Study of two drugs used to treat pulmonary arterial hypertension (PAH)

• Register: EUCTR
• Last refreshed on: 7 October 2014
• Main ID: EUCTR2009-011150-17-DE
• Date of registration: 03/08/2010
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline R&D Ltd
• Public title: Study of two drugs used to treat pulmonary arterial hypertension (PAH)
• 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: 16/08/2010
• Target sample size: 614
• 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

Countries of recruitment

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

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 fi
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 continuously for 14 days or more (PDE5i, ERA, prostanoid) prior to the screening visit. Subjects who previously received PAH therapy for less than 14 days must not have received any PAH therapy within 7 days prior to Screening Visit.
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
Laboratory Values at 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 cardiovas

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] - Cardiovascular Diseases [C14]

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)

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 at least one dose of randomised treatment and being in the study 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.

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: Week 0, 4, 8, 16, 24 and then every 12 weeks until 105 events are reported for the study

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).

Secondary Outcome(s)

Secondary end point(s): 6 Minute Walk Distance and Borg Dyspnea Index: The 6MWD will be assessed at each clinic visit, and The Borg Dyspnea Index score will be collected at each clinic visit. It should be performed immediately after the 6MWD test.

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

Secondary ID(s)

2009-011150-17-NL

AMB112565

Source(s) of Monetary Support

GlaxoSmithKline Research & Development Ltd