Safety and Efficacy Study of Ambrisentan in Subjects With Pulmonary Hypertension

• ClinicalTrials.gov Identifier: NCT00380068
• Recruitment Status: Completed
• First Posted: September 25, 2006
• Results First Posted: November 19, 2010
• Last Update Posted: April 5, 2012
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pulmonary Hypertension
• Intervention: Drug: Ambrisentan
• Enrollment: 224

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 Details	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
Reason Not Completed
Adverse Event	40
Withdrawal by Subject	10
Not compliant	6
Lost to Follow-up	1
Addition of other PAH therapeutic agent	1
Lung transplant	3
Physician Decision	2
Partipant moved away	1
Lack of Efficacy	5

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 Number of Baseline Participants		224
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	224 participants
		55 (16)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	224 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)
Description	[Not Specified]
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).
Overall Number of Participants Analyzed	220
Mean (Standard Deviation); Unit of Measure: meters
	20.5 (65.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	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	[Not Specified]

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).
Overall Number of Participants Analyzed	220
Mean (Standard Deviation); Unit of Measure: Units on a scale
	-0.5 (2.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	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	[Not Specified]

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).
Overall Number of Participants Analyzed	110
Mean (Standard Deviation); Unit of Measure: Units on a scale
	-0.6 (1.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	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
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP)
Description	[Not Specified]
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).
Overall Number of Participants Analyzed	214
Geometric Mean (95% Confidence Interval); Unit of Measure: Percent change in BNP
	-25.5; (-33.6 to -16.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent change from baseline
	Estimated Value	-25.5
	Confidence Interval	95%; -33.6 to -16.3
	Estimation Comments	Percent change from baseline derived from Geometric Mean Ratio

5. Secondary Outcome

Title	Percent Change From Baseline to Week 48 in BNP
Description	[Not Specified]
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).
Overall Number of Participants Analyzed	112
Geometric Mean (95% Confidence Interval); Unit of Measure: Percent change in BNP
	-29.2; (-39.8 to -16.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent change from baseline
	Estimated Value	-29.2
	Confidence Interval	95%; -39.8 to -16.6
	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).
Overall Number of Participants Analyzed	221
Measure Type: Number; Unit of Measure: Percentage of participants
-3	0
-2	0.9
-1	22.2
0	70.1
1	6.8
2	0
3	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

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).
Overall Number of Participants Analyzed	119
Measure Type: Number; Unit of Measure: Percentage of participants
-3	0
-2	1.7
-1	34.5
0	57.1
1	6.7
2	0
3	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
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	[Not Specified]

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).
Overall Number of Participants Analyzed	198
Mean (Standard Deviation); Unit of Measure: Units on a scale
	2.88 (7.943)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	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).
Overall Number of Participants Analyzed	199
Mean (Standard Deviation); Unit of Measure: Units on a scale
	2.80 (8.634)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	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).
Overall Number of Participants Analyzed	224
Measure Type: Number; Unit of Measure: Percentage of participants
	89.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	89.4
	Confidence Interval	95%; 84.4 to 92.8
	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).
Overall Number of Participants Analyzed	224
Measure Type: Number; Unit of Measure: Percentage of participants
	84.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	84.1
	Confidence Interval	95%; 78.2 to 88.6
	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).
Overall Number of Participants Analyzed	224
Measure Type: Number; Unit of Measure: Percentage of participants
	95.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	95.3
	Confidence Interval	95%; 91.4 to 97.4
	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).
Overall Number of Participants Analyzed	224
Measure Type: Number; Unit of Measure: Percentage of participants
	92.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	92.9
	Confidence Interval	95%; 88.3 to 95.8
	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).
Overall Number of Participants Analyzed	107
Measure Type: Number; Unit of Measure: Percentage of participants
	95.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	95.0
	Confidence Interval	95%; 88.5 to 97.9
	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).
Overall Number of Participants Analyzed	107
Measure Type: Number; Unit of Measure: Percentage of participants
	90.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	90.0
	Confidence Interval	95%; 81.6 to 94.7
	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).
Overall Number of Participants Analyzed	224
Measure Type: Number; Unit of Measure: Percentage of participants
	97.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	97.1
	Confidence Interval	95%; 93.6 to 98.7
	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).
Overall Number of Participants Analyzed	224
Measure Type: Number; Unit of Measure: Percentage of participants
	95.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	percent event free
	Estimated Value	95.3
	Confidence Interval	95%; 91.2 to 97.6
	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.
Adverse Event Reporting Description	[Not Specified]
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 (%)
Total	--/--
Serious Adverse Events
	Ambrisentan
	Affected / at Risk (%)
Total	97/224 (43.30%)
Blood and lymphatic system disorders
neutropenia † 1	1/224 (0.45%)
anaemia † 1	1/224 (0.45%)
iron deficiency anaemia † 1	1/224 (0.45%)
thrombocytopenia † 1	1/224 (0.45%)
Cardiac disorders
atrial fibrillation † 1	3/224 (1.34%)
atrial flutter † 1	2/224 (0.89%)
atrioventricular block third degree † 1	1/224 (0.45%)
cardiac failure congestive † 1	2/224 (0.89%)
cardio-respiratory arrest † 1	2/224 (0.89%)
left ventricular failure † 1	1/224 (0.45%)
pericardial effusion † 1	1/224 (0.45%)
right ventricular failure † 1	16/224 (7.14%)
cardiac arrest † 1	1/224 (0.45%)
cardiac failure † 1	1/224 (0.45%)
cor pulmonale † 1	2/224 (0.89%)
palpitations † 1	1/224 (0.45%)
supraventricular tachycardia † 1	1/224 (0.45%)
Congenital, familial and genetic disorders
sickle cell anaemia with crisis † 1	1/224 (0.45%)
Gastrointestinal disorders
abdominal pain † 1	3/224 (1.34%)
gastrooesophageal reflux disease † 1	1/224 (0.45%)
diverticular perforation † 1	1/224 (0.45%)
gastrointestinal haemorrhage † 1	1/224 (0.45%)
lower gastrointestinal haemorrhage † 1	1/224 (0.45%)
peritonitis † 1	1/224 (0.45%)
General disorders
drug interaction † 1	1/224 (0.45%)
chest pain † 1	5/224 (2.23%)
drug hypersensitivity † 1	1/224 (0.45%)
face oedema † 1	1/224 (0.45%)
non-cardiac chest pain † 1	1/224 (0.45%)
oedema † 1	1/224 (0.45%)
oedema peripheral † 1	3/224 (1.34%)
Hepatobiliary disorders
autoimmune hepatitis † 1	1/224 (0.45%)
Infections and infestations
abscess limb † 1	2/224 (0.89%)
bronchiectasis † 1	1/224 (0.45%)
bronchitis † 1	2/224 (0.89%)
bronchitis acute † 1	1/224 (0.45%)
cellulitis † 1	2/224 (0.89%)
central line infection † 1	1/224 (0.45%)
device related infection † 1	1/224 (0.45%)
endocarditis † 1	1/224 (0.45%)
enteritis infectious † 1	1/224 (0.45%)
enterobacter infection † 1	1/224 (0.45%)
gastroenteritis viral † 1	1/224 (0.45%)
influenza † 1	1/224 (0.45%)
lower respiratory tract infection † 1	2/224 (0.89%)
pneumonia † 1	15/224 (6.70%)
pneumonia bacterial † 1	1/224 (0.45%)
respiratory tract infection † 1	2/224 (0.89%)
sepsis † 1	4/224 (1.79%)
urinary tract infection † 1	2/224 (0.89%)
appendicitis † 1	2/224 (0.89%)
arthritis infective † 1	1/224 (0.45%)
catheter sepsis † 1	1/224 (0.45%)
gastroenteritis † 1	1/224 (0.45%)
sepsis syndrome † 1	1/224 (0.45%)
septic shock † 1	1/224 (0.45%)
upper respiratory tract infection † 1	2/224 (0.89%)
Injury, poisoning and procedural complications
narcotic intoxication † 1	1/224 (0.45%)
femur fracture † 1	1/224 (0.45%)
spinal compression fracture † 1	1/224 (0.45%)
accidental overdose † 1	2/224 (0.89%)
fall † 1	1/224 (0.45%)
fibula fracture † 1	1/224 (0.45%)
thrombosis in device † 1	1/224 (0.45%)
tibia fracture † 1	1/224 (0.45%)
Investigations
alanine aminotransferase increased † 1	2/224 (0.89%)
aspartate aminotransferase increased † 1	2/224 (0.89%)
international normalised ratio increased † 1	3/224 (1.34%)
blood glucose increased † 1	1/224 (0.45%)
liver function test abnormal † 1	3/224 (1.34%)
transaminase increased † 1	2/224 (0.89%)
hepatic enzyme increased † 1	1/224 (0.45%)
Metabolism and nutrition disorders
dehydration † 1	1/224 (0.45%)
diabetes mellitus inadequate control † 1	1/224 (0.45%)
fluid overload † 1	2/224 (0.89%)
hypervolaemia † 1	1/224 (0.45%)
hypoglycaemia † 1	1/224 (0.45%)
hypokalaemia † 1	3/224 (1.34%)
hyponatraemia † 1	2/224 (0.89%)
diabetes mellitus † 1	1/224 (0.45%)
hyperkalaemia † 1	3/224 (1.34%)
Musculoskeletal and connective tissue disorders
muscle tightness † 1	1/224 (0.45%)
muscular weakness † 1	1/224 (0.45%)
systemic lupus erythematosus † 1	1/224 (0.45%)
fracture nonunion † 1	1/224 (0.45%)
scleroderma † 1	1/224 (0.45%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
breast cancer † 1	1/224 (0.45%)
lung neoplasm malignant † 1	2/224 (0.89%)
recurrent cancer † 1	1/224 (0.45%)
sedation † 1	1/224 (0.45%)
transitional cell carcinoma † 1	1/224 (0.45%)
tremor † 1	1/224 (0.45%)
Nervous system disorders
cerebrovascular accident † 1	2/224 (0.89%)
dizziness † 1	3/224 (1.34%)
headache † 1	1/224 (0.45%)
migraine † 1	1/224 (0.45%)
migraine with aura † 1	1/224 (0.45%)
syncope † 1	1/224 (0.45%)
presyncope † 1	1/224 (0.45%)
subarachnoid haemorrhage † 1	1/224 (0.45%)
Pregnancy, puerperium and perinatal conditions
pregnancy † 1	1/224 (0.45%)
Psychiatric disorders
mental status changes † 1	1/224 (0.45%)
anxiety † 1	1/224 (0.45%)
confusional state † 1	1/224 (0.45%)
depression † 1	1/224 (0.45%)
nervousness † 1	1/224 (0.45%)
panic attack † 1	1/224 (0.45%)
suicidal ideation † 1	1/224 (0.45%)
suicide attempt † 1	1/224 (0.45%)
Renal and urinary disorders
renal failure † 1	1/224 (0.45%)
renal failure acute † 1	2/224 (0.89%)
renal impairment † 1	1/224 (0.45%)
urinary retention † 1	1/224 (0.45%)
nephrolithiasis † 1	1/224 (0.45%)
renal failure chronic † 1	1/224 (0.45%)
Reproductive system and breast disorders
ovarian cyst ruptured † 1	1/224 (0.45%)
vaginal haemorrhage † 1	1/224 (0.45%)
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease † 1	7/224 (3.13%)
dyspnoea † 1	10/224 (4.46%)
epistaxis † 1	2/224 (0.89%)
haemoptysis † 1	2/224 (0.89%)
hypoventilation † 1	1/224 (0.45%)
hypoxia † 1	4/224 (1.79%)
interstitial lung disease † 1	1/224 (0.45%)
pleural effusion † 1	3/224 (1.34%)
productive cough † 1	1/224 (0.45%)
pulmonary embolism † 1	3/224 (1.34%)
pulmonary fibrosis † 1	4/224 (1.79%)
pulmonary hypertension † 1	8/224 (3.57%)
pulomonary oedema † 1	3/224 (1.34%)
respiratory failure † 1	3/224 (1.34%)
acute respiratory failure † 1	1/224 (0.45%)
pleuritic pain † 1	1/224 (0.45%)
respiratory distress † 1	1/224 (0.45%)
Skin and subcutaneous tissue disorders
skin ulcer † 1	1/224 (0.45%)
Vascular disorders
deep vein thrombosis † 1	1/224 (0.45%)
raynaud's phenomenon † 1	1/224 (0.45%)
shock haemorrhagic † 1	1/224 (0.45%)
hypotension † 1	1/224 (0.45%)
vasculitis † 1	1/224 (0.45%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (9.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ambrisentan
	Affected / at Risk (%)
Total	203/224 (90.63%)
Blood and lymphatic system disorders
anaemia † 1	17/224 (7.59%)
Cardiac disorders
palpitations † 1	17/224 (7.59%)
Gastrointestinal disorders
diarrhoea † 1	22/224 (9.82%)
nausea † 1	33/224 (14.73%)
vomiting † 1	18/224 (8.04%)
abdominal pain † 1	12/224 (5.36%)
constipation † 1	19/224 (8.48%)
General disorders
fatigue † 1	39/224 (17.41%)
oedema peripheral † 1	95/224 (42.41%)
chest pain † 1	16/224 (7.14%)
pyrexia † 1	12/224 (5.36%)
Infections and infestations
upper respiratory tract infection † 1	54/224 (24.11%)
urinary tract infection † 1	22/224 (9.82%)
bronchitis † 1	17/224 (7.59%)
nasopharyngitis † 1	12/224 (5.36%)
sinusitis † 1	17/224 (7.59%)
Investigations
brain natriuretic peptide increased † 1	18/224 (8.04%)
international normalised ratio increased † 1	15/224 (6.70%)
Metabolism and nutrition disorders
hypokalemia † 1	19/224 (8.48%)
fluid overload † 1	12/224 (5.36%)
Musculoskeletal and connective tissue disorders
arthralgia † 1	20/224 (8.93%)
back pain † 1	24/224 (10.71%)
pain in extremity † 1	24/224 (10.71%)
Nervous system disorders
dizziness † 1	30/224 (13.39%)
headache † 1	63/224 (28.13%)
Psychiatric disorders
depression † 1	27/224 (12.05%)
insomnia † 1	17/224 (7.59%)
anxiety † 1	12/224 (5.36%)
Respiratory, thoracic and mediastinal disorders
cough † 1	29/224 (12.95%)
dyspnoea † 1	48/224 (21.43%)
nasal congestion † 1	41/224 (18.30%)
epistaxis † 1	16/224 (7.14%)
Skin and subcutaneous tissue disorders
rash † 1	13/224 (5.80%)
Vascular disorders
flushing † 1	16/224 (7.14%)
hypotension † 1	12/224 (5.36%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (9.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Martine Allard, PhD; Senior Clinical Research Scientist
• Organization: Gilead Sciences Inc
• Phone: 650-524-3898
• EMail: martine.allard@gilead.com

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00380068
• Other Study ID Numbers: AMB-323; ARIES-3
• First Submitted: September 21, 2006
• First Posted: September 25, 2006
• Results First Submitted: July 10, 2009
• Results First Posted: November 19, 2010
• Last Update Posted: April 5, 2012