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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01178073
Other study ID # 112565
Secondary ID
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


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
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