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Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension. (AMBER I)

Primary Purpose

Hypertension

Status

Terminated

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Ambrisentan 5 mg

Placebo

About this trial

This is an interventional treatment trial for Hypertension focused on measuring Endothelin Receptor Antagonist, Inoperable Chronic Thromboembolic Pulmonary Hypertension

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ambrisentan

Placebo

Arm Description

Subjects in this arm will receive ambrisentan 5 mg tablet once daily during the treatment period.

Subjects in this arm will receive ambrisentan-matching placebo tablet once daily during the treatment period.

Outcomes

Primary Outcome Measures

Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16

The 6-minute walk test was conducted according to the American Thoracic Society guidelines in accordance with local standard operating procedures. 6MWD was measured by a 6-minute walk test. This test measures the distance that a participant can walk in a period of 6 minutes. Change from baseline was calculated at Weeks 4, 8, 12 and 16. Change from Baseline was calculated as value at the specified visit minus the Baseline value. Data at Baseline is based on average of two consecutive test results during Screening/Baseline period that differ by <10%. If only one measurement was available, that measurement was used. In any cases where the protocol-defined criteria for Baseline 6MWD was not met, the Baseline value was based on the last two consecutive measurements for a participant.

Secondary Outcome Measures

Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16

PVR is a measure of cardiopulmonary haemodynamics. Change from Baseline was calculated as value at specified visit minus Baseline value. Baseline is the last value recorded on or prior to start of study treatment.

Change From Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal

The WHO FC indicates the severity of PAH and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. There are four grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). This functional classification system links symptoms with activity limitations, and allows clinicians to quickly predict disease progression and prognosis, as well as the need for specific treatment regimens, irrespective of the underlying etiology of PAH. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value. For analyse purposes, the WHO FC Class categories of I-IV were mapped to a numeric scale of 1-4.

Change From Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal

The BCR10S score was collected immediately following completion of the 6-minute walk test. Baseline data was calculated as the average of the two BCR10S values obtained following the two 6MWD tests used in determining the Baseline 6MWD. If only one measurement was available, that measurement has been used. BCR10S scores ranges from 0 to 10 (0=nothing at all, 10=extremely strong). If participant's perception or feeling was stronger than "10", i.e "extremely strong", "Maximal" - a larger number could be used, e.g. 12 or still higher i.e "Absolute maximum"). Change from Baseline was calculated as the value at specified visit minus the Baseline value.

Number of Participants With Clinical Worsening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Clinical worsening of CTEPH is defined by the time from randomization to the first occurrence of death, lung transplantation, hospitalization for CTEPH, atrial septostomy, addition of parenteral prostanoids, or study withdrawal due to two or more early escape criteria included: a decrease from Baseline of at least 20 percent in the distance walked during the six-minute walk test; an increase of one or more WHO functional class; worsening right ventricular failure (e.g., as indicated by increased jugular venous pressure; new/worsening hepatomegaly, ascites, or peripheral edema; worsening echocardiographic parameters such as tricuspid annulus plane systolic excursion (TAPSE) and Tissue Doppler Imaging of the tricuspid annulus); rapidly progressing cardiogenic, hepatic, or renal failure; refractory systolic hypotension (systolic blood pressure less than 85 millimeter of mercury [mmHg]).

Change From Baseline in Mean Right Atrial Pressure (mRAP) and Mean Pulmonary Artery Pressure (mPAP) at Week 16

mPAP and mRAP are measures of cardiopulmonary hemodynamics. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value.

Change From Baseline in Cardiac Index at Week 16

Cardiac index is measure of cardiopulmonary hemodynamics. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value.

Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)

The ratio to baseline [BL] in NT-proBNP was calculated as the ratio of the value at the specified time-point to the BL value and was expressed as a percent change from BL. For each treatment group, the mean change from BL at the specified time-point was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the value at the specified time-point to BL on the original scale. The GM was expressed as a percentage (100*[GM - 1]). Standard Deviation(SD) is the SD of the mean change from baseline values on the log scale.

Change From Baseline in Quality of Life as Measured by Short Form 36 Health Survey (SF-36)

The SF-36 v2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health as well as 2 summary measures (Physical Health and Mental Health). Each domain is scored from 0 (poorer health) to 100 (better health). Change from Baseline was calculated as the post-Baseline score minus the Baseline score. The SF-36 data were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including the SF-36. This decision was documented in the reporting and analysis plan prior to database lock.

Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)

AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect or important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Haemoglobin levels were assessed at Screening, Baseline, Weeks 4, 8, 12, and 16/Early Withdrawal. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Haematocrit levels were assessed at Screening, Baseline, Weeks 4, 8, 12, and 16/Early Withdrawal. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Number of Participants With Significant Liver Events at Weeks 4, 8, 12, and 16/Early Withdrawal

A significant liver chemistry result is defined as any result which met the stopping criteria defined in the study protocol. Liver events were assessed at Screening, Baseline, Weeks 4, 8, 12, and 16/Early Withdrawal. Number of participants who reported a significant liver chemistry result are presented.

Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Vital sign measurements including supine systolic and diastolic blood pressure at Weeks 4, 8, 12, and 16/Early Withdrawal weeks. Supine blood pressure measurement was taken in a supine position having rested in this position for at least 10 minutes before each reading. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Vital sign measurements including heart rate at Weeks 4, 8, 12, and 16/Early Withdrawal weeks. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline

Clinical chemistry parameters including alanine amino transferase (ALT), aspartate amino transferase (AST), creatinine, gamma glutamyl transferase (GGT) and total bilirubin (TB) assessed any time post Baseline. ALT: lower concern value and high concern value was considered as none and >=3xupper limit of normal (ULN) respectively. AST: lower concern value and high concern value was considered as none or >=3xULN respectively. creatinine: lower concern value and high concern value was considered as none and >=176.8 micromoles per liter (umol/L) respectively. GGT: lower concern value and high concern value was considered as none and >=3xULN respectively. For TB: lower concern value was none and high concern value was >=2xULN. Participants with both normal and low values were counted once under their worst case (Low). Participants with both normal and high values were counted once under their worst case (High). Participants with both high and low values are counted under both categories.

Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline

Hematology parameters including hemoglobin, international normalized ratio (INR), and platelet count assessed any time post Baseline. Baseline is the last value recorded on or prior to start of study treatment. For hemoglobin: lower concern value and high concern value was considered as <100 gram per liter (G/L) and none respectively. For INR: lower concern value and high concern value was considered as none or >5 prothrombin time respectively. For platelet count: lower concern value and high concern value was considered as <50 giga cells per liter (GI/L) and >500 GI/L respectively. Participants with both normal and low values were counted once under their worst case (Low). Participants with both normal and high values were counted once under their worst case (High). Participants with both high and low values are counted under both categories.

Number of Participants With Testicular Function (Males Only) of Potential Clinical Concern Any Time Post Baseline

For male participants testicular function (total testosterone, sex hormone binding globulin [SHBG-calculated free testosterone), follicle stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B were assessed at Weeks 4 and 16/early withdrawal. The testicular function data were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including Testicular Function. This decision was documented in the reporting and analysis plan prior to database lock.

Full Information

NCT ID

NCT01884675

First Posted

June 20, 2013

Last Updated

January 20, 2017

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT01884675

Brief Title

Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension.

Acronym

AMBER I

Official Title

A Randomised, Multicentre, Double-Blind, Placebo-Controlled Study Of Ambrisentan In Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Study Type

Interventional

2. Study Status

Record Verification Date

November 2016

Overall Recruitment Status

Terminated

Study Start Date

September 2013 (undefined)

Primary Completion Date

March 2015 (Actual)

Study Completion Date

March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension

Keywords

Endothelin Receptor Antagonist, Inoperable Chronic Thromboembolic Pulmonary Hypertension

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

33 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ambrisentan

Arm Type

Experimental

Arm Description

Subjects in this arm will receive ambrisentan 5 mg tablet once daily during the treatment period.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Subjects in this arm will receive ambrisentan-matching placebo tablet once daily during the treatment period.

Intervention Type

Drug

Intervention Name(s)

Ambrisentan 5 mg

Intervention Description

White, film-coated, immediate-release tablets, containing 5 mg ambrisentan for single dose oral.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

White, film-coated, ambrisentan-matching placebo tablet for single oral dose

Primary Outcome Measure Information:

Title

Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

Secondary Outcome Measure Information:

Title

Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16

Description

Time Frame

Baseline (Week 0) and Week 16

Title

Change From Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

Title

Change From Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

Title

Number of Participants With Clinical Worsening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Description

Time Frame

From randomization to Week 16/Follow up visit (21 weeks)

Title

Change From Baseline in Mean Right Atrial Pressure (mRAP) and Mean Pulmonary Artery Pressure (mPAP) at Week 16

Description

Time Frame

Baseline (Week 0) and Week 16

Title

Change From Baseline in Cardiac Index at Week 16

Description

Time Frame

Baseline (Week 0) and Week 16

Title

Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

Title

Change From Baseline in Quality of Life as Measured by Short Form 36 Health Survey (SF-36)

Description

Time Frame

Baseline and up to Week 16/Early Withdrawal

Title

Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)

Description

Time Frame

From the start of study treatment and until follow up (Week 16/Follow up)

Title

Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Title

Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Title

Number of Participants With Significant Liver Events at Weeks 4, 8, 12, and 16/Early Withdrawal

Description

Time Frame

Weeks 4, 8, 12, and 16/Early Withdrawal

Title

Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Title

Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Description

Time Frame

Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Title

Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline

Description

Time Frame

Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal,

Title

Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline

Description

Time Frame

Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal

Title

Number of Participants With Testicular Function (Males Only) of Potential Clinical Concern Any Time Post Baseline

Description

Time Frame

Baseline, Weeks 4 and 16/early withdrawal

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02118

Country

United States

Facility Name

GSK Investigational Site

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390-8550

Country

United States

Facility Name

GSK Investigational Site

City

Rosario

State/Province

Santa Fe

ZIP/Postal Code

S2000ODA

Country

Argentina

Facility Name

GSK Investigational Site

City

Ciudad Autonoma de Buenos Aires

ZIP/Postal Code

C1181ACH

Country

Argentina

Facility Name

GSK Investigational Site

City

Corrientes

ZIP/Postal Code

W3400AMZ

Country

Argentina

Facility Name

GSK Investigational Site

City

Santa Fe

Country

Argentina

Facility Name

GSK Investigational Site

City

Graz

ZIP/Postal Code

A-8036

Country

Austria

Facility Name

GSK Investigational Site

City

Innsbruck

ZIP/Postal Code

A-6020

Country

Austria

Facility Name

GSK Investigational Site

City

Vienna

ZIP/Postal Code

1090

Country

Austria

Facility Name

GSK Investigational Site

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 2G3

Country

Canada

Facility Name

GSK Investigational Site

City

London

State/Province

Ontario

ZIP/Postal Code

N6A 5W9

Country

Canada

Facility Name

GSK Investigational Site

City

Wuhan

State/Province

Hubei

ZIP/Postal Code

430022

Country

China

Facility Name

GSK Investigational Site

City

Xian

State/Province

Shaanxi

ZIP/Postal Code

710061

Country

China

Facility Name

GSK Investigational Site

City

Beijing

ZIP/Postal Code

100020

Country

China

Facility Name

GSK Investigational Site

City

Beijing

ZIP/Postal Code

100037

Country

China

Facility Name

GSK Investigational Site

City

Beijing

ZIP/Postal Code

100038

Country

China

Facility Name

GSK Investigational Site

City

Shanghai

ZIP/Postal Code

200433

Country

China

Facility Name

GSK Investigational Site

City

Praha 2

ZIP/Postal Code

128 08

Country

Czech Republic

Facility Name

GSK Investigational Site

City

Heidelberg

State/Province

Baden-Wuerttemberg

ZIP/Postal Code

69126

Country

Germany

Facility Name

GSK Investigational Site

City

Regensburg

State/Province

Bayern

ZIP/Postal Code

93053

Country

Germany

Facility Name

GSK Investigational Site

City

Wuerzburg

State/Province

Bayern

ZIP/Postal Code

97074

Country

Germany

Facility Name

GSK Investigational Site

City

Hannover

State/Province

Niedersachsen

ZIP/Postal Code

30625

Country

Germany

Facility Name

GSK Investigational Site

City

Homburg

State/Province

Saarland

ZIP/Postal Code

66421

Country

Germany

Facility Name

GSK Investigational Site

City

Dresden

State/Province

Sachsen

ZIP/Postal Code

01307

Country

Germany

Facility Name

GSK Investigational Site

City

Leipzig

State/Province

Sachsen

ZIP/Postal Code

04103

Country

Germany

Facility Name

GSK Investigational Site

City

Ashkelon

ZIP/Postal Code

78360

Country

Israel

Facility Name

GSK Investigational Site

City

Zrifin

ZIP/Postal Code

70300

Country

Israel

Facility Name

GSK Investigational Site

City

Aichi

ZIP/Postal Code

466-8560

Country

Japan

Facility Name

GSK Investigational Site

City

Fukuoka

ZIP/Postal Code

812-8582

Country

Japan

Facility Name

GSK Investigational Site

City

Hokkaido

ZIP/Postal Code

060-8648

Country

Japan

Facility Name

GSK Investigational Site

City

Hyogo

ZIP/Postal Code

650-0017

Country

Japan

Facility Name

GSK Investigational Site

City

Miyagi

ZIP/Postal Code

980-8574

Country

Japan

Facility Name

GSK Investigational Site

City

Tochigi

ZIP/Postal Code

329-0498

Country

Japan

Facility Name

GSK Investigational Site

City

Tokyo

ZIP/Postal Code

113-8655

Country

Japan

Facility Name

GSK Investigational Site

City

Tokyo

ZIP/Postal Code

181-8611

Country

Japan

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

110-744

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

120-752

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Seoul

ZIP/Postal Code

135-710

Country

Korea, Republic of

Facility Name

GSK Investigational Site

City

Monterrey NL

State/Province

Nuevo León

ZIP/Postal Code

64718

Country

Mexico

Facility Name

GSK Investigational Site

City

Amsterdam

ZIP/Postal Code

1081 HV

Country

Netherlands

Facility Name

GSK Investigational Site

City

Kemerovo

ZIP/Postal Code

650002

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Novosibirsk

ZIP/Postal Code

630055

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Tomsk

ZIP/Postal Code

634012

Country

Russian Federation

Facility Name

GSK Investigational Site

City

Riyadh

Country

Saudi Arabia

Facility Name

GSK Investigational Site

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

GSK Investigational Site

City

Madrid

ZIP/Postal Code

28041

Country

Spain

Facility Name

GSK Investigational Site

City

Majadahonda (Madrid)

ZIP/Postal Code

28222

Country

Spain

Facility Name

GSK Investigational Site

City

Sevilla

ZIP/Postal Code

41013

Country

Spain

Facility Name

GSK Investigational Site

City

Cambridge

ZIP/Postal Code

CB23 3RE

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Clydebank

ZIP/Postal Code

G81 4DY

Country

United Kingdom

Facility Name

GSK Investigational Site

City

London

ZIP/Postal Code

NW3 2QH

Country

United Kingdom

12. IPD Sharing Statement

Learn more about this trial

Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension.

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Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension. (AMBER I)

Hypertension

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial