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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertension, Pulmonary
• Intervention / Treatment: Drug: ambrisentan; Drug: tadalafil

• Study Type: Interventional
• Enrollment (Actual): 610
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • GSK Investigational Site
    • Darlinghurst, New South Wales, Australia, 2010
      • GSK Investigational Site
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • GSK Investigational Site
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • GSK Investigational Site
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • GSK Investigational Site
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • GSK Investigational Site
• Austria
  • Innsbruck, Austria, A-6020
    • GSK Investigational Site
  • Vienna, Austria, 1090
    • GSK Investigational Site
• Belgium
  • Brussels, Belgium, 1070
    • GSK Investigational Site
  • Leuven, Belgium, 3000
    • GSK Investigational Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • GSK Investigational Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • GSK Investigational Site
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R8
      • GSK Investigational Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • GSK Investigational Site
  • Quebec
    • Quebec City, Quebec, Canada, G1V 4G5
      • GSK Investigational Site
• France
  • Brest, France, 29200
    • GSK Investigational Site
  • Bron, France, 69677
    • GSK Investigational Site
  • La Tronche, France, 38700
    • GSK Investigational Site
  • Le Kremlin-Bicêtre cedex, France, 94275
    • GSK Investigational Site
  • Lille, France, 59037
    • GSK Investigational Site
  • Marseille cedex 20, France, 13915
    • GSK Investigational Site
  • Montpellier cedex 5, France, 34295
    • GSK Investigational Site
  • Pessac cedex, France, 33604
    • GSK Investigational Site
  • Saint Pierre cedex, France, 97448
    • GSK Investigational Site
  • Toulouse cedex 9, France, 31059
    • GSK Investigational Site
  • Vandoeuvre-les-Nancy, France, 54511
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 12559
    • GSK Investigational Site
  • Hamburg, Germany, 20246
    • GSK Investigational Site
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • GSK Investigational Site
    • Heidelberg, Baden-Wuerttemberg, Germany, 69126
      • GSK Investigational Site
    • Loewenstein, Baden-Wuerttemberg, Germany, 74245
      • GSK Investigational Site
  • Bayern
    • Muenchen, Bayern, Germany, 81377
      • GSK Investigational Site
    • Regensburg, Bayern, Germany, 93053
      • GSK Investigational Site
    • Wuerzburg, Bayern, Germany, 97074
      • GSK Investigational Site
  • Hessen
    • Giessen, Hessen, Germany, 35392
      • GSK Investigational Site
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17475
      • GSK Investigational Site
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • GSK Investigational Site
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • GSK Investigational Site
  • Saarland
    • Homburg, Saarland, Germany, 66421
      • GSK Investigational Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • GSK Investigational Site
    • Leipzig, Sachsen, Germany, 04103
      • GSK Investigational Site
• Greece
  • Alexandroupolis, Greece, 68100
    • GSK Investigational Site
  • Athens, Greece, 124 62
    • GSK Investigational Site
  • Athens, Greece, 176 74
    • GSK Investigational Site
  • Thessaloniki, Greece, 54636
    • GSK Investigational Site
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • GSK Investigational Site
  • Lazio
    • Roma, Lazio, Italy, 00161
      • GSK Investigational Site
  • Sardegna
    • Cagliari, Sardegna, Italy, 09134
      • GSK Investigational Site
  • Sicilia
    • Catania, Sicilia, Italy, 95100
      • GSK Investigational Site
  • Toscana
    • Pisa, Toscana, Italy, 56124
      • GSK Investigational Site
• Japan
  • Fukuoka, Japan, 812-8582
    • GSK Investigational Site
  • Hokkaido, Japan, 060-8648
    • GSK Investigational Site
  • Shizuoka, Japan, 431-3192
    • GSK Investigational Site
  • Tokyo, Japan, 113-8655
    • GSK Investigational Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • GSK Investigational Site
  • Maastricht, Netherlands, 6229 HX
    • GSK Investigational Site
  • Rotterdam, Netherlands, 3015 CE
    • GSK Investigational Site
• Spain
  • Barcelona, Spain, 08036
    • GSK Investigational Site
  • Barcelona, Spain, 08035
    • GSK Investigational Site
  • Córdoba, Spain, 14004
    • GSK Investigational Site
  • L'Hospitalet de Llobregat, Spain, 08907
    • GSK Investigational Site
  • Madrid, Spain, 28041
    • GSK Investigational Site
  • Madrid, Spain, 28034
    • GSK Investigational Site
  • Majadahonda (Madrid), Spain, 28222
    • GSK Investigational Site
  • Malaga, Spain, 29010
    • GSK Investigational Site
  • Palma de Mallorca, Spain, 07010
    • GSK Investigational Site
  • Santander, Spain, 39008
    • GSK Investigational Site
  • Santiago de Compostela, Spain, 15706
    • GSK Investigational Site
  • Sevilla, Spain, 41013
    • GSK Investigational Site
  • Toledo, Spain, 45004
    • GSK Investigational Site
  • Valencia, Spain, 46026
    • GSK Investigational Site
• Sweden
  • Göteborg, Sweden, SE-413 45
    • GSK Investigational Site
  • Linköping, Sweden, SE-581 85
    • GSK Investigational Site
  • Lund, Sweden, SE-221 85
    • GSK Investigational Site
  • Umeå, Sweden, SE-901 85
    • GSK Investigational Site
  • Uppsala, Sweden, SE-751 85
    • GSK Investigational Site
• United Kingdom
  • Clydebank, United Kingdom, G81 4DY
    • GSK Investigational Site
  • London, United Kingdom, SW3 6NP
    • GSK Investigational Site
  • London, United Kingdom, NW3 2QH
    • GSK Investigational Site
  • Sheffield, United Kingdom, S10 2JF
    • GSK Investigational Site
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB3 8RE
      • GSK Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • GSK Investigational Site
    • Mobile, Alabama, United States, 36617
      • GSK Investigational Site
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • GSK Investigational Site
    • Tucson, Arizona, United States, 85724
      • GSK Investigational Site
  • California
    • La Jolla, California, United States, 92093
      • GSK Investigational Site
    • Los Angeles, California, United States, 90073
      • GSK Investigational Site
    • Sacramento, California, United States, 95817
      • GSK Investigational Site
    • Torrance, California, United States, 90502
      • GSK Investigational Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • GSK Investigational Site
  • Florida
    • Gainesville, Florida, United States, 32610
      • GSK Investigational Site
    • Jacksonville, Florida, United States, 32209
      • GSK Investigational Site
    • Kissimmee, Florida, United States, 34741
      • GSK Investigational Site
    • Orlando, Florida, United States, 32803
      • GSK Investigational Site
    • Weston, Florida, United States, 33331
      • GSK Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • GSK Investigational Site
    • Decatur, Georgia, United States, 30030
      • GSK Investigational Site
  • Illinois
    • Oakbrook Terrace, Illinois, United States, 60181
      • GSK Investigational Site
  • Indiana
    • Carmel, Indiana, United States, 46032
      • GSK Investigational Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • GSK Investigational Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • GSK Investigational Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • GSK Investigational Site
  • Maine
    • Portland, Maine, United States, 04102
      • GSK Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • GSK Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • GSK Investigational Site
    • Boston, Massachusetts, United States, 02111
      • GSK Investigational Site
    • Boston, Massachusetts, United States, 02115
      • GSK Investigational Site
    • Springfield, Massachusetts, United States, 01199
      • GSK Investigational Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • GSK Investigational Site
    • Detroit, Michigan, United States, 48201
      • GSK Investigational Site
    • Troy, Michigan, United States, 48085
      • GSK Investigational Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • GSK Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68131
      • GSK Investigational Site
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • GSK Investigational Site
    • Newark, New Jersey, United States, 07112
      • GSK Investigational Site
  • New York
    • New Hyde Park, New York, United States, 11040
      • GSK Investigational Site
    • New York, New York, United States, 10032
      • GSK Investigational Site
    • New York, New York, United States, 10021
      • GSK Investigational Site
    • New York, New York, United States, 10003
      • GSK Investigational Site
    • New York, New York, United States, 10019
      • GSK Investigational Site
    • Rochester, New York, United States, 14623
      • GSK Investigational Site
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • GSK Investigational Site
    • Chapel Hill, North Carolina, United States, 27599
      • GSK Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • GSK Investigational Site
    • Cincinnati, Ohio, United States, 45267
      • GSK Investigational Site
    • Cleveland, Ohio, United States, 44195
      • GSK Investigational Site
    • Columbus, Ohio, United States, 43221
      • GSK Investigational Site
  • Oregon
    • Portland, Oregon, United States, 97220
      • GSK Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • GSK Investigational Site
    • Philadelphia, Pennsylvania, United States, 19104
      • GSK Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15212
      • GSK Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15213
      • GSK Investigational Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • GSK Investigational Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • GSK Investigational Site
  • Texas
    • Dallas, Texas, United States, 75390
      • GSK Investigational Site
    • Houston, Texas, United States, 77030
      • GSK Investigational Site
    • Temple, Texas, United States, 76508
      • GSK Investigational Site
  • Utah
    • Murray, Utah, United States, 84157
      • GSK Investigational Site
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • GSK Investigational Site
    • Norfolk, Virginia, United States, 23507
      • GSK Investigational Site
    • Richmond, Virginia, United States, 23298
      • GSK Investigational Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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

  a. 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:

  i. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	Baseline (BL) and Week 24

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Collaborators: Gilead Sciences

Publications and helpful links

General 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. Erratum In: Ann Rheum Dis. 2020 Sep;79(9):e118.
• White RJ, Vonk-Noordegraaf A, Rosenkranz S, Oudiz RJ, McLaughlin VV, Hoeper MM, Grunig E, Ghofrani HA, Chakinala MM, Barbera JA, Blair C, Langley J, Frost AE. Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension. Respir Res. 2019 Sep 12;20(1):208. doi: 10.1186/s12931-019-1180-1.
• Coghlan JG, Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, Kuwana M, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Blair C, Gillies H, Miller KL, Harris JHN, Langley J, Rubin LJ; AMBITION investigators. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017 Jul;76(7):1219-1227. doi: 10.1136/annrheumdis-2016-210236. Epub 2016 Dec 30.
• Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grunig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ; AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687.
• Peacock AJ, Zamboni W, Vizza CD. Ambrisentan for the treatment of adults with pulmonary arterial hypertension: a review. Curr Med Res Opin. 2015;31(9):1793-807. doi: 10.1185/03007995.2015.1074890. Epub 2015 Aug 27.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): July 31, 2014
• Study Completion (Actual): July 31, 2014

Study Registration Dates

• First Submitted: July 15, 2010
• First Submitted That Met QC Criteria: August 6, 2010
• First Posted (Estimate): August 9, 2010

Study Record Updates

• Last Update Posted (Actual): September 13, 2017
• Last Update Submitted That Met QC Criteria: August 14, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension; PAH; Tadalafil; Ambrisentan; Sponsor Rest of World: GSK; Sponsor US: Gilead
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil; Ambrisentan
• Other Study ID Numbers: 112565