Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension

• Register: EUCTR
• Last refreshed on: 19 April 2022
• Main ID: EUCTR2009-011150-17-NL
• Date of registration: 26/05/2010
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline R&D Ltd
• Public title: Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension
• Scientific title: AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension - AMBITION
• Date of first enrolment: 26/08/2010
• Target sample size: 545
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-011150-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

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

Contacts

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects eligible for enrolment in the study must meet all of the following criteria:
Demographics
1. Subject must be between 18 and 75 years of age, inclusive, at the Screening Visit
2. Subject must weigh =40 kg at the Screening Visit
PAH Diagnosis and Classification
3. Subjects must have a diagnosis of 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 CTD, systemic lupus erythematosus, or overlap syndrome)
ii. drugs or toxins
iii. 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 PVOD are NOT eligible for the study
NB: Subjects must not have 3 or more of the following left ventricular
disease/dysfunction risk factors:
i. Body Mass Index (BMI) = 30
ii. History of Essential Hypertension
iii. Diabetes Mellitus – any type
iv. Historical evidence of significant coronary disease established by any one of:
• history of myocardial infarction
• history of percutaneous intervention
• angiographic evidence of CAD (>50% stenosis in at least one vessel), either by invasive angiography or by CT Angiography
• positive stress test with imaging (either pharmacologic or with exercise)
• previous coronary artery surgery
• chronic stable angina
4. Subject must have a current diagnosis of being in WHO Functional Class II or III.
5. Subject with a diagnosis of HIV must have stable disease status. For this study, stable HIV status is defined as:
i. No addition of medications for treatment of HIV for at least 8 weeks prior to screening
ii. No active opportunistic infection during the Screening Period
iii. No hospitalizations due to HIV for at least 4 weeks prior to screening
6. Subject must meet all of the following haemodynamic criteria by means of a RHC 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
(refer to section 4.2 for US specific text).
7. Subject must meet all of the following pulmonary function tests completed no more
than 24 weeks before the Screening visit:
i. Total lung capacity (TLC) =60% of predicted normal and
ii. Forced expiratory volume in one second (FEV1) =55% of predicted
normal
Subjects are required to have a documented negative V/Q scan or pulmonary arteriogram confirming the absence of CTEPH prior to screening.
8. Subject must walk a distance of =125m and =500m at the screening visit. In addition the screening and baseline 6MWD tests must not vary by greater than 10% (see Section 6.2.2.1 for further details)
9. Subject, with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) =88% as measured by pulse oximetry at the Screening Visit.
Exercise Programmes
10. Subject has not enrolled in an exercise training program for pulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 24 weeks of the study. Subjects enrolled in an exercise program for pulmonary rehabilitation 12 weeks prior to screening may enter the study if they agree to maintain their current level of rehabilitation for the first 2
Exclusion criteria:
Subjects meeting any of the following criteria must not be enrolled in the study (please
note that screening visit laboratory tests may be performed by local or central laboratory):
PAH Treatments
1. Subject received previous PAH therapy (PDE5i, ERA, chronic prostanoid*) within 4
weeks prior to the screening visit
*Chronic prostanoid use is considered >7 days of treatment
2. 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
3. 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.
4. Subject has a known hypersensitivity to the Investigational Products, the metabolites,
or formulation excipients
Other Therapies
5. Subject receiving intravenous inotropes within 2 weeks prior to the Screening Visit
(e.g. dopamine, dobutamine)
6. Subject is receiving treatment with a potent inhibitor of CYP3A4 (e.g. protease
inhibitors, systemic ketoconazole, or systemic itraconazole)
7. Subject is receiving treatment with a potent inducer of CYP3A4 (e.g. rifampicin)
8. Subject is receiving treatment with cyclosporine A (except ophthalmic formulation)
9. Subjects receiving Calcium Channel Blockers or HMG-CoA reductase inhibitors
(i.e., statins) on an unstable dose 4 weeks prior to the Screening Visit (to be eligible
subjects must not have changed their dose <4 weeks prior to the screening visit)
10. Subject has a history of angina pectoris that was treated with long or short-acting
nitrates <12 weeks of screening or nitrate use for any other condition within 48 hours
of screening
11. Subject has a serum ALT or AST lab value that is > 2xULN at the Screening Visit
12. Subject has serum bilirubin lab value that is >1.5xULN at the screening visit
13. Subject has severe renal impairment (creatinine clearance <30 mL/min) at the
Screening Visit
Medical History/Current Medical Conditions
Liver
14. Subject has severe hepatic impairment (Child-Pugh class C with or without cirrhosis)
at the Screening Visit
Haematology and bleeding disorders
15. Subject has clinically significant anaemia in the opinion of the investigator
16. Subjects with bleeding disorders or significant active peptic ulceration in the opinion
of the investigator
Cardiovascular
17. Subject has uncontrolled hypertension (=180/110 mmHg) at screening
18. Subject has severe hypotension (<90/50 mmHg) at screening
19. Subject has had an acute myocardial infarction within the last 90 days prior to
screening
20. Subject has, in the opinion of the investigator, clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive cardiomyopathy; lifethreatening cardiac arrhythmias; significant left ventricular dysfunction; left
ventricular outflow obstruction; symptomatic coronary artery disease; autonomic
hypotension; fluid depletion.
Ophthalmic
21. Subject has a past medical history of NAION
22. Subject has a hereditary degenerative retinal disorder (e.g. retinitis pigmentosa)
General Medical Conditions
23. Subject has clinically significant fluid retention in the opinion of the investigator
24. Subject with cardiovascular, liver, renal, haematologic, gastrointestinal,
immunologic, endocrine, metabolic, or central nervous system

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary arterial hypotension
MedDRA version: 14.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Therapeutic area: Diseases [C] - Virus Diseases [C02]

Intervention(s)

Trade Name: Volibris
Product Name: ambrisentan 5 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AMBRISENTAN
CAS Number: 177036-94-1
Current Sponsor code: GSK1325760
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Cialis
Product Name: tadalafil 20 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: To compare the change in other clinical measures of PAH after initiating first-line combination therapy or first-line monotherapy, in subjects with PAH.

The safety and tolerability of first-line combination therapy will be compared to first-line monotherapy.

In addition, the effect of ambrisentan on exercise capacity at both peak and trough plasma concentrations will be assessed in subjects with pulmonary arterial hypertension (PAH).

Main Objective: To compare the two treatment strategies; first-line combination therapy (ambrisentan AND tadalafil) versus first-line monotherapy (ambrisentan OR tadalafil) in treatment naive subjects with PAH. This will be assessed by time to the first clinical failure event.

Timepoint(s) of evaluation of this end point: during the trial

Primary end point(s): The primary efficacy endpoint is the time to the first clinical failure event of PAH. Time to clinical failure is defined as the time from randomisation to the first occurrence of:
• Death (all-cause)
• Hospitalization for worsening PAH (adjudicated)
i. Any hospitalization for worsening PAH
ii. Lung or heart/lung transplant
iii. Atrial septostomy
iv. Initiation of parenteral prostanoid therapy
• Disease progression (adjudicated)
i. >15% decrease from baseline in 6MWD combined with WHO class III or IV symptoms (at two consecutive post-baseline clinic visits separated by =14 days)
• Unsatisfactory long-term clinical response (adjudicated, all criteria required)
i. Receiving randomised treatment for at least 6 months
ii. A decrease from baseline in 6MWD at two consecutive post-baseline clinic visits separated by =14 days
iii. Sustained WHO class III symptoms for =6 months (WHO class III symptoms assessed at two clinic visits separated by =6 months)


Time to clinical worsening (death, hospitalization for worsening PAH, or disease progression) and long-term survival (time to death) will be examined as supportive analyses of the primary endpoint.

Secondary Outcome(s)

Secondary end point(s): • Change from baseline 6MWD measured at week 24
• Percentage of subjects with satisfactory clinical response measured at week 24, defined as:
-10% improvement in 6MWD compared to baseline
- Improvement to or maintenance of WHO class I or II symptoms
- No events of clinical worsening prior to or at the week 24 visit
• Change from baseline measured at week 24 in N-terminal pro-B-type natriuretic peptide (NT-proBNP)
• Change from baseline measured at week 24 in WHO Functional Class
• Change from baseline measured at week 24 in BDI immediately following exercise

Timepoint(s) of evaluation of this end point: week 24

Secondary ID(s)

AMB112565

Source(s) of Monetary Support

GlaxoSmithKline Research & Development Ltd

Ethics review

Status: Approved
Approval date: 26/08/2010
Contact:

Results

• Results available: Yes
• Date Posted: 10/04/2015
• Date Completed: 31/07/2014
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011150-17/results