Hypertension, PulmonaryPhase 3AMBITIONNCT01178073

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

A Phase 3 study testing ambrisentan and tadalafil in people with Hypertension, Pulmonary, run by GlaxoSmithKline at 143 sites in 14 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 75 years
Conditions the study is for: Hypertension, Pulmonary
What is being tested?: ambrisentan and tadalafil
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 610 participants
Where: 143 sitesin 14 countries
Study dates: 1 Oct 2010to 31 Jul 2014
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 75 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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.

Trial locations and contacts

143 sites in 14 countries.

Country

City, postcode or hospital

143 sites in 14 countries

United States61 sites

GSK Investigational Site
Ann Arbor, Michigan, 48109
GSK Investigational Site
Asheville, North Carolina, 28803
GSK Investigational Site
Atlanta, Georgia, 30322
GSK Investigational Site
Aurora, Colorado, 80045
GSK Investigational Site
Baltimore, Maryland, 21201
GSK Investigational Site
Birmingham, Alabama, 35294
GSK Investigational Site
Boston, Massachusetts, 02111
GSK Investigational Site
Boston, Massachusetts, 02115
GSK Investigational Site
Boston, Massachusetts, 02118
GSK Investigational Site
Carmel, Indiana, 46032
GSK Investigational Site
Chapel Hill, North Carolina, 27599
GSK Investigational Site
Charlottesville, Virginia, 22908
GSK Investigational Site
Cincinnati, Ohio, 45219
GSK Investigational Site
Cincinnati, Ohio, 45267
GSK Investigational Site
Cleveland, Ohio, 44195
GSK Investigational Site
Columbus, Ohio, 43221
GSK Investigational Site
Dallas, Texas, 75390
GSK Investigational Site
Decatur, Georgia, 30030
GSK Investigational Site
Detroit, Michigan, 48201
GSK Investigational Site
Gainesville, Florida, 32610
GSK Investigational Site
Houston, Texas, 77030
GSK Investigational Site
Iowa City, Iowa, 52242
GSK Investigational Site
Jacksonville, Florida, 32209
GSK Investigational Site
Kansas City, Kansas, 66160
GSK Investigational Site
Kissimmee, Florida, 34741
GSK Investigational Site
La Jolla, California, 92093
GSK Investigational Site
Los Angeles, California, 90073
GSK Investigational Site
Milwaukee, Wisconsin, 53215
GSK Investigational Site
Mobile, Alabama, 36617
GSK Investigational Site
Morristown, New Jersey, 07962
GSK Investigational Site
Murray, Utah, 84157
GSK Investigational Site
Nashville, Tennessee, 37232
GSK Investigational Site
New Hyde Park, New York, 11040
GSK Investigational Site
New Orleans, Louisiana, 70112
GSK Investigational Site
New York, New York, 10003
GSK Investigational Site
New York, New York, 10019
GSK Investigational Site
New York, New York, 10021
GSK Investigational Site
New York, New York, 10032
GSK Investigational Site
Newark, New Jersey, 07112
GSK Investigational Site
Norfolk, Virginia, 23507
GSK Investigational Site
Oakbrook Terrace, Illinois, 60181
GSK Investigational Site
Omaha, Nebraska, 68131
GSK Investigational Site
Orlando, Florida, 32803
GSK Investigational Site
Philadelphia, Pennsylvania, 19104
GSK Investigational Site
Philadelphia, Pennsylvania, 19140
GSK Investigational Site
Phoenix, Arizona, 85012
GSK Investigational Site
Pittsburgh, Pennsylvania, 15212
GSK Investigational Site
Pittsburgh, Pennsylvania, 15213
GSK Investigational Site
Portland, Maine, 04102
GSK Investigational Site
Portland, Oregon, 97220
GSK Investigational Site
Providence, Rhode Island, 02903
GSK Investigational Site
Richmond, Virginia, 23298
GSK Investigational Site
Rochester, New York, 14623
GSK Investigational Site
Sacramento, California, 95817
GSK Investigational Site
Springfield, Massachusetts, 01199
GSK Investigational Site
St Louis, Missouri, 63110
GSK Investigational Site
Temple, Texas, 76508
GSK Investigational Site
Torrance, California, 90502
GSK Investigational Site
Troy, Michigan, 48085
GSK Investigational Site
Tucson, Arizona, 85724
GSK Investigational Site
Weston, Florida, 33331

Other trials in United States

Germany16 sites

GSK Investigational Site
Berlin, 12559
GSK Investigational Site
Bonn, North Rhine-Westphalia, 53127
GSK Investigational Site
Cologne, North Rhine-Westphalia, 50937
GSK Investigational Site
Dresden, Saxony, 01307
GSK Investigational Site
Freiburg im Breisgau, Baden-Wurttemberg, 79106
GSK Investigational Site
Giessen, Hesse, 35392
GSK Investigational Site
Greifswald, Mecklenburg-Vorpommern, 17475
GSK Investigational Site
Hamburg, 20246
GSK Investigational Site
Hanover, Lower Saxony, 30625
GSK Investigational Site
Heidelberg, Baden-Wurttemberg, 69126
GSK Investigational Site
Homburg, Saarland, 66421
GSK Investigational Site
Leipzig, Saxony, 04103
GSK Investigational Site
Löwenstein, Baden-Wurttemberg, 74245
GSK Investigational Site
Munich, Bavaria, 81377
GSK Investigational Site
Regensburg, Bavaria, 93053
GSK Investigational Site
Würzburg, Bavaria, 97074

Other trials in Germany

Spain14 sites

GSK Investigational Site
Barcelona, 08035
GSK Investigational Site
Barcelona, 08036
GSK Investigational Site
Córdoba, 14004
GSK Investigational Site
L'Hospitalet de Llobregat, 08907
GSK Investigational Site
Madrid, 28034
GSK Investigational Site
Madrid, 28041
GSK Investigational Site
Majadahonda (Madrid), 28222
GSK Investigational Site
Málaga, 29010
GSK Investigational Site
Palma de Mallorca, 07010
GSK Investigational Site
Santander, 39008
GSK Investigational Site
Santiago de Compostela, 15706
GSK Investigational Site
Seville, 41013
GSK Investigational Site
Toledo, 45004
GSK Investigational Site
Valencia, 46026

Other trials in Spain

France11 sites

GSK Investigational Site
Brest, 29200
GSK Investigational Site
Bron, 69677
GSK Investigational Site
La Tronche, 38700
GSK Investigational Site
Le Kremlin-Bicêtre, 94275
GSK Investigational Site
Lille, 59037
GSK Investigational Site
Marseille, 13915
GSK Investigational Site
Montpellier, 34295
GSK Investigational Site
Pessac, 33604
GSK Investigational Site
Saint-Pierre, 97448
GSK Investigational Site
Toulouse, 31059
GSK Investigational Site
Vandœuvre-lès-Nancy, 54511

Other trials in France

Australia6 sites

GSK Investigational Site
Camperdown, New South Wales, 2050
GSK Investigational Site
Chermside, Queensland, 4032
GSK Investigational Site
Darlinghurst, New South Wales, 2010
GSK Investigational Site
Hobart, Tasmania, 7000
GSK Investigational Site
Melbourne, Victoria, 3004
GSK Investigational Site
Perth, Western Australia, 6000

Other trials in Australia

Canada5 sites

GSK Investigational Site
Calgary, Alberta, T1Y 6J4
GSK Investigational Site
Québec, Quebec, G1V 4G5
GSK Investigational Site
Toronto, Ontario, M5G 2N2
GSK Investigational Site
Vancouver, British Columbia, V5Z 1M9
GSK Investigational Site
Winnipeg, Manitoba, R3A 1R8

Other trials in Canada

Italy5 sites

GSK Investigational Site
Bologna, Emilia-Romagna, 40138
GSK Investigational Site
Cagliari, Sardinia, 09134
GSK Investigational Site
Catania, Sicily, 95100
GSK Investigational Site
Pisa, Tuscany, 56124
GSK Investigational Site
Rome, Lazio, 00161

Other trials in Italy

Sweden5 sites

GSK Investigational Site
Gothenburg, SE-413 45
GSK Investigational Site
Linköping, SE-581 85
GSK Investigational Site
Lund, SE-221 85
GSK Investigational Site
Umeå, SE-901 85
GSK Investigational Site
Uppsala, SE-751 85

Other trials in Sweden

United Kingdom5 sites

GSK Investigational Site
Cambridge, Cambridgeshire, CB3 8RE
GSK Investigational Site
Clydebank, G81 4DY
GSK Investigational Site
London, NW3 2QH
GSK Investigational Site
London, SW3 6NP
GSK Investigational Site
Sheffield, S10 2JF

Other trials in United Kingdom

Greece4 sites

GSK Investigational Site
Alexandroupoli, 68100
GSK Investigational Site
Athens, 124 62
GSK Investigational Site
Athens, 176 74
GSK Investigational Site
Thessaloniki, 54636

Other trials in Greece

Japan4 sites

GSK Investigational Site
Fukuoka, 812-8582
GSK Investigational Site
Hokkaido, 060-8648
GSK Investigational Site
Shizuoka, 431-3192
GSK Investigational Site
Tokyo, 113-8655

Other trials in Japan

Netherlands3 sites

GSK Investigational Site
Amsterdam, 1081 HV
GSK Investigational Site
Maastricht, 6229 HX
GSK Investigational Site
Rotterdam, 3015 CE

Other trials in Netherlands

Austria2 sites

GSK Investigational Site
Innsbruck, A-6020
GSK Investigational Site
Vienna, 1090

Other trials in Austria

Belgium2 sites

GSK Investigational Site
Brussels, 1070
GSK Investigational Site
Leuven, 3000

Other trials in Belgium

About this study

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

Conditions: Hypertension, Pulmonary
Being tested: ambrisentan, tadalafil
Keywords: Pulmonary Arterial Hypertension, Ambrisentan, Sponsor Rest of World: GSK, Tadalafil, PAH, Sponsor US: Gilead
Medical subject headings: Hypertension, Pulmonary, Pulmonary Arterial Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ambrisentanDrug
ambrisentan (target dose: 10mg)
tadalafilDrug
tadalafil (target dose: 40mg)

Study groups in NCT01178073
Study group	Role	What they receive
Combination ambrisentan + tadalafil	Active comparator	ambrisentan + tadalafil Receives: Drug: ambrisentan; Drug: tadalafil
Monotherapy ambrisentan	Active comparator	ambrisentan Receives: Drug: ambrisentan
Monotherapy tadalafil	Active comparator	tadalafil Receives: Drug: tadalafil

What is being measured

The primary outcome is the main question the study is designed to answer.

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 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).
Measured: From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)

Secondary outcomes (5)

Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at 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.
Measured: Baseline and Week 24
Percentage of Participants With a Satisfactory Clinical Response at 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.
Measured: Baseline and Week 24
Change From Baseline in the 6 Minute Walk Distance Test at 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.
Measured: Baseline and Week 24
Change From Baseline in the World Health Organization Functional Class at 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.
Measured: Baseline and Week 24
Change From Baseline in Borg Dyspnea Index at 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.
Measured: Baseline (BL) and Week 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Oct 201031 Jul 2014

First posted9 Aug 2010 (estimated)
Study start1 Oct 2010
Primary completion31 Jul 2014
Study completion31 Jul 2014

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (5)Papers the sponsor has linked to this study.
Other trials for Hypertension, PulmonaryStudies of the same condition, open and under way.
More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 610 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01178073
Sponsor's protocol ID: 112565
Acronym: AMBITION
Status last verified: Aug 2017
First submitted: 15 Jul 2010
Last updated: 13 Sep 2017
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Kuwana M, Blair C, Takahashi T, Langley J, Coghlan JG. Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis. Ann Rheum Dis. 2020 May;79(5):626-634. doi: 10.1136/annrheumdis-2019-216274. Epub 2020 Mar 11.
PubMed 32161055
White RJ, Vonk-Noordegraaf A, Rosenkranz S, Oudiz RJ, McLaughlin VV, Hoeper MM, Grunig E, Ghofrani HA, Chakinala MM, Barbera JA, Blair C, Langley J, Frost AE. Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension. Respir Res. 2019 Sep 12;20(1):208. doi: 10.1186/s12931-019-1180-1.
PubMed 31511080
Coghlan JG, Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, Kuwana M, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Blair C, Gillies H, Miller KL, Harris JHN, Langley J, Rubin LJ; AMBITION investigators. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017 Jul;76(7):1219-1227. doi: 10.1136/annrheumdis-2016-210236. Epub 2016 Dec 30.
PubMed 28039187
Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grunig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ; AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687.
PubMed 26308684
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.
PubMed 26196225

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 13 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
ClinicalTrials.gov ID: NCT01178073
Acronym / sponsor ID: AMBITION / 112565
Conditions: Hypertension, Pulmonary
Keywords: Pulmonary Arterial Hypertension, Ambrisentan, Sponsor Rest of World: GSK, Tadalafil, PAH, Sponsor US: Gilead
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 610 participants (actual)
Lead sponsor: GlaxoSmithKlineIndustry (pharma, biotech, devices)
Collaborators: Gilead Sciences
Study start: 1 Oct 2010
Primary completion: 31 Jul 2014 (actual)
Study completion: 31 Jul 2014 (actual)
First posted: 9 Aug 2010 (estimated)
Results: Posted 28 Apr 2015

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
Combination ambrisentan + tadalafil	Active comparator	Drug: ambrisentan, Drug: tadalafilambrisentan + tadalafil
Monotherapy ambrisentan	Active comparator	Drug: ambrisentanambrisentan
Monotherapy tadalafil	Active comparator	Drug: tadalafiltadalafil

Who may qualify

Ages: 18 to 75 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

Subjects must have a diagnosis of Pulmonary Arterial Hypertension (PAH) due to the following:
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:
Subject must walk a distance of ≥125m and ≤500m at the screening visit

Key exclusion criteria (3 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
ambrisentanambrisentan (target dose: 10mg)	Drug	Combination ambrisentan + tadalafil, Monotherapy ambrisentan
tadalafiltadalafil (target dose: 40mg)	Drug	Combination ambrisentan + tadalafil, Monotherapy tadalafil

Primary outcome

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)
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).

5 secondary outcomes

Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24
Time frame: Baseline and Week 24
Percentage of Participants With a Satisfactory Clinical Response at Week 24
Time frame: Baseline and Week 24
Change From Baseline in the 6 Minute Walk Distance Test at Week 24
Time frame: Baseline and Week 24
Change From Baseline in the World Health Organization Functional Class at Week 24
Time frame: Baseline and Week 24
Change From Baseline in Borg Dyspnea Index at Week 24
Time frame: Baseline (BL) and Week 24

Results and safety

Results posted to the registry on 28 Apr 2015, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Combination Therapy: Ambrisentan + Tadalafil	302	240
Ambrisentan Monotherapy	152	108
Tadalafil Monotherapy	151	105

Primary outcome: 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). Number. Unit: Participants

Measure	Combination Therapy: Ambrisentan + Tadalafil n = 253	Monotherapy Pooled: Ambrisentan or Tadalafil n = 247	Ambrisentan Monotherapy n = 126	Tadalafil Monotherapy n = 121
First adjudicated clinical failure event	46	77	43	34
Death (all-cause)	9	8	2	6
Hospitalization for worsening PAH	10	30	18	12
Disease progression	10	16	12	4
Unsatisfactory long-term clinical response	17	23	11	12

Combination Therapy: Ambrisentan + Tadalafil vs Monotherapy Pooled: Ambrisentan or Tadalafil: Hazard Ratio (HR): 0.502 (95% CI 0.348 to 0.724), p = 0.0002, Stratified Log Rank
Combination Therapy: Ambrisentan + Tadalafil vs Ambrisentan Monotherapy: Hazard Ratio (HR): 0.477 (95% CI 0.314 to 0.723), p = 0.0004, Stratified Log Rank
Combination Therapy: Ambrisentan + Tadalafil vs Tadalafil Monotherapy: Hazard Ratio (HR): 0.528 (95% CI 0.338 to 0.827), p = 0.0045, Stratified Log Rank

Population analysed: mITT Population

5 secondary outcomes are reported in the full results.

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).. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Combination Therapy: Ambrisentan + Tadalafil	124 of 302 (41.1%)	279 of 302 (92.4%)	Not reported
Ambrisentan Monotherapy	63 of 152 (41.4%)	140 of 152 (92.1%)	Not reported
Tadalafil Monotherapy	68 of 151 (45%)	135 of 151 (89.4%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2017.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32161055Kuwana M, Blair C, Takahashi T, Langley J, Coghlan JG. Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis. Ann Rheum Dis. 2020 May;79(5):626-634. doi: 10.1136/annrheumdis-2019-216274. Epub 2020 Mar 11.
Derived from this study: PubMed 31511080White RJ, Vonk-Noordegraaf A, Rosenkranz S, Oudiz RJ, McLaughlin VV, Hoeper MM, Grunig E, Ghofrani HA, Chakinala MM, Barbera JA, Blair C, Langley J, Frost AE. Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension. Respir Res. 2019 Sep 12;20(1):208. doi: 10.1186/s12931-019-1180-1.
Derived from this study: PubMed 28039187Coghlan JG, Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, Kuwana M, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Blair C, Gillies H, Miller KL, Harris JHN, Langley J, Rubin LJ; AMBITION investigators. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017 Jul;76(7):1219-1227. doi: 10.1136/annrheumdis-2016-210236. Epub 2016 Dec 30.
Derived from this study: PubMed 26308684Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grunig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ; AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687.
Derived from this study: PubMed 26196225Peacock AJ, Zamboni W, Vizza CD. Ambrisentan for the treatment of adults with pulmonary arterial hypertension: a review. Curr Med Res Opin. 2015;31(9):1793-807. doi: 10.1185/03007995.2015.1074890. Epub 2015 Aug 27.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

GSK Clinical Trials study director

GlaxoSmithKline

143 sites in 14 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing ambrisentan and tadalafil in people with Hypertension, Pulmonary, run by GlaxoSmithKline at 143 sites in 14 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 143 sites in United States, Germany, Spain, France, Australia and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Apr 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01178073, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2017.