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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01178073
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 610
• Locations: 143
• Arms: 3
• Duration (Months): 46
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the two treatment strategies; first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in subjects with Pulmonary Arterial Hypertension. This will be assessed by time to the first clinical failure event.

Condition or Disease	Intervention/Treatment	Phase
Hypertension, Pulmonary	Drug: ambrisentan; Drug: tadalafil	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 610 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Jul 31, 2014
• Actual Study Completion Date: Jul 31, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Combination ambrisentan + tadalafil ambrisentan + tadalafil	Drug: ambrisentan; ambrisentan (target dose: 10mg); Drug: tadalafil; tadalafil (target dose: 40mg)
Active Comparator: Monotherapy ambrisentan ambrisentan	Drug: ambrisentan; ambrisentan (target dose: 10mg)
Active Comparator: Monotherapy tadalafil tadalafil	Drug: tadalafil; tadalafil (target dose: 40mg)

Outcome Measures

Primary Outcome Measures

1. 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 [From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)]

   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).

Secondary Outcome Measures

1. Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24 [Baseline and Week 24]

   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.

2. Percentage of Participants With a Satisfactory Clinical Response at Week 24 [Baseline and Week 24]

   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.

3. Change From Baseline in the 6 Minute Walk Distance Test at Week 24 [Baseline and Week 24]

   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.

4. Change From Baseline in the World Health Organization Functional Class at Week 24 [Baseline and Week 24]

   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.

5. Change From Baseline in Borg Dyspnea Index at Week 24 [Baseline (BL) and Week 24]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must have a diagnosis of Pulmonary Arterial Hypertension (PAH) due to the following:

1. idiopathic or heritable PAH b. PAH associated with: i. connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed connective tissue disease, systemic lupus erythematosus, or overlap syndrome) ii. drugs or toxins iii. Human Immunodeficiency Virus (HIV) infection iv. congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus) NB: subjects with portopulmonary hypertension and pulmonary veno-occlusive disease are NOT eligible for the study

• Subject must have a current diagnosis of being in World Health Organisation (WHO) Functional Class II or III.

• Subject must meet all of the following haemodynamic criteria by means of a right heart catheterization prior to screening:

1. mPAP of ≥25 mmHg ii. PVR ≥ 300 dynes/sec/cm5 iii. PCWP or LVEDP of ≤12 mmHg if PVR ≥300 to <500 dyne/sec/cm5 , or PCWP/LVEDP ≤ 15 mmHg if PVR ≥500 dynes/sec/cm5

• Subject must walk a distance of ≥125m and ≤500m at the screening visit

Exclusion Criteria:

• Subject received previous PAH therapy (phosphodiesterase type 5 inhibitor (PDE5i), endothelin receptor antagonist (ERA), chronic prostanoid*) within 4 weeks prior to the screening visit (*Chronic prostanoid use is considered >7 days of treatment)

• Subject received ERA treatment (e.g., bosentan or sitaxentan) or PDE5i treatment (e.g. Sildenafil) at any time AND discontinued due to tolerance issues other than those associated with liver function abnormalities

• Subjects who have previously discontinued ambrisentan or tadalafil in either another clinical study or commercial product (Volibris/Letairis or Adcirca) for safety or tolerability reasons.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Birmingham	Alabama	United States	35294
2	GSK Investigational Site	Mobile	Alabama	United States	36617
3	GSK Investigational Site	Phoenix	Arizona	United States	85012
4	GSK Investigational Site	Tucson	Arizona	United States	85724
5	GSK Investigational Site	La Jolla	California	United States	92093
6	GSK Investigational Site	Los Angeles	California	United States	90073
7	GSK Investigational Site	Sacramento	California	United States	95817
8	GSK Investigational Site	Torrance	California	United States	90502
9	GSK Investigational Site	Aurora	Colorado	United States	80045
10	GSK Investigational Site	Gainesville	Florida	United States	32610
11	GSK Investigational Site	Jacksonville	Florida	United States	32209
12	GSK Investigational Site	Kissimmee	Florida	United States	34741
13	GSK Investigational Site	Orlando	Florida	United States	32803
14	GSK Investigational Site	Weston	Florida	United States	33331
15	GSK Investigational Site	Atlanta	Georgia	United States	30322
16	GSK Investigational Site	Decatur	Georgia	United States	30030
17	GSK Investigational Site	Oakbrook Terrace	Illinois	United States	60181
18	GSK Investigational Site	Carmel	Indiana	United States	46032
19	GSK Investigational Site	Iowa City	Iowa	United States	52242
20	GSK Investigational Site	Kansas City	Kansas	United States	66160
21	GSK Investigational Site	New Orleans	Louisiana	United States	70112
22	GSK Investigational Site	Portland	Maine	United States	04102
23	GSK Investigational Site	Baltimore	Maryland	United States	21201
24	GSK Investigational Site	Boston	Massachusetts	United States	02111
25	GSK Investigational Site	Boston	Massachusetts	United States	02115
26	GSK Investigational Site	Boston	Massachusetts	United States	02118
27	GSK Investigational Site	Springfield	Massachusetts	United States	01199
28	GSK Investigational Site	Ann Arbor	Michigan	United States	48109
29	GSK Investigational Site	Detroit	Michigan	United States	48201
30	GSK Investigational Site	Troy	Michigan	United States	48085
31	GSK Investigational Site	Saint Louis	Missouri	United States	63110
32	GSK Investigational Site	Omaha	Nebraska	United States	68131
33	GSK Investigational Site	Morristown	New Jersey	United States	07962
34	GSK Investigational Site	Newark	New Jersey	United States	07112
35	GSK Investigational Site	New Hyde Park	New York	United States	11040
36	GSK Investigational Site	New York	New York	United States	10003
37	GSK Investigational Site	New York	New York	United States	10019
38	GSK Investigational Site	New York	New York	United States	10021
39	GSK Investigational Site	New York	New York	United States	10032
40	GSK Investigational Site	Rochester	New York	United States	14623
41	GSK Investigational Site	Asheville	North Carolina	United States	28803
42	GSK Investigational Site	Chapel Hill	North Carolina	United States	27599
43	GSK Investigational Site	Cincinnati	Ohio	United States	45219
44	GSK Investigational Site	Cincinnati	Ohio	United States	45267
45	GSK Investigational Site	Cleveland	Ohio	United States	44195
46	GSK Investigational Site	Columbus	Ohio	United States	43221
47	GSK Investigational Site	Portland	Oregon	United States	97220
48	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19104
49	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19140
50	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15212
51	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15213
52	GSK Investigational Site	Providence	Rhode Island	United States	02903
53	GSK Investigational Site	Nashville	Tennessee	United States	37232
54	GSK Investigational Site	Dallas	Texas	United States	75390
55	GSK Investigational Site	Houston	Texas	United States	77030
56	GSK Investigational Site	Temple	Texas	United States	76508
57	GSK Investigational Site	Murray	Utah	United States	84157
58	GSK Investigational Site	Charlottesville	Virginia	United States	22908
59	GSK Investigational Site	Norfolk	Virginia	United States	23507
60	GSK Investigational Site	Richmond	Virginia	United States	23298
61	GSK Investigational Site	Milwaukee	Wisconsin	United States	53215
62	GSK Investigational Site	Camperdown	New South Wales	Australia	2050
63	GSK Investigational Site	Darlinghurst	New South Wales	Australia	2010
64	GSK Investigational Site	Chermside	Queensland	Australia	4032
65	GSK Investigational Site	Hobart	Tasmania	Australia	7000
66	GSK Investigational Site	Melbourne	Victoria	Australia	3004
67	GSK Investigational Site	Perth	Western Australia	Australia	6000
68	GSK Investigational Site	Innsbruck		Austria	A-6020
69	GSK Investigational Site	Vienna		Austria	1090
70	GSK Investigational Site	Brussels		Belgium	1070
71	GSK Investigational Site	Leuven		Belgium	3000
72	GSK Investigational Site	Calgary	Alberta	Canada	T1Y 6J4
73	GSK Investigational Site	Vancouver	British Columbia	Canada	V5Z 1M9
74	GSK Investigational Site	Winnipeg	Manitoba	Canada	R3A 1R8
75	GSK Investigational Site	Toronto	Ontario	Canada	M5G 2N2
76	GSK Investigational Site	Quebec City	Quebec	Canada	G1V 4G5
77	GSK Investigational Site	Brest		France	29200
78	GSK Investigational Site	Bron		France	69677
79	GSK Investigational Site	La Tronche		France	38700
80	GSK Investigational Site	Le Kremlin-Bicêtre cedex		France	94275
81	GSK Investigational Site	Lille		France	59037
82	GSK Investigational Site	Marseille cedex 20		France	13915
83	GSK Investigational Site	Montpellier cedex 5		France	34295
84	GSK Investigational Site	Pessac cedex		France	33604
85	GSK Investigational Site	Saint Pierre cedex		France	97448
86	GSK Investigational Site	Toulouse cedex 9		France	31059
87	GSK Investigational Site	Vandoeuvre-les-Nancy		France	54511
88	GSK Investigational Site	Freiburg	Baden-Wuerttemberg	Germany	79106
89	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg	Germany	69126
90	GSK Investigational Site	Loewenstein	Baden-Wuerttemberg	Germany	74245
91	GSK Investigational Site	Muenchen	Bayern	Germany	81377
92	GSK Investigational Site	Regensburg	Bayern	Germany	93053
93	GSK Investigational Site	Wuerzburg	Bayern	Germany	97074
94	GSK Investigational Site	Giessen	Hessen	Germany	35392
95	GSK Investigational Site	Greifswald	Mecklenburg-Vorpommern	Germany	17475
96	GSK Investigational Site	Hannover	Niedersachsen	Germany	30625
97	GSK Investigational Site	Bonn	Nordrhein-Westfalen	Germany	53127
98	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50937
99	GSK Investigational Site	Homburg	Saarland	Germany	66421
100	GSK Investigational Site	Dresden	Sachsen	Germany	01307
101	GSK Investigational Site	Leipzig	Sachsen	Germany	04103
102	GSK Investigational Site	Berlin		Germany	12559
103	GSK Investigational Site	Hamburg		Germany	20246
104	GSK Investigational Site	Alexandroupolis		Greece	68100
105	GSK Investigational Site	Athens		Greece	124 62
106	GSK Investigational Site	Athens		Greece	176 74
107	GSK Investigational Site	Thessaloniki		Greece	54636
108	GSK Investigational Site	Bologna	Emilia-Romagna	Italy	40138
109	GSK Investigational Site	Roma	Lazio	Italy	00161
110	GSK Investigational Site	Cagliari	Sardegna	Italy	09134
111	GSK Investigational Site	Catania	Sicilia	Italy	95100
112	GSK Investigational Site	Pisa	Toscana	Italy	56124
113	GSK Investigational Site	Fukuoka		Japan	812-8582
114	GSK Investigational Site	Hokkaido		Japan	060-8648
115	GSK Investigational Site	Shizuoka		Japan	431-3192
116	GSK Investigational Site	Tokyo		Japan	113-8655
117	GSK Investigational Site	Amsterdam		Netherlands	1081 HV
118	GSK Investigational Site	Maastricht		Netherlands	6229 HX
119	GSK Investigational Site	Rotterdam		Netherlands	3015 CE
120	GSK Investigational Site	Barcelona		Spain	08035
121	GSK Investigational Site	Barcelona		Spain	08036
122	GSK Investigational Site	Córdoba		Spain	14004
123	GSK Investigational Site	L'Hospitalet de Llobregat		Spain	08907
124	GSK Investigational Site	Madrid		Spain	28034
125	GSK Investigational Site	Madrid		Spain	28041
126	GSK Investigational Site	Majadahonda (Madrid)		Spain	28222
127	GSK Investigational Site	Malaga		Spain	29010
128	GSK Investigational Site	Palma de Mallorca		Spain	07010
129	GSK Investigational Site	Santander		Spain	39008
130	GSK Investigational Site	Santiago de Compostela		Spain	15706
131	GSK Investigational Site	Sevilla		Spain	41013
132	GSK Investigational Site	Toledo		Spain	45004
133	GSK Investigational Site	Valencia		Spain	46026
134	GSK Investigational Site	Göteborg		Sweden	SE-413 45
135	GSK Investigational Site	Linköping		Sweden	SE-581 85
136	GSK Investigational Site	Lund		Sweden	SE-221 85
137	GSK Investigational Site	Umeå		Sweden	SE-901 85
138	GSK Investigational Site	Uppsala		Sweden	SE-751 85
139	GSK Investigational Site	Cambridge	Cambridgeshire	United Kingdom	CB3 8RE
140	GSK Investigational Site	Clydebank		United Kingdom	G81 4DY
141	GSK Investigational Site	London		United Kingdom	NW3 2QH
142	GSK Investigational Site	London		United Kingdom	SW3 6NP
143	GSK Investigational Site	Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• GlaxoSmithKline
• Gilead Sciences

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01178073
• Other Study ID Numbers: 112565
• First Posted: Aug 9, 2010
• Last Update Posted: Sep 13, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by GlaxoSmithKline: Pulmonary Arterial Hypertension; Ambrisentan; Sponsor Rest of World: GSK; Tadalafil; PAH; Sponsor US: Gilead
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension; Ambrisentan; Tadalafil

Study Results

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 Detail	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 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

Baseline Characteristics

Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy	Total
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 Participants	302	152	151	605
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.9 (13.86)	55.2 (14.41)	55.9 (14.75)	55.7 (14.21)
Sex: Female, Male (Count of Participants)
Female	223 73.8%	117 77%	121 80.1%	461 76.2%
Male	79 26.2%	35 23%	30 19.9%	144 23.8%
Race/Ethnicity, Customized (Number) [Number]
African American/African Heritage	11 3.6%	14 9.2%	13 8.6%	38 6.3%
American Indian or Alaskan Native	2 0.7%	0 0%	0 0%	2 0.3%
Asian - Central/South Asian Heritage	1 0.3%	2 1.3%	1 0.7%	4 0.7%
Asian - Japanese Heritage	3 1%	0 0%	1 0.7%	4 0.7%
Asian - South East Asian Heritage	1 0.3%	2 1.3%	1 0.7%	4 0.7%
Native Hawaiian or Other Pacific Islander	1 0.3%	0 0%	2 1.3%	3 0.5%
White - Arabic /North African Heritage	1 0.3%	1 0.7%	0 0%	2 0.3%
White - White/Caucasian/European Heritage	280 92.7%	131 86.2%	133 88.1%	544 89.9%
Mixed Race	2 0.7%	1 0.7%	0 0%	3 0.5%
Missing	0 0%	1 0.7%	0 0%	1 0.2%

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 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 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.
Measure Participants	253	247	126	121
First adjudicated clinical failure event	46 15.2%	77 50.7%	43 28.5%	34 5.6%
Death (all-cause)	9 3%	8 5.3%	2 1.3%	6 1%
Hospitalization for worsening PAH	10 3.3%	30 19.7%	18 11.9%	12 2%
Disease progression	10 3.3%	16 10.5%	12 7.9%	4 0.7%
Unsatisfactory long-term clinical response	17 5.6%	23 15.1%	11 7.3%	12 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Stratified Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.502
	Confidence Interval	(2-Sided) 95%; 0.348 to 0.724
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Stratified Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.477
	Confidence Interval	(2-Sided) 95%; 0.314 to 0.723
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	Comments
	Method	Stratified Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.528
	Confidence Interval	(2-Sided) 95%; 0.338 to 0.827
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	204	199	99	100
Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Percent Difference
	Estimated Value	-33.81
	Confidence Interval	(2-Sided) 95%; -44.78 to -20.66
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0111
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Percent Difference
	Estimated Value	-25.09
	Confidence Interval	(2-Sided) 95%; -40.04 to -6.40
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Percent Difference
	Estimated Value	-41.51
	Confidence Interval	(2-Sided) 95%; -53.16 to -26.97
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	234	226	113	113
Number [Percentage of participants]	39 12.9%	29 19.1%	31 20.5%	27 4.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0264
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.563
	Confidence Interval	(2-Sided) 95%; 1.054 to 2.319
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1518
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.424
	Confidence Interval	(2-Sided) 95%; 0.878 to 2.308
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0321
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.723
	Confidence Interval	(2-Sided) 95%; 1.047 to 2.833
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	248	244	124	120
Median (95% Confidence Interval) [Meters]	48.98	23.80	27.00	22.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Stratified Wilcoxon Rank Sum Test
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	22.75
	Confidence Interval	(2-Sided) 95%; 12.00 to 33.50
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Stratified Wilcoxon Rank Sum Test
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	24.75
	Confidence Interval	(2-Sided) 95%; 11.00 to 38.50
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0030
	Comments
	Method	Stratified Wilcoxon Rank Sum Test
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	20.85
	Confidence Interval	(2-Sided) 95%; 8.00 to 33.70
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	252	244	124	120
Median (Inter-Quartile Range) [Scores on a scale]	0.0	0.0	0.0	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2287
	Comments
	Method	Stratified Wilcoxon Rank Sum Test
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; 0.0 to 0.0
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; 0.0 to 0.0
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; 0.0 to 0.0
	Parameter Dispersion	Type: Value:
	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 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 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.
Measure Participants	247	244	124	120
Median (Inter-Quartile Range) [Scores on a scale]	-1.00	-0.50	-0.50	-0.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combination Therapy: Ambrisentan + Tadalafil, Monotherapy Pooled: Ambrisentan or Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.75 to 0.00
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -1.00 to 0.00
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -1.00 to 0.00
	Parameter Dispersion	Type: Value:
	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 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Combination Therapy: Ambrisentan + Tadalafil		Ambrisentan Monotherapy		Tadalafil Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	124/302 (41.1%)		63/152 (41.4%)		68/151 (45%)
Blood and lymphatic system disorders
Anaemia	10/302 (3.3%)		3/152 (2%)		5/151 (3.3%)
Iron deficiency anaemia	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Anaemia macrocytic	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hypochromic anaemia	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Immune thrombocytopenic purpura	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Spontaneous haematoma	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hyperchromic anaemia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Leukocytosis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Cardiac disorders
Cardiac failure	6/302 (2%)		6/152 (3.9%)		3/151 (2%)
Right ventricular failure	5/302 (1.7%)		8/152 (5.3%)		3/151 (2%)
Atrial flutter	3/302 (1%)		1/152 (0.7%)		0/151 (0%)
Cardiac failure congestive	3/302 (1%)		2/152 (1.3%)		1/151 (0.7%)
Angina pectoris	2/302 (0.7%)		2/152 (1.3%)		0/151 (0%)
Cardiac arrest	2/302 (0.7%)		0/152 (0%)		2/151 (1.3%)
Coronary artery stenosis	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Supraventricular tachyarrhythmia	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Atrial fibrillation	1/302 (0.3%)		1/152 (0.7%)		3/151 (2%)
Atrial tachycardia	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Bradycardia	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Cardiac disorder	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Cardiac failure acute	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Cor pulmonale	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Cor pulmonale acute	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Coronary artery occlusion	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Myocardial infarction	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pericardial effusion	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pleuropericarditis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Arrhythmia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Arrhythmia supraventricular	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Atrioventricular block complete	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Atrioventricular block second degree	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Cardiorenal syndrome	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Left ventricular dysfunction	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Mitral valve incompetence	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Nodal arrhythmia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Palpitations	0/302 (0%)		1/152 (0.7%)		1/151 (0.7%)
Supraventricular extrasystoles	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Supraventricular tachycardia	0/302 (0%)		0/152 (0%)		2/151 (1.3%)
Ear and labyrinth disorders
Sudden hearing loss	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Vertigo	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Endocrine disorders
Diabetes insipidus	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Eye disorders
Retinal vein occlusion	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Retinal detachment	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	3/302 (1%)		3/152 (2%)		1/151 (0.7%)
Gastritis	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Ileus	2/302 (0.7%)		0/152 (0%)		1/151 (0.7%)
Abdominal hernia	1/302 (0.3%)		0/152 (0%)		1/151 (0.7%)
Abdominal pain upper	1/302 (0.3%)		0/152 (0%)		1/151 (0.7%)
Duodenogastric reflux	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Epiploic appendagitis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Gastric ulcer	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Gastritis erosive	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Gastrointestinal angiodysplasia	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Gastrointestinal inflammation	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Gastrooesophageal reflux disease	1/302 (0.3%)		0/152 (0%)		2/151 (1.3%)
Haemorrhoidal haemorrhage	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hiatus hernia	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Large intestinal ulcer	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pancreatitis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Umbilical hernia	1/302 (0.3%)		0/152 (0%)		1/151 (0.7%)
Upper gastrointestinal haemorrhage	1/302 (0.3%)		1/152 (0.7%)		0/151 (0%)
Abdominal distension	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Abdominal pain	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Diverticulum	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Melaena	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Oesophageal haemorrhage	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Rectal haemorrhage	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
General disorders
Non-cardiac chest pain	7/302 (2.3%)		0/152 (0%)		0/151 (0%)
Oedema peripheral	5/302 (1.7%)		1/152 (0.7%)		0/151 (0%)
Pyrexia	4/302 (1.3%)		1/152 (0.7%)		1/151 (0.7%)
Death	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
General physical health deterioration	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Generalised oedema	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Asthenia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Chest discomfort	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Chest pain	0/302 (0%)		0/152 (0%)		2/151 (1.3%)
Drug withdrawal syndrome	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Euthanasia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Infusion site phlebitis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Sudden cardiac death	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Hepatobiliary disorders
Cholelithiasis	2/302 (0.7%)		1/152 (0.7%)		0/151 (0%)
Bile duct stone	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Biliary colic	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Cholecystitis acute	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hepatitis acute	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Cholecystitis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Cholecystitis chronic	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Immune system disorders
Autoimmune disorder	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Infections and infestations
Pneumonia	15/302 (5%)		10/152 (6.6%)		7/151 (4.6%)
Respiratory tract infection	4/302 (1.3%)		1/152 (0.7%)		1/151 (0.7%)
Lung infection	3/302 (1%)		0/152 (0%)		1/151 (0.7%)
Cellulitis	2/302 (0.7%)		5/152 (3.3%)		3/151 (2%)
Gastroenteritis	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Urinary tract infection	2/302 (0.7%)		1/152 (0.7%)		1/151 (0.7%)
Abscess limb	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Bronchitis	1/302 (0.3%)		0/152 (0%)		3/151 (2%)
Catheter site infection	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Conjunctivitis viral	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Diverticulitis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Erysipelas	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hepatitis C	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Infective exacerbation of chronic obstructive airways diseas	1/302 (0.3%)		1/152 (0.7%)		0/151 (0%)
Influenza	1/302 (0.3%)		0/152 (0%)		1/151 (0.7%)
Pneumonia bacterial	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pneumonia mycoplasmal	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Postoperative wound infection	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Sepsis	1/302 (0.3%)		1/152 (0.7%)		3/151 (2%)
Septic shock	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Upper respiratory tract infection	1/302 (0.3%)		0/152 (0%)		2/151 (1.3%)
Vaginal infection	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Viral infection	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Alveolar osteitis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Bacterial pyelonephritis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Bronchitis viral	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Catheter site cellulitis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Cholecystitis infective	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Escherichia infection	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Herpes zoster	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Infected skin ulcer	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Infection	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Lobar pneumonia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Lower respiratory tract infection	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Necrotising fasciitis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Pyelonephritis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Staphylococcal bacteraemia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
West Nile viral infection	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Wound infection	0/302 (0%)		1/152 (0.7%)		1/151 (0.7%)
Injury, poisoning and procedural complications
Fall	1/302 (0.3%)		0/152 (0%)		1/151 (0.7%)
Femoral neck fracture	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hip fracture	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Muscle rupture	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Post procedural complication	1/302 (0.3%)		1/152 (0.7%)		1/151 (0.7%)
Spinal fracture	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Subdural haematoma	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Upper limb fracture	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Vascular pseudoaneurysm	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Burns second degree	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Concussion	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Lower limb fracture	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Mountain sickness acute	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Muscle injury	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Post procedural haemorrhage	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Post procedural myocardial infarction	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Radiation pneumonitis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Respiratory fume inhalation disorder	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Tendon rupture	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Toxicity to various agents	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Traumatic ulcer	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Investigations
Transaminases increased	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Blood pressure systolic increased	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Gamma-glutamyltransferase increased	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Oxygen saturation decreased	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Blood potassium decreased	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Metabolism and nutrition disorders
Fluid overload	5/302 (1.7%)		1/152 (0.7%)		4/151 (2.6%)
Fluid retention	3/302 (1%)		0/152 (0%)		0/151 (0%)
Dehydration	1/302 (0.3%)		2/152 (1.3%)		1/151 (0.7%)
Diabetes mellitus	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Electrolyte imbalance	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hypokalaemia	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Diabetic ketoacidosis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Hyperkalaemia	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Hypovolaemia	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Metabolic syndrome	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Musculoskeletal and connective tissue disorders
Osteonecrosis	2/302 (0.7%)		1/152 (0.7%)		0/151 (0%)
Arthritis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Connective tissue disorder	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Intervertebral disc disorder	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Intervertebral disc protrusion	1/302 (0.3%)		1/152 (0.7%)		0/151 (0%)
Juvenile idiopathic arthritis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Mixed connective tissue disease	1/302 (0.3%)		0/152 (0%)		1/151 (0.7%)
Musculoskeletal chest pain	1/302 (0.3%)		1/152 (0.7%)		0/151 (0%)
Myopathy	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Osteoarthritis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Systemic sclerosis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Back pain	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Chondromalacia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Musculoskeletal pain	0/302 (0%)		1/152 (0.7%)		1/151 (0.7%)
Myalgia	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Myositis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Periarthritis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Colon adenoma	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Metastases to liver	2/302 (0.7%)		1/152 (0.7%)		0/151 (0%)
Adenocarcinoma of colon	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Endometrial adenocarcinoma	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Lipoma	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Metastatic neoplasm	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pancreatic carcinoma stage IV	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Prostate cancer	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Salivary gland neoplasm	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Thyroid cancer	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Uterine cancer	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Adenocarcinoma of the cervix	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Basal cell carcinoma	0/302 (0%)		2/152 (1.3%)		0/151 (0%)
Invasive ductal breast carcinoma	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Leukaemia	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Lung neoplasm	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Lung neoplasm malignant	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Nervous system disorders
Syncope	9/302 (3%)		5/152 (3.3%)		7/151 (4.6%)
Cerebrovascular accident	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Headache	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Presyncope	1/302 (0.3%)		2/152 (1.3%)		1/151 (0.7%)
Restless legs syndrome	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Altered state of consciousness	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Carotid artery stenosis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Convulsion	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Dizziness	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Ischaemic stroke	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Somnolence	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Transient ischaemic attack	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Psychiatric disorders
Abnormal behaviour	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Depression	1/302 (0.3%)		0/152 (0%)		1/151 (0.7%)
Psychotic disorder	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Suicidal ideation	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Renal and urinary disorders
Renal failure acute	3/302 (1%)		0/152 (0%)		1/151 (0.7%)
Renal failure	2/302 (0.7%)		2/152 (1.3%)		1/151 (0.7%)
Haematuria	0/302 (0%)		1/152 (0.7%)		1/151 (0.7%)
Nephrolithiasis	0/302 (0%)		1/152 (0.7%)		1/151 (0.7%)
Renal impairment	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	2/302 (0.7%)		0/152 (0%)		0/151 (0%)
Ovarian cyst ruptured	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Prostatitis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension	11/302 (3.6%)		16/152 (10.5%)		12/151 (7.9%)
Dyspnoea	10/302 (3.3%)		2/152 (1.3%)		4/151 (2.6%)
Respiratory failure	5/302 (1.7%)		2/152 (1.3%)		1/151 (0.7%)
Pleural effusion	4/302 (1.3%)		0/152 (0%)		2/151 (1.3%)
Pulmonary oedema	4/302 (1.3%)		2/152 (1.3%)		0/151 (0%)
Acute respiratory failure	3/302 (1%)		1/152 (0.7%)		0/151 (0%)
Pulmonary embolism	3/302 (1%)		0/152 (0%)		2/151 (1.3%)
Atelectasis	2/302 (0.7%)		1/152 (0.7%)		0/151 (0%)
Hypoxia	2/302 (0.7%)		1/152 (0.7%)		1/151 (0.7%)
Pulmonary arterial hypertension	2/302 (0.7%)		1/152 (0.7%)		1/151 (0.7%)
Aspiration	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Chronic obstructive pulmonary disease	1/302 (0.3%)		1/152 (0.7%)		1/151 (0.7%)
Chronic respiratory failure	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Interstitial lung disease	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pleurisy	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pleuritic pain	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pneumonia aspiration	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pneumothorax spontaneous	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Pulmonary vasculitis	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Respiratory distress	1/302 (0.3%)		1/152 (0.7%)		1/151 (0.7%)
Sleep apnoea syndrome	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Acute pulmonary oedema	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Dyspnoea exertional	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Haemoptysis	0/302 (0%)		2/152 (1.3%)		0/151 (0%)
Hypoventilation	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Lung disorder	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Obliterative bronchiolitis	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Organising pneumonia	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Pulmonary fibrosis	0/302 (0%)		0/152 (0%)		2/151 (1.3%)
Skin and subcutaneous tissue disorders
Rash	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Drug eruption	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Skin ulcer	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Vascular disorders
Hypotension	3/302 (1%)		2/152 (1.3%)		2/151 (1.3%)
Circulatory collapse	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Venous thrombosis limb	1/302 (0.3%)		0/152 (0%)		0/151 (0%)
Hypertension	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Hypovolaemic shock	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Subclavian artery stenosis	0/302 (0%)		1/152 (0.7%)		0/151 (0%)
Vascular insufficiency	0/302 (0%)		0/152 (0%)		1/151 (0.7%)
Other (Not Including Serious) Adverse Events
	Combination Therapy: Ambrisentan + Tadalafil		Ambrisentan Monotherapy		Tadalafil Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	279/302 (92.4%)		140/152 (92.1%)		135/151 (89.4%)
Blood and lymphatic system disorders
Anaemia	38/302 (12.6%)		8/152 (5.3%)		11/151 (7.3%)
Cardiac disorders
Palpitations	33/302 (10.9%)		22/152 (14.5%)		20/151 (13.2%)
Ear and labyrinth disorders
Vertigo	5/302 (1.7%)		6/152 (3.9%)		8/151 (5.3%)
Eye disorders
Vision blurred	19/302 (6.3%)		8/152 (5.3%)		4/151 (2.6%)
Gastrointestinal disorders
Diarrhoea	63/302 (20.9%)		35/152 (23%)		26/151 (17.2%)
Nausea	47/302 (15.6%)		23/152 (15.1%)		23/151 (15.2%)
Vomiting	35/302 (11.6%)		13/152 (8.6%)		13/151 (8.6%)
Dyspepsia	32/302 (10.6%)		6/152 (3.9%)		18/151 (11.9%)
Gastrooesophageal reflux disease	23/302 (7.6%)		10/152 (6.6%)		15/151 (9.9%)
Constipation	17/302 (5.6%)		10/152 (6.6%)		6/151 (4%)
Abdominal pain	9/302 (3%)		9/152 (5.9%)		7/151 (4.6%)
Abdominal pain upper	8/302 (2.6%)		6/152 (3.9%)		8/151 (5.3%)
Dry mouth	8/302 (2.6%)		11/152 (7.2%)		3/151 (2%)
Abdominal distension	4/302 (1.3%)		8/152 (5.3%)		11/151 (7.3%)
General disorders
Oedema peripheral	133/302 (44%)		60/152 (39.5%)		44/151 (29.1%)
Fatigue	35/302 (11.6%)		22/152 (14.5%)		20/151 (13.2%)
Non-cardiac chest pain	26/302 (8.6%)		14/152 (9.2%)		9/151 (6%)
Pyrexia	17/302 (5.6%)		6/152 (3.9%)		2/151 (1.3%)
Chest discomfort	16/302 (5.3%)		6/152 (3.9%)		5/151 (3.3%)
Asthenia	9/302 (3%)		4/152 (2.6%)		8/151 (5.3%)
Pain	8/302 (2.6%)		2/152 (1.3%)		8/151 (5.3%)
Infections and infestations
Nasopharyngitis	51/302 (16.9%)		32/152 (21.1%)		24/151 (15.9%)
Upper respiratory tract infection	41/302 (13.6%)		23/152 (15.1%)		22/151 (14.6%)
Bronchitis	34/302 (11.3%)		7/152 (4.6%)		10/151 (6.6%)
Urinary tract infection	24/302 (7.9%)		12/152 (7.9%)		18/151 (11.9%)
Sinusitis	22/302 (7.3%)		11/152 (7.2%)		11/151 (7.3%)
Influenza	14/302 (4.6%)		9/152 (5.9%)		7/151 (4.6%)
Metabolism and nutrition disorders
Hypokalaemia	17/302 (5.6%)		8/152 (5.3%)		5/151 (3.3%)
Fluid retention	16/302 (5.3%)		7/152 (4.6%)		9/151 (6%)
Decreased appetite	10/302 (3.3%)		9/152 (5.9%)		8/151 (5.3%)
Musculoskeletal and connective tissue disorders
Pain in extremity	49/302 (16.2%)		16/152 (10.5%)		22/151 (14.6%)
Back pain	43/302 (14.2%)		17/152 (11.2%)		23/151 (15.2%)
Arthralgia	41/302 (13.6%)		21/152 (13.8%)		23/151 (15.2%)
Myalgia	30/302 (9.9%)		12/152 (7.9%)		18/151 (11.9%)
Muscle spasms	25/302 (8.3%)		8/152 (5.3%)		10/151 (6.6%)
Neck pain	10/302 (3.3%)		4/152 (2.6%)		8/151 (5.3%)
Nervous system disorders
Headache	124/302 (41.1%)		51/152 (33.6%)		55/151 (36.4%)
Dizziness	62/302 (20.5%)		31/152 (20.4%)		22/151 (14.6%)
Presyncope	11/302 (3.6%)		6/152 (3.9%)		11/151 (7.3%)
Syncope	9/302 (3%)		4/152 (2.6%)		8/151 (5.3%)
Psychiatric disorders
Insomnia	21/302 (7%)		6/152 (3.9%)		10/151 (6.6%)
Depression	13/302 (4.3%)		3/152 (2%)		8/151 (5.3%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	58/302 (19.2%)		25/152 (16.4%)		17/151 (11.3%)
Cough	53/302 (17.5%)		20/152 (13.2%)		25/151 (16.6%)
Dyspnoea	46/302 (15.2%)		27/152 (17.8%)		28/151 (18.5%)
Epistaxis	27/302 (8.9%)		7/152 (4.6%)		15/151 (9.9%)
Sinus congestion	18/302 (6%)		9/152 (5.9%)		4/151 (2.6%)
Oropharyngeal pain	7/302 (2.3%)		9/152 (5.9%)		9/151 (6%)
Skin and subcutaneous tissue disorders
Rash	24/302 (7.9%)		6/152 (3.9%)		5/151 (3.3%)
Pruritus	13/302 (4.3%)		10/152 (6.6%)		6/151 (4%)
Vascular disorders
Flushing	41/302 (13.6%)		18/152 (11.8%)		15/151 (9.9%)
Hypotension	21/302 (7%)		8/152 (5.3%)		9/151 (6%)

Limitations/Caveats

[Not Specified]

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

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.