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

Hypertension, Pulmonary Clinical Trial

— AMBITION  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01178073
• Other study ID #: 112565
• Status: Completed
• Phase: Phase 3
• First received: July 15, 2010
• Last updated: May 28, 2015
• Start date: October 2010
• Est. completion date: August 2014

Study information

• Verified date: May 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española del Medicamento y Productos SanitariosUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyAustria: Agency for Health and Food SafetyBelgium: Agence Fédérale des Médicaments et des Produits de la SantéItaly: Comitato Etico IndipendenteCanada: Health CanadaGermany: Bundesinstitut für Arzneimittel und MedizinprodukteFrance: Agence Française de Sécurité Sanitaire des Produits de SantéJapan: Pharmaceuticals and Medical Devices AgencyNetherlands: De Centrale Commissie Mensgebonden OnderzoekUnited States: Food and Drug AdministrationSweden: LäkemedelsverketAustralia: Therapeutic Goods AdministrationGreece: National Drug Organisation
• Study type: Interventional

Clinical 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 610
• Est. completion date: August 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary

Intervention

Drug:
• ambrisentan
ambrisentan (target dose: 10mg)
• tadalafil
tadalafil (target dose: 40mg)

Locations

Country	Name	City	State
Australia	GSK Investigational Site	Camperdown	New South Wales
Australia	GSK Investigational Site	Chermside	Queensland
Australia	GSK Investigational Site	Darlinghurst	New South Wales
Australia	GSK Investigational Site	Hobart	Tasmania
Australia	GSK Investigational Site	Melbourne	Victoria
Australia	GSK Investigational Site	Perth	Western Australia
Austria	GSK Investigational Site	Innsbruck
Austria	GSK Investigational Site	Vienna
Belgium	GSK Investigational Site	Brussels
Belgium	GSK Investigational Site	Leuven
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Quebec City	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Vancouver	British Columbia
Canada	GSK Investigational Site	Winnipeg	Manitoba
France	GSK Investigational Site	Brest
France	GSK Investigational Site	Bron
France	GSK Investigational Site	La Tronche
France	GSK Investigational Site	Le Kremlin-Bicêtre cedex
France	GSK Investigational Site	Lille
France	GSK Investigational Site	Marseille cedex 20
France	GSK Investigational Site	Montpellier cedex 5
France	GSK Investigational Site	Pessac cedex
France	GSK Investigational Site	Saint Pierre cedex
France	GSK Investigational Site	Toulouse cedex 9
France	GSK Investigational Site	Vandoeuvre-les-Nancy
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bonn	Nordrhein-Westfalen
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Giessen	Hessen
Germany	GSK Investigational Site	Greifswald	Mecklenburg-Vorpommern
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Homburg	Saarland
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Loewenstein	Baden-Wuerttemberg
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Regensburg	Bayern
Germany	GSK Investigational Site	Wuerzburg	Bayern
Greece	GSK Investigational Site	Alexandroupolis
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Thessaloniki
Italy	GSK Investigational Site	Bologna	Emilia-Romagna
Italy	GSK Investigational Site	Cagliari	Sardegna
Italy	GSK Investigational Site	Catania	Sicilia
Italy	GSK Investigational Site	Pisa	Toscana
Italy	GSK Investigational Site	Roma	Lazio
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Shizuoka
Japan	GSK Investigational Site	Tokyo
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Maastricht
Netherlands	GSK Investigational Site	Rotterdam
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Córdoba
Spain	GSK Investigational Site	L'Hospitalet de Llobregat
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Majadahonda (Madrid)
Spain	GSK Investigational Site	Malaga
Spain	GSK Investigational Site	Palma de Mallorca
Spain	GSK Investigational Site	Santander
Spain	GSK Investigational Site	Santiago de Compostela
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Toledo
Spain	GSK Investigational Site	Valencia
Sweden	GSK Investigational Site	Göteborg
Sweden	GSK Investigational Site	Linköping
Sweden	GSK Investigational Site	Lund
Sweden	GSK Investigational Site	Umeå
Sweden	GSK Investigational Site	Uppsala
United Kingdom	GSK Investigational Site	Cambridge	Cambridgeshire
United Kingdom	GSK Investigational Site	Clydebank
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Sheffield
United States	GSK Investigational Site	Ann Arbor	Michigan
United States	GSK Investigational Site	Asheville	North Carolina
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Carmel	Indiana
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Charlottesville	Virginia
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Decatur	Georgia
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Gainesville	Florida
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Iowa City	Iowa
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Kansas City	Kansas
United States	GSK Investigational Site	Kissimmee	Florida
United States	GSK Investigational Site	La Jolla	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Milwaukee	Wisconsin
United States	GSK Investigational Site	Mobile	Alabama
United States	GSK Investigational Site	Morristown	New Jersey
United States	GSK Investigational Site	Murray	Utah
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New Hyde Park	New York
United States	GSK Investigational Site	New Orleans	Louisiana
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Newark	New Jersey
United States	GSK Investigational Site	Norfolk	Virginia
United States	GSK Investigational Site	Oakbrook Terrace	Illinois
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Pittsburgh	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Portland	Maine
United States	GSK Investigational Site	Providence	Rhode Island
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Rochester	New York
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	Springfield	Massachusetts
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	Temple	Texas
United States	GSK Investigational Site	Torrance	California
United States	GSK Investigational Site	Troy	Michigan
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	Weston	Florida

Sponsors (2)

Lead Sponsor	Collaborator
GlaxoSmithKline	Gilead Sciences

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Greece,  Italy,  Japan,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV	Time 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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No