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

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

Participant Flow

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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

Baseline Characteristics

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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

Sex: Female, Male ^[1]
[Units: Participants]
Count of 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]	Intent-to-Treat Population

Race/Ethnicity, Customized ^[1]
[Units: Participants]

African American/African Heritage

American Indian or Alaskan Native

Asian - Central/South Asian Heritage

Asian - Japanese Heritage

Asian - South East Asian Heritage

Native Hawaiian or Other Pacific Islander

White - Arabic /North African Heritage

White - White/Caucasian/European Heritage

280

131

133

544

Mixed Race

Missing

^[1]	Intent-to-Treat Population

Outcome Measures

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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) ]

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2. Secondary:

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

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3. Secondary:

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

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4. Secondary:

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

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5. Secondary:

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

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6. Secondary:

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

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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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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More Information

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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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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:

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

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

Coghlan JG, Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, Kuwana M, McLaughlin VV, Peacock AJ, Simonneau G, Vachiéry 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.

Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grünig 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. Review.

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT01178073 History of Changes
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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