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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01178073
Registration number
NCT01178073
Ethics application status
Date submitted
15/07/2010
Date registered
9/08/2010
Date last updated
13/09/2017
Titles & IDs
Public title
A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
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Scientific title
AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
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Secondary ID [1]
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112565
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Universal Trial Number (UTN)
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Trial acronym
AMBITION
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Hypertension, Pulmonary
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Condition category
Condition code
Respiratory
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Other respiratory disorders / diseases
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Cardiovascular
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Hypertension
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - ambrisentan
Treatment: Drugs - tadalafil
Active Comparator: Combination ambrisentan + tadalafil - ambrisentan + tadalafil
Active Comparator: Monotherapy ambrisentan - ambrisentan
Active Comparator: Monotherapy tadalafil - tadalafil
Treatment: Drugs: ambrisentan
ambrisentan (target dose: 10mg)
Treatment: Drugs: tadalafil
tadalafil (target dose: 40mg)
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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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
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Assessment method [1]
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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).
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Timepoint [1]
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From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)
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Secondary outcome [1]
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Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and Week 24
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Secondary outcome [2]
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Percentage of Participants With a Satisfactory Clinical Response at Week 24
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline and Week 24
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Secondary outcome [3]
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Change From Baseline in the 6 Minute Walk Distance Test at Week 24
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline and Week 24
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Secondary outcome [4]
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Change From Baseline in the World Health Organization Functional Class at Week 24
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Assessment method [4]
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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.
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Timepoint [4]
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Baseline and Week 24
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Secondary outcome [5]
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Change From Baseline in Borg Dyspnea Index at Week 24
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Assessment method [5]
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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.
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Timepoint [5]
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Baseline (BL) and Week 24
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Eligibility
Key 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
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Minimum age
18
Years
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Maximum age
75
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/10/2010
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
31/07/2014
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Sample size
Target
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Accrual to date
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Final
610
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,VIC,WA
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Recruitment hospital [1]
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GSK Investigational Site - Camperdown
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GSK Investigational Site - Darlinghurst
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2050 - Camperdown
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2010 - Darlinghurst
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4032 - Chermside
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7000 - Hobart
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3004 - Melbourne
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6000 - Perth
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London
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Sheffield
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
GlaxoSmithKline
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Gilead Sciences
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Ethics approval
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01178073
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
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GSK Clinical Trials
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GlaxoSmithKline
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Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01178073
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