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

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Combination Therapy: Ambrisentan + Tadalafil	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.
Ambrisentan Monotherapy	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.
Tadalafil Monotherapy	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.

Participant Flow:   Overall Study

	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
STARTED	302	152	151
COMPLETED	240	108	105
NOT COMPLETED	62	44	46
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

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Combination Therapy: Ambrisentan + Tadalafil	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.
Ambrisentan Monotherapy	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.
Tadalafil Monotherapy	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	Total of all reporting groups

Baseline Measures

	Combination Therapy: Ambrisentan + Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy	Total
Overall Participants Analyzed  [Units: Participants]	302	152	151	605
Age [1]  [Units: Years] Mean (Standard Deviation)	55.9  (13.86)	55.2  (14.41)	55.9  (14.75)	55.7  (14.21)
[1] Intent-to-Treat Population
Gender [1]  [Units: Participants]
Female	223	117	121	461
Male	79	35	30	144
[1] Intent-to-Treat Population
Race/Ethnicity, Customized [1]  [Units: 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] Intent-to-Treat Population

1.  Primary:

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   [ Time Frame: From Baseline up to the Final Assessment Visit (FAV) (average of 609 days) ]

2.  Secondary:

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

3.  Secondary:

Percentage of Participants With a Satisfactory Clinical Response at Week 24   [ Time Frame: Baseline and Week 24 ]

4.  Secondary:

Change From Baseline in the 6 Minute Walk Distance Test at Week 24   [ Time Frame: Baseline and Week 24 ]

5.  Secondary:

Change From Baseline in the World Health Organization Functional Class at Week 24   [ Time Frame: Baseline and Week 24 ]

6.  Secondary:

Change From Baseline in Borg Dyspnea Index at Week 24   [ Time Frame: Baseline (BL) and Week 24 ]

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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