Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension.
Condition: Hypertension
MeSH terms: Hypertension, Pulmonary; Hypertension
Intervention: Ambrisentan 5 mg; Placebo
Intervention description: White, film-coated, immediate-release tablets, containing 5 mg ambrisentan for single dose oral.; White, film-coated, ambrisentan-matching placebo tablet for single oral dose
Intervention MeSH terms: Ambrisentan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 33.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Endothelin Receptor Antagonist; Inoperable Chronic Thromboembolic Pulmonary Hypertension

Summary:

      It is hypothesised that ambrisentan may provide benefit to subjects with inoperable chronic
      thromboembolic pulmonary hypertension (CTEPH), where currently no proven or licensed
      treatment options exist. This Phase III, randomized, double-blind placebo controlled parallel
      group, 16 week study will compare the safety and efficacy of ambrisentan 5 milligrams (mg)
      versus placebo in subjects with inoperable CTEPH. The study will enrol 160 subjects, to
      assure at least 72 evaluable subjects per treatment arm, based on 10% drop-out rate.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed written informed consent prior to beginning study-related procedures.

          -  Subject must be between 18-80 years of age, inclusive, at the Screening Visit.

          -  Subjects must have a diagnosis of CTEPH at an expert centre with a positive V/Q and CT
             angiogram and a pulmonary angiogram if available within 6 months prior to screening.

          -  Subject must meet all of the following haemodynamic criteria by means of a RHC within
             3 months prior to screening: Mean pulmonary artery pressure (mPAP) of >25 millimeters
             of mercury (mmHg), Pulmonary vascular resistance (PVR) >400 dynes.sec/centimetre
             (cm)^5, Pulmonary capillary wedge pressure (PCWP) or Left ventricle end diastolic
             pressure (LVEDP) of <15 mmHg.

          -  Subjects must have previously been judged inoperable due to the obstruction being
             surgically inaccessible (i.e. distal disease) by an expert multidisciplinary team
             which must include at least one cardiology or respiratory consultant, and one
             consultant PEA surgeon. For countries with CTEPH expert centers [including at least a
             surgeon with sound experience performing Pulmonary Endarterectomy (PEAs)] the expert
             team will be the local expert centre. For countries without a CTEPH surgical expert
             center a central adjudication committee will assess the operability of the subjects
             during the screening period.

          -  Subject must walk a distance of >150 Meters (m) and < 475 m at the screening visit.

          -  Subject must have a current diagnosis of being in WHO Functional Class II or III.

          -  Subject, with or without supplemental oxygen, must have a resting arterial oxygen
             saturation (SaO2) > 92% as measured by pulse oximetry at the Screening Visit.

          -  Subjects must have received anticoagulation for a minimum of 3 months prior to
             Screening

          -  Female subject of childbearing potential must agree to use 2 reliable methods of
             contraception from the Screening Visit until study completion and for at least 30 days
             following the last dose of Investigational Product

          -  Subject must agree not to participate in a clinical study involving another
             investigational drug or device throughout this study.

          -  Subject must be competent to understand the information given in the Institutional
             Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent
             form (ICF) and must sign the form prior to the initiation of any study procedures.

        Exclusion Criteria:

          -  Subject received previous Pulmonary arterial hypertension (PAH) therapy
             (Phosphodiesterase type 5 [PDE5i], Endothelin receptor antagonist [ERA], chronic
             prostanoid use)

          -  Subject has previously discontinued other ERA in either another clinical study or
             commercial product for safety or tolerability reasons other than for liver function
             abnormalities.

          -  Subject has a known hypersensitivity to the Investigational Products, the metabolites,
             or formulation excipients

          -  Subject has previously undergone a pulmonary endarterectomy or a balloon pulmonary
             angioplasty

          -  Subject receiving intravenous inotropes within 2 weeks prior to the Screening Visit
             (e.g. dopamine, dobutamine)

          -  Subjects receiving Calcium Channel Blockers or 5-hydroxy-3-methylglutaryl-coenzyme A
             5-hydroxy-3-methylglutaryl-coenzyme A (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)

          -  Subject has not enrolled in an exercise training program for cardiopulmonary
             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 16 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 16 weeks
             of the study.

          -  Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) > 3x Upper
             limit of normal (ULN)

          -  Bilirubin > 1.5xULN (>35% direct bilirubin)

          -  Subject has severe renal impairment [estimated creatinine clearance <30
             millilitre/minute (mL/min)] at the Screening Visit

          -  Subject has moderate - severe hepatic impairment (Child-Pugh class B-C with or without
             cirrhosis) at the Screening Visit

          -  Subject has clinically significant anaemia: Hemoglobin (Hb) < 10 grams/decilitre
             (g/dL)

          -  Subjects with bleeding disorders or significant active peptic ulceration in the
             opinion of the investigator

          -  Subject has uncontrolled hypertension (>180/110 mmHg) at screening

          -  Subject has severe hypotension (<90/50 mmHg) at screening

          -  Subject has had an acute myocardial infarction within the last 90 days prior to
             screening

          -  Subject has, in the opinion of the investigator, clinically significant aortic or
             mitral valve disease; pericardial constriction; restrictive or congestive
             cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular
             dysfunction (ejection fraction <50% of normal); left ventricular outflow obstruction;
             symptomatic coronary artery disease; autonomic hypotension; fluid depletion.

          -  Subject with significant pulmonary disease Forced expiratory volume in 1 second (FEV1)
             <70% of predicted): Chronic obstructive pulmonary disease (COPD), Emphysema, evidence
             of fibrotic lung disease on imaging

          -  Subject has clinically significant fluid retention in the opinion of the investigator

          -  Subject with significant obesity [Body mass index (BMI) ≥35], cardiovascular,
             musculoskeletal or any other condition that in the opinion of the investigator may
             involve an impairment of exercise capacity or the performance of the 6MWD test (e.g.
             previous history of hip/knee surgery, lower limb ulcers associated with autoimmune
             diseases)

          -  Subject with cardiovascular, liver, renal, haematologic, gastrointestinal,
             immunologic, endocrine, metabolic, or central nervous system disease that, in the
             opinion of the Investigator, may adversely affect the safety of the subject and/or
             efficacy of the investigational product or severely limit the lifespan of the subject
             other than the condition being studied

          -  Subjects with a prior malignancy whose cancer is expected to require additional active
             treatment in the next 2 years and whose prior malignancy would prevent them from fully
             participating in the study

          -  Female subject who is pregnant or breastfeeding

          -  Subject has demonstrated noncompliance with previous medical regimens

          -  Subject has a recent (within 1 year) history of abusing alcohol or illicit drugs

          -  Subject has participated in a clinical study involving another investigational drug or
             device within 4 weeks before the Screening Visit.