A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH) (AMBITION)

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ClinicalTrials.gov Identifier: NCT01178073

Recruitment Status : Completed

First Posted : August 9, 2010

Results First Posted : April 28, 2015

Last Update Posted : September 13, 2017

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

Gilead Sciences

Information provided by (Responsible Party):

GlaxoSmithKline

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Hypertension, Pulmonary
Interventions	Drug: ambrisentan Drug: tadalafil
Enrollment	610

Participant Flow

Recruitment Details	500 participants (par.) in the ITT Population were also included in the modified ITT Population (those who also met the modified inclusion/exclusion criteria defined in the protocol amendment 2). Disposition results below have been presented for the ITT Population.
Pre-assignment Details	A total of 610 par. were randomized; however, only 605 were included in the Intent-to-Treat (ITT) Population (randomized par. who received at least one dose of IP). All par. received a minimum of 24 weeks of therapy unless they died or withdrew.


Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Period Title: Overall Study
Started	302	152	151
Completed	240	108	105
Not Completed	62	44	46
Reason Not Completed
Adverse Event	34	27	24
Protocol Violation	1	1	1
Lost to Follow-up	2	0	3
Physician Decision	14	10	10
Withdrawal by Subject	10	6	8
Missing Completion Status	1	0	0

Baseline Characteristics

Arm/Group Title		Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy	Total
Arm/Group Description		Participants initially received one...	Participants initially received one...	Participants initially received one...	Total of all reporting groups
Arm/Group Description		Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		302	152	151	605
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous ^[1] Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	302 participants	152 participants	151 participants	605 participants
		55.9 (13.86)	55.2 (14.41)	55.9 (14.75)	55.7 (14.21)
		[1] Measure Description: Intent-to-Treat Population
Sex: Female, Male ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	302 participants	152 participants	151 participants	605 participants
	Female	223 73.8%	117 77.0%	121 80.1%	461 76.2%
	Male	79 26.2%	35 23.0%	30 19.9%	144 23.8%
		[1] Measure Description: Intent-to-Treat Population
Race/Ethnicity, Customized ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	302 participants	152 participants	151 participants	605 participants
African American/African Heritage		11	14	13	38
American Indian or Alaskan Native		2	0	0	2
Asian - Central/South Asian Heritage		1	2	1	4
Asian - Japanese Heritage		3	0	1	4
Asian - South East Asian Heritage		1	2	1	4
Native Hawaiian or Other Pacific Islander		1	0	2	3
White - Arabic /North African Heritage		1	1	0	2
White - White/Caucasian/European Heritage		280	131	133	544
Mixed Race		2	1	0	3
Missing		0	1	0	1
		[1] Measure Description: Intent-to-Treat Population

Outcome Measures

1.Primary Outcome


Title	Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV
Description	Time to the first adjudicated CF event (death, hospitalization for wor...
Description	Time to the first adjudicated CF event (death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) after initiating either first-line combination therapy with AMB and TAD or first-line monotherapy with either drug (AMB or TAD) in par. with PAH was assessed. If data was not available for some par. following a loss to follow-up, their event times were treated as censored at their last assessment time for the statistical analyses. FAV occurred approximately 4 weeks after the predicted 105th adjudicated first CF event was reached. Par. who had an FAV, and who had no adjudicated events or whose first adjudicated event occurred after their FAV, were censored at their individual FAV. Modified Intent-to-Treat (mITT) Population: all randomized par. who met the PAH diagnosis and inclusion/exclusion criteria defined in protocol amendment 2 and who also received at least one dose of investigational product (IP).
Time Frame	From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)

Outcome Measure Data

Analysis Population Description

mITT Population


Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one...	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	253	247	126	121
Measure Type: Number Unit of Measure: Participants
First adjudicated clinical failure event	46	77	43	34
Death (all-cause)	9	8	2	6
Hospitalization for worsening PAH	10	30	18	12
Disease progression	10	16	12	4
Unsatisfactory long-term clinical response	17	23	11	12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.502
	Confidence Interval	(2-Sided) 95% 0.348 to 0.724
	Estimation Comments	Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Monotherapy Pooled: Ambrisentan or Tadalafil.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0004
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.477
	Confidence Interval	(2-Sided) 95% 0.314 to 0.723
	Estimation Comments	Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Ambrisentan Monotherapy.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0045
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.528
	Confidence Interval	(2-Sided) 95% 0.338 to 0.827
	Estimation Comments	Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Tadalafil Monotherapy.

2.Secondary Outcome


Title	Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24
Description	N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate m...
Description	N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate marker of heart failure. The data were log-transformed. The geometric mean was calculated (based on the log-transformed data). The geometric mean ratio was calculated as the ratio between the Week 24 value and the Baseline value (based on the log-transformed data) and presented as percent change = 100 * (geometric mean ratio - 1). The Baseline value is the last value prior to administration of study drug; this may be prior to or on the day of study drug initiation. No imputation was performed for missing data. The secondary endpoints were analyzed according to a pre-specified hierarchical testing procedure.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

mITT Population. Only participants with data available at the specified time points were analyzed.


Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one...	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	204	199	99	100
Mean (Standard Error) Unit of Measure: Percent change
	-67.15 (0.069)	-50.37 (0.070)	-56.15 (0.096)	-43.83 (0.095)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Percent Difference
	Estimated Value	-33.81
	Confidence Interval	(2-Sided) 95% -44.78 to -20.66
	Estimation Comments	Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0111
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Percent Difference
	Estimated Value	-25.09
	Confidence Interval	(2-Sided) 95% -40.04 to -6.40
	Estimation Comments	Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Percent Difference
	Estimated Value	-41.51
	Confidence Interval	(2-Sided) 95% -53.16 to -26.97
	Estimation Comments	Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

3.Secondary Outcome


Title	Percentage of Participants With a Satisfactory Clinical Response at Week 24
Description	A satisfactory clinical response at Week 24 is defined as a participan...
Description	A satisfactory clinical response at Week 24 is defined as a participant who meets all of the following criteria: 10% improvement in 6MWD compared with Baseline; improvement to or maintenance of World Health Organization (WHO) class I or II symptoms; no events of clinical worsening prior to or at the Week 24 visit. Clinical worsening events included: death, hospitalization for pulmonary arterial hypertension (PAH), and disease progression. Participants without an event of clinical worsening prior to or at the Week 24 visit who did not have a 6MWD value or a WHO functional class value at Week 24 were excluded from the analysis.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

mITT Population. Only those participants who had a "Yes"/"No" response were analyzed.


Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one...	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	234	226	113	113
Measure Type: Number Unit of Measure: Percentage of participants
	39	29	31	27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0264
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.563
	Confidence Interval	(2-Sided) 95% 1.054 to 2.319
	Estimation Comments	Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Monotherapy Pooled: Ambrisentan or Tadalafil.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1518
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.424
	Confidence Interval	(2-Sided) 95% 0.878 to 2.308
	Estimation Comments	Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Ambrisentan Monotherapy.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0321
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.723
	Confidence Interval	(2-Sided) 95% 1.047 to 2.833
	Estimation Comments	Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Tadalafil Monotherapy.

4.Secondary Outcome


Title	Change From Baseline in the 6 Minute Walk Distance Test at Week 24
Description	The 6-minute walk distance (6MWD) test measures the distance that a pa...
Description	The 6-minute walk distance (6MWD) test measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned a rank reflecting the relative order of the actual event times. Baseline 6MWD comprised of an average of the last two consecutive measurements prior to randomization that varied by no greater than 10%. If only one measurement was available, that measurement was used. If no two consecutive measures vary by no greater than 10% then Baseline was based on the last two consecutive measures for a participant.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

mITT Population. Only participants with Baseline data were analyzed.


Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one...	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	248	244	124	120
Median (95% Confidence Interval) Unit of Measure: Meters
	48.98 (39.00 to 57.50)	23.80 (19.00 to 33.50)	27.00 (12.50 to 38.00)	22.70 (16.50 to 35.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	22.75
	Confidence Interval	(2-Sided) 95% 12.00 to 33.50
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	24.75
	Confidence Interval	(2-Sided) 95% 11.00 to 38.50
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0030
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	20.85
	Confidence Interval	(2-Sided) 95% 8.00 to 33.70
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

5.Secondary Outcome


Title	Change From Baseline in the World Health Organization Functional Class at Week 24
Description	The WHO Functional Class (FC) indicates the severity of PAH and is an ...
Description	The WHO Functional Class (FC) indicates the severity of PAH and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. There are four grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). Baseline WHO FC is the latest assessment prior to dosing (i.e., at Randomization or Screening). Change from Baseline at Week 24 was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observations was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

mITT Population. Only participants with Baseline data were analyzed.


Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one...	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	252	244	124	120
Median (Inter-Quartile Range) Unit of Measure: Scores on a scale
	0.0 (-1.0 to 0.0)	0.0 (-1.0 to 0.0)	0.0 (-1.0 to 0.0)	0.0 (-1.0 to 0.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2287
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% 0.0 to 0.0
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	This comparison was not formally tested according to the pre-defined hierarchical testing procedure.

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% 0.0 to 0.0
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	This comparison was not formally tested according to the pre-defined hierarchical testing procedure.

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95% 0.0 to 0.0
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

6.Secondary Outcome


Title	Change From Baseline in Borg Dyspnea Index at Week 24
Description	Borg Dyspnea Index (BDI) indicates the degree of breathlessness after ...
Description	Borg Dyspnea Index (BDI) indicates the degree of breathlessness after completion of the 6 minute walk test. The BDI was calculated by using the Borg category (C) ratio (R) CR10 scale which starts at 0 (nothing at all) and has no upper limit (extremely strong). Change from BL was calculated as the Week 24 values minus the BL value. The BDI scale was assessed by each participant. The BL BDI score is the average of the two BDI values obtained following the two 6MWD tests used in determining the BL 6MWD. A negative change from BL in the BDI score represented an improvement for the participant. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
Time Frame	Baseline (BL) and Week 24

Outcome Measure Data

Analysis Population Description

mITT Population. Only participants with Baseline data were analyzed.


Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one...	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	247	244	124	120
Median (Inter-Quartile Range) Unit of Measure: Scores on a scale
	-1.00 (-2.00 to 0.50)	-0.50 (-1.50 to 0.50)	-0.50 (-1.50 to 0.50)	-0.50 (-2.00 to 0.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95% -0.75 to 0.00
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Ambrisentan Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95% -1.00 to 0.00
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Tadalafil Monotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Stratified Wilcoxon Rank Sum Test
	Comments	This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.

Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95% -1.00 to 0.00
	Estimation Comments	Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs were collected from the start of investigational product until 30 days after the last dose of investigational product (average of 639 days on investigational product).
Adverse Event Reporting Description	SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of investigational product. Only AEs for the "On-Randomized Treatment" arms are tabulated.

Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description	Participants initially received one...	Participants initially received one...	Participants initially received one...
Arm/Group Description	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
All-Cause Mortality
	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	124/302 (41.06%)	63/152 (41.45%)	68/151 (45.03%)
Blood and lymphatic system disorders
Anaemia ^† 1	10/302 (3.31%)	3/152 (1.97%)	5/151 (3.31%)
Iron deficiency anaemia ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Anaemia macrocytic ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hypochromic anaemia ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Immune thrombocytopenic purpura ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Spontaneous haematoma ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hyperchromic anaemia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Leukocytosis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Cardiac disorders
Cardiac failure ^† 1	6/302 (1.99%)	6/152 (3.95%)	3/151 (1.99%)
Right ventricular failure ^† 1	5/302 (1.66%)	8/152 (5.26%)	3/151 (1.99%)
Atrial flutter ^† 1	3/302 (0.99%)	1/152 (0.66%)	0/151 (0.00%)
Cardiac failure congestive ^† 1	3/302 (0.99%)	2/152 (1.32%)	1/151 (0.66%)
Angina pectoris ^† 1	2/302 (0.66%)	2/152 (1.32%)	0/151 (0.00%)
Cardiac arrest ^† 1	2/302 (0.66%)	0/152 (0.00%)	2/151 (1.32%)
Coronary artery stenosis ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Supraventricular tachyarrhythmia ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Atrial fibrillation ^† 1	1/302 (0.33%)	1/152 (0.66%)	3/151 (1.99%)
Atrial tachycardia ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Bradycardia ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Cardiac disorder ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Cardiac failure acute ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Cor pulmonale ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Cor pulmonale acute ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Coronary artery occlusion ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Myocardial infarction ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pericardial effusion ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pleuropericarditis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Arrhythmia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Arrhythmia supraventricular ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Atrioventricular block complete ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Atrioventricular block second degree ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Cardiorenal syndrome ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Left ventricular dysfunction ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Mitral valve incompetence ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Nodal arrhythmia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Palpitations ^† 1	0/302 (0.00%)	1/152 (0.66%)	1/151 (0.66%)
Supraventricular extrasystoles ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Supraventricular tachycardia ^† 1	0/302 (0.00%)	0/152 (0.00%)	2/151 (1.32%)
Ear and labyrinth disorders
Sudden hearing loss ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Vertigo ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Endocrine disorders
Diabetes insipidus ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Eye disorders
Retinal vein occlusion ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Retinal detachment ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Gastrointestinal disorders
Gastrointestinal haemorrhage ^† 1	3/302 (0.99%)	3/152 (1.97%)	1/151 (0.66%)
Gastritis ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Ileus ^† 1	2/302 (0.66%)	0/152 (0.00%)	1/151 (0.66%)
Abdominal hernia ^† 1	1/302 (0.33%)	0/152 (0.00%)	1/151 (0.66%)
Abdominal pain upper ^† 1	1/302 (0.33%)	0/152 (0.00%)	1/151 (0.66%)
Duodenogastric reflux ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Epiploic appendagitis ^† 3	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Gastric ulcer ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Gastritis erosive ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Gastrointestinal angiodysplasia ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Gastrointestinal inflammation ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Gastrooesophageal reflux disease ^† 1	1/302 (0.33%)	0/152 (0.00%)	2/151 (1.32%)
Haemorrhoidal haemorrhage ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hiatus hernia ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Large intestinal ulcer ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pancreatitis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Umbilical hernia ^† 1	1/302 (0.33%)	0/152 (0.00%)	1/151 (0.66%)
Upper gastrointestinal haemorrhage ^† 1	1/302 (0.33%)	1/152 (0.66%)	0/151 (0.00%)
Abdominal distension ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Abdominal pain ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Diverticulum ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Melaena ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Oesophageal haemorrhage ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Rectal haemorrhage ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
General disorders
Non-cardiac chest pain ^† 1	7/302 (2.32%)	0/152 (0.00%)	0/151 (0.00%)
Oedema peripheral ^† 1	5/302 (1.66%)	1/152 (0.66%)	0/151 (0.00%)
Pyrexia ^† 1	4/302 (1.32%)	1/152 (0.66%)	1/151 (0.66%)
Death ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
General physical health deterioration ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Generalised oedema ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Asthenia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Chest discomfort ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Chest pain ^† 1	0/302 (0.00%)	0/152 (0.00%)	2/151 (1.32%)
Drug withdrawal syndrome ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Euthanasia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Infusion site phlebitis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Sudden cardiac death ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Hepatobiliary disorders
Cholelithiasis ^† 1	2/302 (0.66%)	1/152 (0.66%)	0/151 (0.00%)
Bile duct stone ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Biliary colic ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Cholecystitis acute ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hepatitis acute ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Cholecystitis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Cholecystitis chronic ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Immune system disorders
Autoimmune disorder ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Infections and infestations
Pneumonia ^† 1	15/302 (4.97%)	10/152 (6.58%)	7/151 (4.64%)
Respiratory tract infection ^† 1	4/302 (1.32%)	1/152 (0.66%)	1/151 (0.66%)
Lung infection ^† 1	3/302 (0.99%)	0/152 (0.00%)	1/151 (0.66%)
Cellulitis ^† 1	2/302 (0.66%)	5/152 (3.29%)	3/151 (1.99%)
Gastroenteritis ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Urinary tract infection ^† 1	2/302 (0.66%)	1/152 (0.66%)	1/151 (0.66%)
Abscess limb ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Bronchitis ^† 1	1/302 (0.33%)	0/152 (0.00%)	3/151 (1.99%)
Catheter site infection ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Conjunctivitis viral ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Diverticulitis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Erysipelas ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hepatitis C ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Infective exacerbation of chronic obstructive airways diseas ^† 2	1/302 (0.33%)	1/152 (0.66%)	0/151 (0.00%)
Influenza ^† 1	1/302 (0.33%)	0/152 (0.00%)	1/151 (0.66%)
Pneumonia bacterial ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pneumonia mycoplasmal ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Postoperative wound infection ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Sepsis ^† 1	1/302 (0.33%)	1/152 (0.66%)	3/151 (1.99%)
Septic shock ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Upper respiratory tract infection ^† 1	1/302 (0.33%)	0/152 (0.00%)	2/151 (1.32%)
Vaginal infection ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Viral infection ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Alveolar osteitis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Bacterial pyelonephritis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Bronchitis viral ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Catheter site cellulitis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Cholecystitis infective ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Escherichia infection ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Herpes zoster ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Infected skin ulcer ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Infection ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Lobar pneumonia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Lower respiratory tract infection ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Necrotising fasciitis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Pyelonephritis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Staphylococcal bacteraemia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
West Nile viral infection ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Wound infection ^† 1	0/302 (0.00%)	1/152 (0.66%)	1/151 (0.66%)
Injury, poisoning and procedural complications
Fall ^† 1	1/302 (0.33%)	0/152 (0.00%)	1/151 (0.66%)
Femoral neck fracture ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hip fracture ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Muscle rupture ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Post procedural complication ^† 1	1/302 (0.33%)	1/152 (0.66%)	1/151 (0.66%)
Spinal fracture ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Subdural haematoma ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Upper limb fracture ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Vascular pseudoaneurysm ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Burns second degree ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Concussion ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Lower limb fracture ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Mountain sickness acute ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Muscle injury ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Post procedural haemorrhage ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Post procedural myocardial infarction ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Radiation pneumonitis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Respiratory fume inhalation disorder ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Tendon rupture ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Toxicity to various agents ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Traumatic ulcer ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Investigations
Transaminases increased ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Blood pressure systolic increased ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Gamma-glutamyltransferase increased ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Oxygen saturation decreased ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Blood potassium decreased ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Metabolism and nutrition disorders
Fluid overload ^† 1	5/302 (1.66%)	1/152 (0.66%)	4/151 (2.65%)
Fluid retention ^† 1	3/302 (0.99%)	0/152 (0.00%)	0/151 (0.00%)
Dehydration ^† 1	1/302 (0.33%)	2/152 (1.32%)	1/151 (0.66%)
Diabetes mellitus ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Electrolyte imbalance ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hypokalaemia ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Diabetic ketoacidosis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Hyperkalaemia ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Hypovolaemia ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Metabolic syndrome ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Musculoskeletal and connective tissue disorders
Osteonecrosis ^† 1	2/302 (0.66%)	1/152 (0.66%)	0/151 (0.00%)
Arthritis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Connective tissue disorder ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Intervertebral disc disorder ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Intervertebral disc protrusion ^† 1	1/302 (0.33%)	1/152 (0.66%)	0/151 (0.00%)
Juvenile idiopathic arthritis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Mixed connective tissue disease ^† 1	1/302 (0.33%)	0/152 (0.00%)	1/151 (0.66%)
Musculoskeletal chest pain ^† 1	1/302 (0.33%)	1/152 (0.66%)	0/151 (0.00%)
Myopathy ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Osteoarthritis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Systemic sclerosis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Back pain ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Chondromalacia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Musculoskeletal pain ^† 1	0/302 (0.00%)	1/152 (0.66%)	1/151 (0.66%)
Myalgia ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Myositis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Periarthritis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Colon adenoma ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Metastases to liver ^† 1	2/302 (0.66%)	1/152 (0.66%)	0/151 (0.00%)
Adenocarcinoma of colon ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Endometrial adenocarcinoma ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Lipoma ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Metastatic neoplasm ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pancreatic carcinoma stage IV ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Prostate cancer ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Salivary gland neoplasm ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Thyroid cancer ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Uterine cancer ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Adenocarcinoma of the cervix ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Basal cell carcinoma ^† 1	0/302 (0.00%)	2/152 (1.32%)	0/151 (0.00%)
Invasive ductal breast carcinoma ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Leukaemia ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Lung neoplasm ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Lung neoplasm malignant ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Nervous system disorders
Syncope ^† 1	9/302 (2.98%)	5/152 (3.29%)	7/151 (4.64%)
Cerebrovascular accident ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Headache ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Presyncope ^† 1	1/302 (0.33%)	2/152 (1.32%)	1/151 (0.66%)
Restless legs syndrome ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Altered state of consciousness ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Carotid artery stenosis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Convulsion ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Dizziness ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Ischaemic stroke ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Somnolence ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Transient ischaemic attack ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Psychiatric disorders
Abnormal behaviour ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Depression ^† 1	1/302 (0.33%)	0/152 (0.00%)	1/151 (0.66%)
Psychotic disorder ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Suicidal ideation ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Renal and urinary disorders
Renal failure acute ^† 1	3/302 (0.99%)	0/152 (0.00%)	1/151 (0.66%)
Renal failure ^† 1	2/302 (0.66%)	2/152 (1.32%)	1/151 (0.66%)
Haematuria ^† 1	0/302 (0.00%)	1/152 (0.66%)	1/151 (0.66%)
Nephrolithiasis ^† 1	0/302 (0.00%)	1/152 (0.66%)	1/151 (0.66%)
Renal impairment ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Reproductive system and breast disorders
Vaginal haemorrhage ^† 1	2/302 (0.66%)	0/152 (0.00%)	0/151 (0.00%)
Ovarian cyst ruptured ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Prostatitis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension ^† 1	11/302 (3.64%)	16/152 (10.53%)	12/151 (7.95%)
Dyspnoea ^† 1	10/302 (3.31%)	2/152 (1.32%)	4/151 (2.65%)
Respiratory failure ^† 1	5/302 (1.66%)	2/152 (1.32%)	1/151 (0.66%)
Pleural effusion ^† 1	4/302 (1.32%)	0/152 (0.00%)	2/151 (1.32%)
Pulmonary oedema ^† 1	4/302 (1.32%)	2/152 (1.32%)	0/151 (0.00%)
Acute respiratory failure ^† 1	3/302 (0.99%)	1/152 (0.66%)	0/151 (0.00%)
Pulmonary embolism ^† 1	3/302 (0.99%)	0/152 (0.00%)	2/151 (1.32%)
Atelectasis ^† 1	2/302 (0.66%)	1/152 (0.66%)	0/151 (0.00%)
Hypoxia ^† 1	2/302 (0.66%)	1/152 (0.66%)	1/151 (0.66%)
Pulmonary arterial hypertension ^† 1	2/302 (0.66%)	1/152 (0.66%)	1/151 (0.66%)
Aspiration ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Chronic obstructive pulmonary disease ^† 1	1/302 (0.33%)	1/152 (0.66%)	1/151 (0.66%)
Chronic respiratory failure ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Interstitial lung disease ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pleurisy ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pleuritic pain ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pneumonia aspiration ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pneumothorax spontaneous ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Pulmonary vasculitis ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Respiratory distress ^† 1	1/302 (0.33%)	1/152 (0.66%)	1/151 (0.66%)
Sleep apnoea syndrome ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Acute pulmonary oedema ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Dyspnoea exertional ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Haemoptysis ^† 1	0/302 (0.00%)	2/152 (1.32%)	0/151 (0.00%)
Hypoventilation ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Lung disorder ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Obliterative bronchiolitis ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Organising pneumonia ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Pulmonary fibrosis ^† 1	0/302 (0.00%)	0/152 (0.00%)	2/151 (1.32%)
Skin and subcutaneous tissue disorders
Rash ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Drug eruption ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Skin ulcer ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Vascular disorders
Hypotension ^† 1	3/302 (0.99%)	2/152 (1.32%)	2/151 (1.32%)
Circulatory collapse ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Venous thrombosis limb ^† 1	1/302 (0.33%)	0/152 (0.00%)	0/151 (0.00%)
Hypertension ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
Hypovolaemic shock ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Subclavian artery stenosis ^† 1	0/302 (0.00%)	1/152 (0.66%)	0/151 (0.00%)
Vascular insufficiency ^† 1	0/302 (0.00%)	0/152 (0.00%)	1/151 (0.66%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA, 16.0 2 Term from vocabulary, RA, 16.0 3 Term from vocabulary, MedDRA
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	279/302 (92.38%)	140/152 (92.11%)	135/151 (89.40%)
Blood and lymphatic system disorders
Anaemia ^† 1	38/302 (12.58%)	8/152 (5.26%)	11/151 (7.28%)
Cardiac disorders
Palpitations ^† 1	33/302 (10.93%)	22/152 (14.47%)	20/151 (13.25%)
Ear and labyrinth disorders
Vertigo ^† 1	5/302 (1.66%)	6/152 (3.95%)	8/151 (5.30%)
Eye disorders
Vision blurred ^† 1	19/302 (6.29%)	8/152 (5.26%)	4/151 (2.65%)
Gastrointestinal disorders
Diarrhoea ^† 1	63/302 (20.86%)	35/152 (23.03%)	26/151 (17.22%)
Nausea ^† 1	47/302 (15.56%)	23/152 (15.13%)	23/151 (15.23%)
Vomiting ^† 1	35/302 (11.59%)	13/152 (8.55%)	13/151 (8.61%)
Dyspepsia ^† 1	32/302 (10.60%)	6/152 (3.95%)	18/151 (11.92%)
Gastrooesophageal reflux disease ^† 1	23/302 (7.62%)	10/152 (6.58%)	15/151 (9.93%)
Constipation ^† 1	17/302 (5.63%)	10/152 (6.58%)	6/151 (3.97%)
Abdominal pain ^† 1	9/302 (2.98%)	9/152 (5.92%)	7/151 (4.64%)
Abdominal pain upper ^† 1	8/302 (2.65%)	6/152 (3.95%)	8/151 (5.30%)
Dry mouth ^† 1	8/302 (2.65%)	11/152 (7.24%)	3/151 (1.99%)
Abdominal distension ^† 1	4/302 (1.32%)	8/152 (5.26%)	11/151 (7.28%)
General disorders
Oedema peripheral ^† 1	133/302 (44.04%)	60/152 (39.47%)	44/151 (29.14%)
Fatigue ^† 1	35/302 (11.59%)	22/152 (14.47%)	20/151 (13.25%)
Non-cardiac chest pain ^† 1	26/302 (8.61%)	14/152 (9.21%)	9/151 (5.96%)
Pyrexia ^† 1	17/302 (5.63%)	6/152 (3.95%)	2/151 (1.32%)
Chest discomfort ^† 1	16/302 (5.30%)	6/152 (3.95%)	5/151 (3.31%)
Asthenia ^† 1	9/302 (2.98%)	4/152 (2.63%)	8/151 (5.30%)
Pain ^† 1	8/302 (2.65%)	2/152 (1.32%)	8/151 (5.30%)
Infections and infestations
Nasopharyngitis ^† 1	51/302 (16.89%)	32/152 (21.05%)	24/151 (15.89%)
Upper respiratory tract infection ^† 1	41/302 (13.58%)	23/152 (15.13%)	22/151 (14.57%)
Bronchitis ^† 1	34/302 (11.26%)	7/152 (4.61%)	10/151 (6.62%)
Urinary tract infection ^† 1	24/302 (7.95%)	12/152 (7.89%)	18/151 (11.92%)
Sinusitis ^† 1	22/302 (7.28%)	11/152 (7.24%)	11/151 (7.28%)
Influenza ^† 1	14/302 (4.64%)	9/152 (5.92%)	7/151 (4.64%)
Metabolism and nutrition disorders
Hypokalaemia ^† 1	17/302 (5.63%)	8/152 (5.26%)	5/151 (3.31%)
Fluid retention ^† 1	16/302 (5.30%)	7/152 (4.61%)	9/151 (5.96%)
Decreased appetite ^† 1	10/302 (3.31%)	9/152 (5.92%)	8/151 (5.30%)
Musculoskeletal and connective tissue disorders
Pain in extremity ^† 1	49/302 (16.23%)	16/152 (10.53%)	22/151 (14.57%)
Back pain ^† 1	43/302 (14.24%)	17/152 (11.18%)	23/151 (15.23%)
Arthralgia ^† 1	41/302 (13.58%)	21/152 (13.82%)	23/151 (15.23%)
Myalgia ^† 1	30/302 (9.93%)	12/152 (7.89%)	18/151 (11.92%)
Muscle spasms ^† 1	25/302 (8.28%)	8/152 (5.26%)	10/151 (6.62%)
Neck pain ^† 1	10/302 (3.31%)	4/152 (2.63%)	8/151 (5.30%)
Nervous system disorders
Headache ^† 1	124/302 (41.06%)	51/152 (33.55%)	55/151 (36.42%)
Dizziness ^† 1	62/302 (20.53%)	31/152 (20.39%)	22/151 (14.57%)
Presyncope ^† 1	11/302 (3.64%)	6/152 (3.95%)	11/151 (7.28%)
Syncope ^† 1	9/302 (2.98%)	4/152 (2.63%)	8/151 (5.30%)
Psychiatric disorders
Insomnia ^† 1	21/302 (6.95%)	6/152 (3.95%)	10/151 (6.62%)
Depression ^† 1	13/302 (4.30%)	3/152 (1.97%)	8/151 (5.30%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion ^† 1	58/302 (19.21%)	25/152 (16.45%)	17/151 (11.26%)
Cough ^† 1	53/302 (17.55%)	20/152 (13.16%)	25/151 (16.56%)
Dyspnoea ^† 1	46/302 (15.23%)	27/152 (17.76%)	28/151 (18.54%)
Epistaxis ^† 1	27/302 (8.94%)	7/152 (4.61%)	15/151 (9.93%)
Sinus congestion ^† 1	18/302 (5.96%)	9/152 (5.92%)	4/151 (2.65%)
Oropharyngeal pain ^† 1	7/302 (2.32%)	9/152 (5.92%)	9/151 (5.96%)
Skin and subcutaneous tissue disorders
Rash ^† 1	24/302 (7.95%)	6/152 (3.95%)	5/151 (3.31%)
Pruritus ^† 1	13/302 (4.30%)	10/152 (6.58%)	6/151 (3.97%)
Vascular disorders
Flushing ^† 1	41/302 (13.58%)	18/152 (11.84%)	15/151 (9.93%)
Hypotension ^† 1	21/302 (6.95%)	8/152 (5.26%)	9/151 (5.96%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA, 16.0

Limitations and Caveats

[Not Specified]

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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.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

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Name/Title:	GSK Response Center
Organization:	GlaxoSmithKline
Phone:	866-435-7343

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kuwana M, Blair C, Takahashi T, Langley J, Coghlan JG. Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis. Ann Rheum Dis. 2020 May;79(5):626-634. doi: 10.1136/annrheumdis-2019-216274. Epub 2020 Mar 11. Erratum In: Ann Rheum Dis. 2020 Sep;79(9):e118.

White RJ, Vonk-Noordegraaf A, Rosenkranz S, Oudiz RJ, McLaughlin VV, Hoeper MM, Grunig E, Ghofrani HA, Chakinala MM, Barbera JA, Blair C, Langley J, Frost AE. Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension. Respir Res. 2019 Sep 12;20(1):208. doi: 10.1186/s12931-019-1180-1.

Coghlan JG, Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, Kuwana M, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Blair C, Gillies H, Miller KL, Harris JHN, Langley J, Rubin LJ; AMBITION investigators. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017 Jul;76(7):1219-1227. doi: 10.1136/annrheumdis-2016-210236. Epub 2016 Dec 30.

Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grunig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ; AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687.

Peacock AJ, Zamboni W, Vizza CD. Ambrisentan for the treatment of adults with pulmonary arterial hypertension: a review. Curr Med Res Opin. 2015;31(9):1793-807. doi: 10.1185/03007995.2015.1074890. Epub 2015 Aug 27.

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Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT01178073
Other Study ID Numbers:	112565
First Submitted:	July 15, 2010
First Posted:	August 9, 2010
Results First Submitted:	March 23, 2015
Results First Posted:	April 28, 2015
Last Update Posted:	September 13, 2017

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