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

NCT01178073 | Completed Phase 3 Results DMC

• 1 other identifier: 112565
• Study Type: interventional
• Target: 610
• Locations: 13 countries
• Sites: 137

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.

Conditions

Hypertension, Pulmonary

Keywords

Pulmonary Arterial Hypertension; Ambrisentan; Sponsor Rest of World: GSK; Tadalafil; PAH; Sponsor US: Gilead

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24

  Baseline and Week 24

• Percentage of Participants With a Satisfactory Clinical Response at Week 24

  Baseline and Week 24

• Change From Baseline in the 6 Minute Walk Distance Test at Week 24

  Baseline and Week 24

• Change From Baseline in the World Health Organization Functional Class at Week 24

  Baseline and Week 24

• Change From Baseline in Borg Dyspnea Index at Week 24

  Baseline (BL) and Week 24

Study Arms (3)

Combination ambrisentan + tadalafil

ACTIVE COMPARATOR

ambrisentan + tadalafil

Drug: ambrisentan; Drug: tadalafil

Monotherapy ambrisentan

ACTIVE COMPARATOR

ambrisentan

Drug: ambrisentan

Monotherapy tadalafil

ACTIVE COMPARATOR

tadalafil

Drug: tadalafil

Interventions

ambrisentan DRUG

ambrisentan (target dose: 10mg)

Combination ambrisentan + tadalafil; Monotherapy ambrisentan

tadalafil DRUG

tadalafil (target dose: 40mg)

Combination ambrisentan + tadalafil; Monotherapy tadalafil

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Gilead Sciences: collaborator

Study Sites (143)

GSK Investigational Site

Birmingham, Alabama, 35294, United States

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GSK Investigational Site

Mobile, Alabama, 36617, United States

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Phoenix, Arizona, 85012, United States

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Tucson, Arizona, 85724, United States

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La Jolla, California, 92093, United States

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Los Angeles, California, 90073, United States

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Sacramento, California, 95817, United States

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GSK Investigational Site

Torrance, California, 90502, United States

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Aurora, Colorado, 80045, United States

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Gainesville, Florida, 32610, United States

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Jacksonville, Florida, 32209, United States

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Kissimmee, Florida, 34741, United States

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GSK Investigational Site

Orlando, Florida, 32803, United States

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Weston, Florida, 33331, United States

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Atlanta, Georgia, 30322, United States

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Decatur, Georgia, 30030, United States

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Oakbrook Terrace, Illinois, 60181, United States

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Carmel, Indiana, 46032, United States

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Iowa City, Iowa, 52242, United States

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Kansas City, Kansas, 66160, United States

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New Orleans, Louisiana, 70112, United States

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Portland, Maine, 04102, United States

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Baltimore, Maryland, 21201, United States

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Boston, Massachusetts, 02111, United States

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Boston, Massachusetts, 02115, United States

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Boston, Massachusetts, 02118, United States

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Springfield, Massachusetts, 01199, United States

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Ann Arbor, Michigan, 48109, United States

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Detroit, Michigan, 48201, United States

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Troy, Michigan, 48085, United States

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St Louis, Missouri, 63110, United States

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Omaha, Nebraska, 68131, United States

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Morristown, New Jersey, 07962, United States

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Newark, New Jersey, 07112, United States

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New Hyde Park, New York, 11040, United States

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New York, New York, 10003, United States

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GSK Investigational Site

New York, New York, 10019, United States

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GSK Investigational Site

New York, New York, 10021, United States

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GSK Investigational Site

New York, New York, 10032, United States

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Rochester, New York, 14623, United States

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Asheville, North Carolina, 28803, United States

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Chapel Hill, North Carolina, 27599, United States

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Cincinnati, Ohio, 45219, United States

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Cincinnati, Ohio, 45267, United States

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Cleveland, Ohio, 44195, United States

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Columbus, Ohio, 43221, United States

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Portland, Oregon, 97220, United States

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Philadelphia, Pennsylvania, 19104, United States

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Philadelphia, Pennsylvania, 19140, United States

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Pittsburgh, Pennsylvania, 15212, United States

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Pittsburgh, Pennsylvania, 15213, United States

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Providence, Rhode Island, 02903, United States

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Nashville, Tennessee, 37232, United States

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Dallas, Texas, 75390, United States

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Houston, Texas, 77030, United States

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Temple, Texas, 76508, United States

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Murray, Utah, 84157, United States

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Charlottesville, Virginia, 22908, United States

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Norfolk, Virginia, 23507, United States

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Richmond, Virginia, 23298, United States

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Milwaukee, Wisconsin, 53215, United States

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Camperdown, New South Wales, 2050, Australia

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Darlinghurst, New South Wales, 2010, Australia

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Chermside, Queensland, 4032, Australia

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Hobart, Tasmania, 7000, Australia

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Melbourne, Victoria, 3004, Australia

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Perth, Western Australia, 6000, Australia

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Innsbruck, A-6020, Austria

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Vienna, 1090, Austria

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Brussels, 1070, Belgium

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Leuven, 3000, Belgium

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Calgary, Alberta, T1Y 6J4, Canada

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Vancouver, British Columbia, V5Z 1M9, Canada

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Winnipeg, Manitoba, R3A 1R8, Canada

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Toronto, Ontario, M5G 2N2, Canada

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Québec, Quebec, G1V 4G5, Canada

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Brest, 29200, France

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Bron, 69677, France

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La Tronche, 38700, France

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Le Kremlin-Bicêtre, 94275, France

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Lille, 59037, France

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Marseille, 13915, France

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Montpellier, 34295, France

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Pessac, 33604, France

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Saint-Pierre, 97448, France

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Toulouse, 31059, France

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Vandœuvre-lès-Nancy, 54511, France

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Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

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Heidelberg, Baden-Wurttemberg, 69126, Germany

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Löwenstein, Baden-Wurttemberg, 74245, Germany

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Munich, Bavaria, 81377, Germany

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Regensburg, Bavaria, 93053, Germany

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Würzburg, Bavaria, 97074, Germany

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Giessen, Hesse, 35392, Germany

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Hanover, Lower Saxony, 30625, Germany

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Greifswald, Mecklenburg-Vorpommern, 17475, Germany

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Bonn, North Rhine-Westphalia, 53127, Germany

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Cologne, North Rhine-Westphalia, 50937, Germany

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Homburg, Saarland, 66421, Germany

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Dresden, Saxony, 01307, Germany

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Leipzig, Saxony, 04103, Germany

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Berlin, 12559, Germany

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Hamburg, 20246, Germany

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Alexandroupoli, 68100, Greece

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Athens, 124 62, Greece

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Athens, 176 74, Greece

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Thessaloniki, 54636, Greece

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Bologna, Emilia-Romagna, 40138, Italy

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Rome, Lazio, 00161, Italy

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Cagliari, Sardinia, 09134, Italy

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Catania, Sicily, 95100, Italy

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Pisa, Tuscany, 56124, Italy

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Fukuoka, 812-8582, Japan

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Hokkaido, 060-8648, Japan

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Shizuoka, 431-3192, Japan

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Tokyo, 113-8655, Japan

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Amsterdam, 1081 HV, Netherlands

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Maastricht, 6229 HX, Netherlands

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Rotterdam, 3015 CE, Netherlands

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Barcelona, 08035, Spain

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Barcelona, 08036, Spain

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Córdoba, 14004, Spain

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L'Hospitalet de Llobregat, 08907, Spain

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Madrid, 28034, Spain

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Madrid, 28041, Spain

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Majadahonda (Madrid), 28222, Spain

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Málaga, 29010, Spain

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Palma de Mallorca, 07010, Spain

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Santander, 39008, Spain

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Santiago de Compostela, 15706, Spain

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Seville, 41013, Spain

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Toledo, 45004, Spain

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Valencia, 46026, Spain

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Gothenburg, SE-413 45, Sweden

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Linköping, SE-581 85, Sweden

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Lund, SE-221 85, Sweden

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Umeå, SE-901 85, Sweden

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Uppsala, SE-751 85, Sweden

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Cambridge, Cambridgeshire, CB3 8RE, United Kingdom

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Clydebank, G81 4DY, United Kingdom

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London, NW3 2QH, United Kingdom

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London, SW3 6NP, United Kingdom

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Sheffield, S10 2JF, United Kingdom

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Related Publications (5)

• 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.

  PMID: 32161055 DERIVED

• 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.

  PMID: 31511080 DERIVED

• 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.

  PMID: 28039187 DERIVED

• 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.

  PMID: 26308684 DERIVED

• 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.

  PMID: 26196225 DERIVED

MeSH Terms

Conditions

Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Interventions

ambrisentan; Tadalafil

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2010
• First Posted: August 9, 2010
• Study Start: October 1, 2010
• Primary Completion: July 31, 2014
• Study Completion: July 31, 2014
• Last Updated: September 13, 2017
• Results First Posted: April 28, 2015

Record last verified: 2017-08

Locations

US (61); BE (2); CA (5); IT (5); SE (5); GB (5); AU (2); FR (11); DE (16); GR (4); JP (4); NL (3); ES (14)