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
Conditions
Interventions
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: GSK132576
Sponsors
GlaxoSmithKline R&D Ltd
Eligibility
Sex/Gender
All
Inclusion 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
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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.;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). ;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
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: week 24;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 | — |
Countries
Austria, Belgium, France, Germany, Greece, Italy, Japan, Netherlands, Spain, Sweden, United Kingdom
Contacts
Public ContactClinical Trials Helpdesk
GlaxoSmithKline Research & Development Ltd
Outcome results
None listed