Clinical trial NCT01884675: Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension.
Official title: A Randomised, Multicentre, Double-Blind, Placebo-Controlled Study Of Ambrisentan In Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH).
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hypertension
Keywords: Endothelin Receptor Antagonist
Inoperable Chronic Thromboembolic Pulmonary Hypertension
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-06-24
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16
timeFrame: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal
Secondary outcomes:
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16
timeFrame: Baseline (Week 0) and Week 16
measure: Change From Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal
timeFrame: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal
measure: Change From Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal
timeFrame: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal
measure: Number of Participants With Clinical Worsening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
timeFrame: From randomization to Week 16/Follow up visit (21 weeks)
measure: Change From Baseline in Mean Right Atrial Pressure (mRAP) and Mean Pulmonary Artery Pressure (mPAP) at Week 16
timeFrame: Baseline (Week 0) and Week 16
measure: Change From Baseline in Cardiac Index at Week 16
timeFrame: Baseline (Week 0) and Week 16
measure: Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)
timeFrame: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal
measure: Change From Baseline in Quality of Life as Measured by Short Form 36 Health Survey (SF-36)
timeFrame: Baseline and up to Week 16/Early Withdrawal
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From the start of study treatment and until follow up (Week 16/Follow up)
measure: Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal
timeFrame: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal
measure: Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal
timeFrame: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal
measure: Number of Participants With Significant Liver Events at Weeks 4, 8, 12, and 16/Early Withdrawal
timeFrame: Weeks 4, 8, 12, and 16/Early Withdrawal
measure: Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal
timeFrame: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal
measure: Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal
timeFrame: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal
measure: Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline
timeFrame: Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal,
measure: Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline
timeFrame: Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal
measure: Number of Participants With Testicular Function (Males Only) of Potential Clinical Concern Any Time Post Baseline
timeFrame: Baseline, Weeks 4 and 16/early withdrawal
Other outcomes:
Locations:
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Corrientes
country: Argentina
facility: GSK Investigational Site
city: Santa Fe
country: Argentina
facility: GSK Investigational Site
city: Graz
country: Austria
facility: GSK Investigational Site
city: Innsbruck
country: Austria
facility: GSK Investigational Site
city: Vienna
country: Austria
facility: GSK Investigational Site
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Wuhan
country: China
facility: GSK Investigational Site
state: Hubei
city: Xian
country: China
facility: GSK Investigational Site
state: Shaanxi
city: Beijing
country: China
facility: GSK Investigational Site
city: Beijing
country: China
facility: GSK Investigational Site
city: Beijing
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Praha 2
country: Czech Republic
facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Regensburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Wuerzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Homburg
country: Germany
facility: GSK Investigational Site
state: Saarland
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Ashkelon
country: Israel
facility: GSK Investigational Site
city: Zrifin
country: Israel
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hyogo
country: Japan
facility: GSK Investigational Site
city: Miyagi
country: Japan
facility: GSK Investigational Site
city: Tochigi
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Monterrey NL
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
country: Russian Federation
facility: GSK Investigational Site
city: Riyadh
country: Saudi Arabia
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Majadahonda (Madrid)
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Clydebank
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: