Clinical trial NCT01178073: A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
Official title: AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypertension, Pulmonary
Keywords: Pulmonary Arterial Hypertension
Ambrisentan
Sponsor Rest of World: GSK
Tadalafil
PAH
Sponsor US: Gilead
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Gilead Sciences
First posted: 2010-08-09
Enrollment: 610
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
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
timeFrame: From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)
Secondary outcomes:
measure: Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24
timeFrame: Baseline and Week 24
measure: Percentage of Participants With a Satisfactory Clinical Response at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the 6 Minute Walk Distance Test at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in the World Health Organization Functional Class at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Borg Dyspnea Index at Week 24
timeFrame: Baseline (BL) and Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Mobile
country: United States
facility: GSK Investigational Site
state: Alabama
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: La Jolla
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Gainesville
country: United States
facility: GSK Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Kissimmee
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Weston
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Decatur
country: United States
facility: GSK Investigational Site
state: Georgia
city: Oakbrook Terrace
country: United States
facility: GSK Investigational Site
state: Illinois
city: Carmel
country: United States
facility: GSK Investigational Site
state: Indiana
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Kansas
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Portland
country: United States
facility: GSK Investigational Site
state: Maine
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Springfield
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Troy
country: United States
facility: GSK Investigational Site
state: Michigan
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Morristown
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Newark
country: United States
facility: GSK Investigational Site
state: New Jersey
city: New Hyde Park
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Rochester
country: United States
facility: GSK Investigational Site
state: New York
city: Asheville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Providence
country: United States
facility: GSK Investigational Site
state: Rhode Island
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Temple
country: United States
facility: GSK Investigational Site
state: Texas
city: Murray
country: United States
facility: GSK Investigational Site
state: Utah
city: Charlottesville
country: United States
facility: GSK Investigational Site
state: Virginia
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Virginia
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Milwaukee
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Camperdown
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Darlinghurst
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Chermside
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Hobart
country: Australia
facility: GSK Investigational Site
state: Tasmania
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Perth
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Innsbruck
country: Austria
facility: GSK Investigational Site
city: Vienna
country: Austria
facility: GSK Investigational Site
city: Brussels
country: Belgium
facility: GSK Investigational Site
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Winnipeg
country: Canada
facility: GSK Investigational Site
state: Manitoba
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Quebec City
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Brest
country: France
facility: GSK Investigational Site
city: Bron
country: France
facility: GSK Investigational Site
city: La Tronche
country: France
facility: GSK Investigational Site
city: Le Kremlin-Bicêtre cedex
country: France
facility: GSK Investigational Site
city: Lille
country: France
facility: GSK Investigational Site
city: Marseille cedex 20
country: France
facility: GSK Investigational Site
city: Montpellier cedex 5
country: France
facility: GSK Investigational Site
city: Pessac cedex
country: France
facility: GSK Investigational Site
city: Saint Pierre cedex
country: France
facility: GSK Investigational Site
city: Toulouse cedex 9
country: France
facility: GSK Investigational Site
city: Vandoeuvre-les-Nancy
country: France
facility: GSK Investigational Site
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Loewenstein
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Regensburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Wuerzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Giessen
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Greifswald
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Bonn
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Homburg
country: Germany
facility: GSK Investigational Site
state: Saarland
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Alexandroupolis
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Bologna
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Cagliari
country: Italy
facility: GSK Investigational Site
state: Sardegna
city: Catania
country: Italy
facility: GSK Investigational Site
state: Sicilia
city: Pisa
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Shizuoka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Maastricht
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Córdoba
country: Spain
facility: GSK Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Majadahonda (Madrid)
country: Spain
facility: GSK Investigational Site
city: Malaga
country: Spain
facility: GSK Investigational Site
city: Palma de Mallorca
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Toledo
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Göteborg
country: Sweden
facility: GSK Investigational Site
city: Linköping
country: Sweden
facility: GSK Investigational Site
city: Lund
country: Sweden
facility: GSK Investigational Site
city: Umeå
country: Sweden
facility: GSK Investigational Site
city: Uppsala
country: Sweden
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
city: Clydebank
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.