
8	Pulmonary Hypertension Clinic Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
9	Suncoast Lung Center	Sarasota	Florida	United States	34233
10	Medical College of Georgia	Augusta	Georgia	United States	30912
11	Atlanta Institute for Medical Research, Inc.	Decatur	Georgia	United States	30030
12	University of Chicago Hospitals	Chicago	Illinois	United States	60637
13	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
14	Johns Hopkins University	Baltimore	Maryland	United States	21287
15	Tufts-New England Medical Center	Boston	Massachusetts	United States	02111
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	Boston Adult Congenital Heart Service	Boston	Massachusetts	United States	02115
18	Boston University School of Medicine	Boston	Massachusetts	United States	02118
19	Mayo Clinic	Rochester	Minnesota	United States	55905
20	Washington University School of Medicine	St. Louis	Missouri	United States	63110
21	University of Medicine & Dentistry of New Jersey	Newark	New Jersey	United States	07103
22	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
23	New York Presbyterian Pulmonary Hypertension Center	New York	New York	United States	10032
24	Mary Parkes Asthma Center	Rochester	New York	United States	14623
25	Duke University Medical Center	Durham	North Carolina	United States	27710
26	The Lindner Clinical Trial Center	Cincinnati	Ohio	United States	45219
27	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
28	Legacy Clinical Northwest	Portland	Oregon	United States	97210
29	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
30	University of Pittsburgh Medical Center Presbyterian	Pittsburgh	Pennsylvania	United States	15213
31	Rhode Island Hospital	Providence	Rhode Island	United States	02903
32	Lexington Pulmonary and Critical Care	Lexington	South Carolina	United States	29072
33	Baylor College of Medicine	Houston	Texas	United States	77030
34	University of Virginia Health Sciences Center	Charlottesville	Virginia	United States	22908
35	St. Vincent's Hospital	Darlinghurst	New South Wales	Australia	2010
36	Royal Perth Hospital	Perth		Australia	6000
37	Peter Lougheed Centre	Calgary	Alberta	Canada	T1Y 6J4
38	University of Alberta Hospitals	Edmonton	Alberta	Canada	T6G 2B7
39	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2N2

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Principal Investigator: Lewis J Rubin, MD, University of California, San Diego

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00380068
• Other Study ID Numbers: AMB-323; ARIES-3
• First Posted: Sep 25, 2006
• Last Update Posted: Apr 5, 2012
• Last Verified: Apr 1, 2012

• Additional relevant MeSH terms: Hypertension, Pulmonary; Hypertension; Ambrisentan

Study Results

Participant Flow

Recruitment Details	Enrollment occurred between September 2006 and January 2008 and the study was conducted between August 2006 and May 2009 in 39 centers in the United States, Australia and Canada
Pre-assignment Detail	The screening period was 4 weeks. Participants who received bosentan or sitaxsentan within 4 weeks prior to the screening visit were excluded.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Period Title: Overall Study
STARTED	224
COMPLETED	155
NOT COMPLETED	69

Baseline Characteristics

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Overall Participants	224
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (16)
Sex: Female, Male (Count of Participants)
Female	156 69.6%
Male	68 30.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD)
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Last Observation Carried forward. 4 participants were excluded from the analysis due to lack of post-baseline 6MWD data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	220
Mean (Standard Deviation) [meters]	20.5 (65.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test on change from Baseline to Week 24
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	20.5
	Confidence Interval	() 95%; 11.8 to 29.3
	Parameter Dispersion	Type: Standard Deviation; Value: 65.64
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 24 in Borg Dyspnea Index
Description	Change from Baseline to Week 24 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Last Observation Carried forward. 4 participants were excluded from the analysis due to lack of post-baseline Borg Dyspnea Index data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	220
Mean (Standard Deviation) [Units on a scale]	-0.5 (2.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test on change from Baseline to Week 24
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.5
	Confidence Interval	() 95%; -0.8 to -0.3
	Parameter Dispersion	Type: Standard Deviation; Value: 2.11
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to Week 48 in Borg Dyspnea Index
Description	Change from Baseline to Week 48 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Observed data. 114 participants were excluded from the analysis due to lack of Week 48 Borg Dyspnea Index data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	110
Mean (Standard Deviation) [Units on a scale]	-0.6 (1.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test on change from Baseline to Week 48
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.6
	Confidence Interval	() 95%; -1.0 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP)
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Last Observation Carried forward. 10 participants were excluded from the analysis due to lack of baseline or post-baseline BNP data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	214
Geometric Mean (95% Confidence Interval) [Percent change in BNP]	-25.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent change from baseline
	Estimated Value	-25.5
	Confidence Interval	() 95%; -33.6 to -16.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change from baseline derived from Geometric Mean Ratio

5. Secondary Outcome

Title	Percent Change From Baseline to Week 48 in BNP
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Observed data. 111 participants were excluded from the analysis due to lack of baseline or Week 48 BNP data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	112
Geometric Mean (95% Confidence Interval) [Percent change in BNP]	-29.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent change from baseline
	Estimated Value	-29.2
	Confidence Interval	() 95%; -39.8 to -16.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change from baseline derived from Geometric Mean Ratio

6. Secondary Outcome

Title	Change From Baseline to Week 24 in WHO Functional Class
Description	Change from baseline in World Health Organization functional class (WHO) at Week 24 is the incidence of participants that improved, had no change, or worsened. WHO categories are 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Last Observation Carried Forward. 3 participants were not analyzed due to lack of post-baseline WHO functional class data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	221
-3	0 0%
-2	0.9 0.4%
-1	22.2 9.9%
0	70.1 31.3%
1	6.8 3%
2	0 0%
3	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test performed on actual change from baseline WHO functional Class (eg, a change from WHO Class III to II is -1; a change from WHO Class IV to II is -2; etc).
	Method	Wilcoxon signed-rank test
	Comments

7. Secondary Outcome

Title	Change From Baseline to Week 48 in WHO Functional Class
Description	Change from baseline in WHO at Week 48 is expressed as the incidence of participants that improved, had no change or worsened. WHO categories range from 1 to 4 with the worse category at 4. Improvement = a category change from baseline of <= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Observed Data. 3 participants were not analyzed due to lack of post-baseline WHO functional class data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	119
-3	0 0%
-2	1.7 0.8%
-1	34.5 15.4%
0	57.1 25.5%
1	6.7 3%
2	0 0%
3	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test performed on actual change from baseline WHO functional Class (eg, a change from WHO Class III to II is -1; a change from WHO Class IV to II is -2; etc).
	Method	Wilcoxon signed-rank test
	Comments

8. Secondary Outcome

Title	Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale
Description	Change from baseline to Week 24 in the SF-36 health survey physical functioning scale. 10 activities rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Last Observation Carried forward. 26 participants were excluded from the analysis due to lack of baseline or post-baseline SF-36 data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	198
Mean (Standard Deviation) [Units on a scale]	2.88 (7.943)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test on change from Baseline to Week 24

9. Secondary Outcome

Title	Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale
Description	Change from baseline to Week 48 in the SF-36 health survey physical functioning scale. 10 activities are rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General US population mean and standard deviation. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and standard deviation of 10.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Last Observation Carried forward. 25 participants were excluded from the analysis due to lack of baseline or post-baseline SF-36 data.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	199
Mean (Standard Deviation) [Units on a scale]	2.80 (8.634)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test on change from Baseline to Week 48

10. Secondary Outcome

Title	Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24
Description	Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants who were lost to follow-up were censored at the date of last contact.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	224
Number [Percentage of participants]	89.4 39.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	89.4
	Confidence Interval	() 95%; 84.4 to 92.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

11. Secondary Outcome

Title	Percent of Participants With no Clinical Worsening of PH at Week 48
Description	Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants who were lost to follow-up were censored at the date of last contact.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	224
Number [Percentage of participants]	84.1 37.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	84.1
	Confidence Interval	() 95%; 78.2 to 88.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

12. Secondary Outcome

Title	Failure-free Treatment Status
Description	Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	224
Number [Percentage of participants]	95.3 42.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	95.3
	Confidence Interval	() 95%; 91.4 to 97.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

13. Secondary Outcome

Title	Failure-free Treatment Status
Description	Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	224
Number [Percentage of participants]	92.9 41.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	92.9
	Confidence Interval	() 95%; 88.3 to 95.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

14. Secondary Outcome

Title	Monotherapy Treatment Status
Description	Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Subset of participants who were not receiving other PH therapy at baseline.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	107
Number [Percentage of participants]	95.0 42.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	95.0
	Confidence Interval	() 95%; 88.5 to 97.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

15. Secondary Outcome

Title	Monotherapy Treatment Status
Description	Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Subset of participants who were not receiving other PH therapy at baseline.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	107
Number [Percentage of participants]	90.0 40.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	90.0
	Confidence Interval	() 95%; 81.6 to 94.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

16. Secondary Outcome

Title	Long-term Survival
Description	Defined as not dying during study participation
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	224
Number [Percentage of participants]	97.1 43.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	97.1
	Confidence Interval	() 95%; 93.6 to 98.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

17. Secondary Outcome

Title	Long-term Survival
Description	Defined as not dying during study participation
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.

Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	224
Number [Percentage of participants]	95.3 42.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	95.3
	Confidence Interval	() 95%; 91.2 to 97.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimate obtained through Kaplan-Meier methods

Adverse Events

Time Frame	AEs were to be collected during study and up to 72 hours after last dose. SAEs, including deaths, that occurred during the study or within 4 weeks of receiving the last dose of study drug, whether or not related to study drug, were to be reported.
Arm/Group Title	Ambrisentan
Arm/Group Description	Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg).
All Cause Mortality
	Ambrisentan
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ambrisentan
	Affected / at Risk (%)	# Events
Total	97/224 (43.3%)
Blood and lymphatic system disorders
neutropenia	1/224 (0.4%)
anaemia	1/224 (0.4%)
iron deficiency anaemia	1/224 (0.4%)
thrombocytopenia	1/224 (0.4%)
Cardiac disorders
atrial fibrillation	3/224 (1.3%)
atrial flutter	2/224 (0.9%)
atrioventricular block third degree	1/224 (0.4%)
cardiac failure congestive	2/224 (0.9%)
cardio-respiratory arrest	2/224 (0.9%)
left ventricular failure	1/224 (0.4%)
pericardial effusion	1/224 (0.4%)
right ventricular failure	16/224 (7.1%)
cardiac arrest	1/224 (0.4%)
cardiac failure	1/224 (0.4%)
cor pulmonale	2/224 (0.9%)
palpitations	1/224 (0.4%)
supraventricular tachycardia	1/224 (0.4%)
Congenital, familial and genetic disorders
sickle cell anaemia with crisis	1/224 (0.4%)
Gastrointestinal disorders
abdominal pain	3/224 (1.3%)
gastrooesophageal reflux disease	1/224 (0.4%)
diverticular perforation	1/224 (0.4%)
gastrointestinal haemorrhage	1/224 (0.4%)
lower gastrointestinal haemorrhage	1/224 (0.4%)
peritonitis	1/224 (0.4%)
General disorders
drug interaction	1/224 (0.4%)
chest pain	5/224 (2.2%)
drug hypersensitivity	1/224 (0.4%)
face oedema	1/224 (0.4%)
non-cardiac chest pain	1/224 (0.4%)
oedema	1/224 (0.4%)
oedema peripheral	3/224 (1.3%)
Hepatobiliary disorders
autoimmune hepatitis	1/224 (0.4%)
Infections and infestations
abscess limb	2/224 (0.9%)
bronchiectasis	1/224 (0.4%)
bronchitis	2/224 (0.9%)
bronchitis acute	1/224 (0.4%)
cellulitis	2/224 (0.9%)
central line infection	1/224 (0.4%)
device related infection	1/224 (0.4%)
endocarditis	1/224 (0.4%)
enteritis infectious	1/224 (0.4%)
enterobacter infection	1/224 (0.4%)
gastroenteritis viral	1/224 (0.4%)
influenza	1/224 (0.4%)
lower respiratory tract infection	2/224 (0.9%)
pneumonia	15/224 (6.7%)
pneumonia bacterial	1/224 (0.4%)
respiratory tract infection	2/224 (0.9%)
sepsis	4/224 (1.8%)
urinary tract infection	2/224 (0.9%)
appendicitis	2/224 (0.9%)
arthritis infective	1/224 (0.4%)
catheter sepsis	1/224 (0.4%)
gastroenteritis	1/224 (0.4%)
sepsis syndrome	1/224 (0.4%)
septic shock	1/224 (0.4%)
upper respiratory tract infection	2/224 (0.9%)
Injury, poisoning and procedural complications
narcotic intoxication	1/224 (0.4%)
femur fracture	1/224 (0.4%)
spinal compression fracture	1/224 (0.4%)
accidental overdose	2/224 (0.9%)
fall	1/224 (0.4%)
fibula fracture	1/224 (0.4%)
thrombosis in device	1/224 (0.4%)
tibia fracture	1/224 (0.4%)
Investigations
alanine aminotransferase increased	2/224 (0.9%)
aspartate aminotransferase increased	2/224 (0.9%)
international normalised ratio increased	3/224 (1.3%)
blood glucose increased	1/224 (0.4%)
liver function test abnormal	3/224 (1.3%)
transaminase increased	2/224 (0.9%)
hepatic enzyme increased	1/224 (0.4%)
Metabolism and nutrition disorders
dehydration	1/224 (0.4%)
diabetes mellitus inadequate control	1/224 (0.4%)
fluid overload	2/224 (0.9%)
hypervolaemia	1/224 (0.4%)
hypoglycaemia	1/224 (0.4%)
hypokalaemia	3/224 (1.3%)
hyponatraemia	2/224 (0.9%)
diabetes mellitus	1/224 (0.4%)
hyperkalaemia	3/224 (1.3%)
Musculoskeletal and connective tissue disorders
muscle tightness	1/224 (0.4%)
muscular weakness	1/224 (0.4%)
systemic lupus erythematosus	1/224 (0.4%)
fracture nonunion	1/224 (0.4%)
scleroderma	1/224 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
breast cancer	1/224 (0.4%)
lung neoplasm malignant	2/224 (0.9%)
recurrent cancer	1/224 (0.4%)
sedation	1/224 (0.4%)
transitional cell carcinoma	1/224 (0.4%)
tremor	1/224 (0.4%)
Nervous system disorders
cerebrovascular accident	2/224 (0.9%)
dizziness	3/224 (1.3%)
headache	1/224 (0.4%)
migraine	1/224 (0.4%)
migraine with aura	1/224 (0.4%)
syncope	1/224 (0.4%)
presyncope	1/224 (0.4%)
subarachnoid haemorrhage	1/224 (0.4%)
Pregnancy, puerperium and perinatal conditions
pregnancy	1/224 (0.4%)
Psychiatric disorders
mental status changes	1/224 (0.4%)
anxiety	1/224 (0.4%)
confusional state	1/224 (0.4%)
depression	1/224 (0.4%)
nervousness	1/224 (0.4%)
panic attack	1/224 (0.4%)
suicidal ideation	1/224 (0.4%)
suicide attempt	1/224 (0.4%)
Renal and urinary disorders
renal failure	1/224 (0.4%)
renal failure acute	2/224 (0.9%)
renal impairment	1/224 (0.4%)
urinary retention	1/224 (0.4%)
nephrolithiasis	1/224 (0.4%)
renal failure chronic	1/224 (0.4%)
Reproductive system and breast disorders
ovarian cyst ruptured	1/224 (0.4%)
vaginal haemorrhage	1/224 (0.4%)
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease	7/224 (3.1%)
dyspnoea	10/224 (4.5%)
epistaxis	2/224 (0.9%)
haemoptysis	2/224 (0.9%)
hypoventilation	1/224 (0.4%)
hypoxia	4/224 (1.8%)
interstitial lung disease	1/224 (0.4%)
pleural effusion	3/224 (1.3%)
productive cough	1/224 (0.4%)
pulmonary embolism	3/224 (1.3%)
pulmonary fibrosis	4/224 (1.8%)
pulmonary hypertension	8/224 (3.6%)
pulomonary oedema	3/224 (1.3%)
respiratory failure	3/224 (1.3%)
acute respiratory failure	1/224 (0.4%)
pleuritic pain	1/224 (0.4%)
respiratory distress	1/224 (0.4%)
Skin and subcutaneous tissue disorders
skin ulcer	1/224 (0.4%)
Vascular disorders
deep vein thrombosis	1/224 (0.4%)
raynaud's phenomenon	1/224 (0.4%)
shock haemorrhagic	1/224 (0.4%)
hypotension	1/224 (0.4%)
vasculitis	1/224 (0.4%)
Other (Not Including Serious) Adverse Events
	Ambrisentan
	Affected / at Risk (%)	# Events
Total	203/224 (90.6%)
Blood and lymphatic system disorders
anaemia	17/224 (7.6%)
Cardiac disorders
palpitations	17/224 (7.6%)
Gastrointestinal disorders
diarrhoea	22/224 (9.8%)
nausea	33/224 (14.7%)
vomiting	18/224 (8%)
abdominal pain	12/224 (5.4%)
constipation	19/224 (8.5%)
General disorders
fatigue	39/224 (17.4%)
oedema peripheral	95/224 (42.4%)
chest pain	16/224 (7.1%)
pyrexia	12/224 (5.4%)
Infections and infestations
upper respiratory tract infection	54/224 (24.1%)
urinary tract infection	22/224 (9.8%)
bronchitis	17/224 (7.6%)
nasopharyngitis	12/224 (5.4%)
sinusitis	17/224 (7.6%)
Investigations
brain natriuretic peptide increased	18/224 (8%)
international normalised ratio increased	15/224 (6.7%)
Metabolism and nutrition disorders
hypokalemia	19/224 (8.5%)
fluid overload	12/224 (5.4%)
Musculoskeletal and connective tissue disorders
arthralgia	20/224 (8.9%)
back pain	24/224 (10.7%)
pain in extremity	24/224 (10.7%)
Nervous system disorders
dizziness	30/224 (13.4%)
headache	63/224 (28.1%)
Psychiatric disorders
depression	27/224 (12.1%)
insomnia	17/224 (7.6%)
anxiety	12/224 (5.4%)
Respiratory, thoracic and mediastinal disorders
cough	29/224 (12.9%)
dyspnoea	48/224 (21.4%)
nasal congestion	41/224 (18.3%)
epistaxis	16/224 (7.1%)
Skin and subcutaneous tissue disorders
rash	13/224 (5.8%)
Vascular disorders
flushing	16/224 (7.1%)
hypotension	12/224 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PIs have right disclose data upon publication of a multi-center publication coordinated by Sponsor or 18 months after Study is completed at all sites if multi-center publication is not submitted by Sponsor within 12 mos. PI to furnish Sponsor with copy of proposed disclosure at least 90 days prior to proposed disclosure. Sponsor has right to ensure accuracy of disclosure and request deletion of confidential information. Sponsor may not make editorial changes to the results or conclusions.