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Efficacy Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

Primary Purpose

Vascular Disease

Status

Completed

Phase

Phase 3

Locations

China

Study Type

Interventional

Intervention

ambrisentan

About this trial

This is an interventional treatment trial for Vascular Disease

Eligibility Criteria

18 Years - 75 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 18-75 years of age, inclusive, at the Screening Visit.
Subjects must weight ≥40 kg at the Screening Visit.
Subjects must have symptomatic or severe PAH (WHO functional class II or III) and be categorised as class 1 PAH (defined by the Updated Clinical Classification of Pulmonary Hypertension 2009), due to iPAH, congenital heart disease-congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects or patent ductus arteriosus) or CTD-related PAH (e.g., limited scleroderma, diffuse scleroderma, mixed CTD, systemic lupus erythematosus or overlap syndrome).

NOTE: subjects with portopulmonary hypertension and pulmonary venoocclusive disease are NOT eligible for the study.

Subjects must have had a right heart catheterisation within 6 months prior to screening and meet all of the following haemodynamic criteria:
1. Mean PAP ≥ 25 mmHg.
2. A PVR ≥ 240 dyn/sec/cm5.
3. A PCWP or left ventricular (LV) end-diastolic pressure of ≤ 15 mmHg.
Subjects must be able to walk a distance of at least 150 m but no more than 450 m. In addition, the screening and baseline 6MWT test values must not vary by greater than 10% (calculated using (baseline - screening)/screening with the result to be between -0.1 and 0.1).
Subjects must meet both of the following pulmonary function criteria. The tests should have been completed no more than 24 weeks prior to the Screening Visit, if not performed within the previous 24 weeks, the test must be completed at Day 0:
1. Total lung capacity (TLC) ≥ 60% of predicted normal.
2. Forced expiratory volume in one second (FEV1) ≥ 55% of predicted normal.
Subjects receiving CCBs must be on stable therapy (i.e., the dose level does not need to change to maintain disease control) for at least 1 month prior to the Screening Visit.
Subjects receiving 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) must be on stable therapy (i.e., the dose level does not need to change to maintain disease control) for at least 12 weeks prior to the Screening Visit.
Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and Day 0.
Female subjects of childbearing potential who are sexually active must agree to use two reliable methods of contraception (as described in Appendix 3 ) from the Screening Visit until study completion and for at least 30 days following the last dose of IP. Subjects who have had a Copper T 380A intrauterine device (IUD) or LNg 20 IUD inserted are not required to use an additional method of contraception.
Subject must agree not to participate in a clinical study involving another IP or device throughout this study.

Exclusion Criteria:

The subject has received PAH therapy (PDE-5 inhibitors, ERA, chronic prostanoid*) within 4 weeks prior to the Screening Visit.
*Prostanoid use is classed as chronic when treatment continues for more than 7 days.
The subject has received intravenous inotropes (e.g., dopamine, dobutamine) within 2 weeks prior to the Screening Visit.
The subject has previously been discontinued from ERA treatment (e.g., bosentan) due to safety or tolerance issues other than those associated with liver function abnormalities.
The subject has a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is >2 x the upper limit of normal (ULN) at the Screening Visit.
The subject has serum bilirubin value that is >1.5 x ULN at the Screening Visit.
The subject has severe hepatic impairment (Child-Pugh class C with or without cirrhosis) at the Screening Visit.
The subject has severe renal impairment (creatinine clearance <30 mL/min) at the Screening Visit.
The subject has clinically significant anaemia, defined as haemoglobin concentration <10 g/dL or haematocrit <30% at the Screening Visit.
The subject has a laboratory result, physical examination finding, medical history incident or other finding, which is a contraindication for treatment with an ERA. Contraindications for treatment include, but are not limited to, evidence of elevated liver functions test or previously experiencing an event that would be defined as a serious AE (SAE) in a clinical trial (see Section 6.3.3.2), which was attributed to treatment with an ERA.
The subject has severe hypotension (either diastolic blood pressure <50 mmHg or systolic blood pressure <90 mmHg).
The 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 LV dysfunction (defined as LV ejection fraction <45%), LV outflow obstruction, symptomatic coronary artery disease, autonomic hypotension or fluid depletion.
The subject has a history of malignancies within the past 5 years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix.
The subject has cardiovascular, liver, renal, haematological, gastrointestinal, immunological, 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 study drug or severely limit the lifespan of the subject.
A female subject who is pregnant or breastfeeding.
The subject has demonstrated non-compliance with previous medical regimens or is unable to comply with the procedures described in this protocol.
The subject has a history of abusing alcohol or drugs of abuse (including amphetamines, methamphetamines, opiates, cannabinoids, cocaine, benzodiazepines or barbiturates) within 12 months prior to the Screening Visit. Use of such drugs if prescribed by a Doctor and used according to the prescription would not exclude a subject.
The subject has participated in a clinical study involving another IP or device within 4 weeks or five half-lives of an IP, whichever is longer, before the Screening Visit.

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ambrisentan

Arm Description

ambrisentan 5 mg will be administered to eligible subjects for 12 weeks

Outcomes

Primary Outcome Measures

Change From Baseline in 6-minutes Walk Test (6MWT) at Week 12

The 6MWT measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 12 value minus the Baseline value. Baseline 6MWT comprised of an average of the last two consecutive measurements prior to dosing that varied by not greater than 10 percent (%). If only one measurement was available, that measurement was used as the Baseline value. The last observation carried forward method was used to impute missing values.

Secondary Outcome Measures

Change From Baseline in 6MWT at Week 24

The 6MWT measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 24 value minus the Baseline value. Baseline 6MWT comprised of an average of the last two consecutive measurements prior to dosing that varied by not greater than 10%. If only one measurement was available, that measurement was used as the Baseline value. The last observation carried forward method was used to impute missing values.

Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24

The WHO FC was determined by the investigator as follows: Class I- Participants with pulmonary hypertension (PH) but without resulting limitation of physical activity, II- Participants with PH resulting in slight limitation of physical activity, III- Participants with PH resulting in marked limitation of physical activity, IV- Participants with PH with inability to carry out any physical activity without symptoms. Changes from Baseline in functional class were summarized at Weeks 12 and 24. The number of participants improving by 2 classes, improving by 1 class, not changing, worsening by 1 class or worsening by 2 classes from Baseline at Weeks 12 and 24 were evaluated. The Baseline value was the last non-missing assessment value before treatment. Only participants with non-missing Baseline values and at least one non-missing post-Baseline value of the response variable were included. The last observation carried forward method was used to impute missing values.

Change From Baseline in the Borg Dyspnea Index (BDI) at Weeks 12 and 24

The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum). Change from Baseline was calculated as the Week 12 and 24 values minus the Baseline values. The BDI indicates the degree of exertion, breathlessness, fatigue, or difficulty breathing after completion of the 6MWT. The lower values, 0 as the lowest, indicates no exertion, fatigue, or breathlessness felt, and 10 would be the maximum amount of exertion felt as assessed by each participant. The last observation carried forward method was used to impute missing values.

Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Weeks 12 and 24

N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate maker of heart failure and was measured by a central laboratory. Mean change from Baseline at Weeks 12 and 24 were calculated as the Weeks 12 and 24 values minus the Baseline values.Observed data was analyzed (no imputation technique was performed for missing data). Log transformed mean change from Baseline at Weeks 12 and 24 data are summarized.

Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) up to Week 24, Assessed as the First Occurrence of a Particular Event

Time to clinical worsening is defined as the time from Baseline to the first occurrence of death, lung transplantation, hospitalization for PAH treatment, atrial septostomy, or Investigational product (IP) discontinuation (discon) due to change to other PAH treatment. Time to clinical worsening was measured as the number of participants who experienced these events during 12 and 24 Weeks.

Number of Participants With Any Adverse Events, Any Serious Adverse Events and Adverse Events Leading to Discontinuation

An adverse event (AE) is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be 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. A serious adverse event (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, a congenital anomaly/birth defect, or important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Number of Participants With Physical Examination Findings

Complete physical examinations of each participant by the investigator were performed at the Screening Visit, Week 12 and Week 24 Visit/Early withdrawal visits. The physical examination included an examination of the following: general appearance, skin, head, ears, eyes, nose, throat, neck, thyroid, lymph nodes, cardiovascular system, respiratory system, abdomen, musculoskeletal system, neurological system and height. Physical examination summary results were not collected therefore there is no data to present for this outcome measure.

Change From Baseline in Electrocardiogram (ECG) Heart Rate Values at Weeks 12 and 24

Heart rate was measured in order to monitor vital signs by the 12-lead ECG at Baseline, Weeks 12 and 24. Change from Baseline in ECG heart rate is summarized for each post-Baseline assessment at Weeks 12 and 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing observed value before treatment.

Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Interval Corrected Bazett's Formula (QTcB) Values at Weeks 12 and 24

The ECG parameters, PR interval, QRS duration, uncorrected QT interval, QTcB were measured at Baseline, Weeks 12 and 24. Change from Baseline in ECG heart rate is summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing observed value before treatment.

Change From Baseline in Systolic and Diastolic Blood Pressure at the Indicated Time Points up to Week 24

Blood pressure measurements (pre-6MWT and post-6MWT) were taken to monitor vital signs and included systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the Baseline, Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in SBP and DBP were summarized for each post-Baseline assessment upto Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing observed value before treatment.

Change From Baseline in Heart Rate at the Indicated Time Points up to Week 24

Vital sign monitoring included heart rate measurements at (pre-6MWT and post-6MWT at the Baseline visit, Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in heart rate was summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing value observed before treatment. At Baseline, Weeks 12 and 28, heart rate was recorded at the end of the 6MWT and at 1 minute (M), 2 M and 3 M, after completion of the 6MWT with the participants seated, and the time that heart rate recovered to the level of pre-6MWT.

Oral Temperature

Oral temperature was used to monitor vital signs and collected at the Screening visit.

Number of Participants With Shift From Baseline in Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST) and Total Bilirubin (BILT) up to Week 24

Blood samples were collected for the measurement of ALT, ALP, AST and BILT at the Baseline visit and up to Week 24. Shift from Baseline (BL) was calculated as the individual maximum of post-BL value minus the BL value. The BL value is defined as the last pre-treatment value observed. Threshold values for the liver function test results, which were considered as potential values of clinical concern, were 3 times the upper limit of normal (ULN) for ALT, AST and ALP and 2 times the ULN for BILT. Maximum liver function abnormal values of post-BL are summarized.

Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and WBC count at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and WBC count values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Change From Baseline in Hemoglobin at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of hemoglobin at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the hemoglobin count values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Change From Baseline in Hematocrit at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of hematocrit at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the hematocrit values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value is defined as the last Pre-treatment value observed. The unit of measure is defined as the proprtion of red blood cells in blood.

Change From Baseline in Mean Corpuscle Hemoglobin at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of mean corpuscle hemoglobin at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the hemoglobin values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of mean corpuscle volume at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the mean corpuscle volume values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Change From Baseline in Red Blood Cell (RBC) Count at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of RBC count at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the red blood cell count values were summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Change From Baseline in Albumin, Globulin and Total Protein at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of albumin, globulin and total protein at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the albumin, globulin and total protein values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Change From Baseline in Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), creatine kinase (CK), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the ALP, ALT, AST, CK, GGT and LDH values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Mean Change From Baseline in Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of direct bilirubin, total bilirubin, creatinine and uric acid at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the direct bilirubin, total bilirubin, creatinine and uric acid values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Change From Baseline in Calcium, Cholesterol, Chloride, Glucose, Potassium, Magnesium, Sodium, Inorganic Phosphorus, Triglycerides and Urea/Blood Urea Nitrogen (BUN) at the Indicated Time Points up to Week 24

Blood samples were collected for the measurement of calcium, cholesterol, chloride, glucose, potassium, magnesium, sodium, inorganic phosphorus, triglycerides and urea/Bun at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the calcium, cholesterol, chloride, glucose, potassium, magnesium, sodium, inorganic phosphorus, triglycerides and urea/BUN values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Number of Participants With Urinalysis Data at Baseline and Week 24

Urine samples were collected for urinalysis at Baseline and Week 24. The Number of participants with urinalysis to negative and positives (trace, +, ++ and +++) data at Baseline and Week 24 are summarized for urine bilirubin (UBIL), urine glucose (UGLU), urine ketones (UKET), urine nitrite (UNIT), urine protein (UM) and urine urobilinogen (UUBIL) were performed with dipstick method. Other urinalysis parameters included urine pH (UpH), urine specific gravity (USG). The Baseline value is defined as the last pre-treatment value observed.

Full Information

NCT ID

NCT01808313

First Posted

February 28, 2013

Last Updated

May 9, 2017

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT01808313

Brief Title

Efficacy Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

Official Title

An Open Label Phase IIIb Study to Evaluate Efficacy and Safety of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

Study Type

Interventional

2. Study Status

Record Verification Date

May 2017

Overall Recruitment Status

Completed

Study Start Date

December 1, 2012 (Actual)

Primary Completion Date

August 15, 2014 (Actual)

Study Completion Date

August 15, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

This open label, single-arm, non-controlled, multicentre study will determine the effect of ambrisentan on exercise capacity (6MWT) in Chinese subjects with PAH. The study consists of a screening period of 4 weeks, a 12-week primary evaluation period (PEP) and a 12-week dose-adjustment period (DAP). Ambrisentan 5 mg will be administered to eligible subjects for 12 weeks (PEP).

Detailed Description

Pulmonary arterial hypertension (PAH) consists of a group of progressive and incurable diseases of the pulmonary vasculature. These are characterised by profound vasoconstriction and abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries, which leads to a progressive increase in pulmonary vascular resistance (PVR) and sustained elevations in pulmonary artery pressure (PAP). A variety of drug classes have been used to treat PAH but no single compound has yet been shown to be effective in treating all patients with the disease. Three widely used treatment options are calcium channel blockers (CCBs), diuretics and anticoagulants but all have varying responses.There is a lack of clinical data on ambrisentan among the Chinese population,Ambrisentan is conditionally approved for the treatment of PAH in China.A clinical trial with a minimum of 100 patients in the ambrisentan arm was requested by SFDA.Several PAH medications have been approved in China, so a placebo-controlled study is not ethically appropriate while an active control non-inferiority design is unfeasible due to sample size requirements and inconsistency in indications.

6. Conditions and Keywords

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

Vascular Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

134 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ambrisentan

Arm Type

Experimental

Arm Description

ambrisentan 5 mg will be administered to eligible subjects for 12 weeks

Intervention Type

Drug

Intervention Name(s)

ambrisentan

Intervention Description

Ambrisentan 5 mg will be administered to eligible subjects for 12 weeks

Primary Outcome Measure Information:

Title

Change From Baseline in 6-minutes Walk Test (6MWT) at Week 12

Description

Time Frame

Baseline and Week 12

Secondary Outcome Measure Information:

Title

Change From Baseline in 6MWT at Week 24

Description

Time Frame

Baseline and Week 24

Title

Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24

Description

Time Frame

Baseline, Week 12 and Week 24

Title

Change From Baseline in the Borg Dyspnea Index (BDI) at Weeks 12 and 24

Description

Time Frame

Baseline, Week 12 and Week 24

Title

Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Weeks 12 and 24

Description

Time Frame

Baseline, Week 12 and Week 24

Title

Description

Time Frame

Baseline up to Week 24

Title

Number of Participants With Any Adverse Events, Any Serious Adverse Events and Adverse Events Leading to Discontinuation

Description

Time Frame

From the start of study treatment up to Week 24

Title

Number of Participants With Physical Examination Findings

Description

Time Frame

Baseline, Week 12 and Week 24

Title

Change From Baseline in Electrocardiogram (ECG) Heart Rate Values at Weeks 12 and 24

Description

Time Frame

Baseline, Week 12 and Week 24

Title

Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Interval Corrected Bazett's Formula (QTcB) Values at Weeks 12 and 24

Description

Time Frame

Baseline, Week 12 and Week 24

Title

Change From Baseline in Systolic and Diastolic Blood Pressure at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Heart Rate at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Oral Temperature

Description

Oral temperature was used to monitor vital signs and collected at the Screening visit.

Time Frame

Baseline

Title

Number of Participants With Shift From Baseline in Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST) and Total Bilirubin (BILT) up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Hemoglobin at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Hematocrit at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Mean Corpuscle Hemoglobin at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Red Blood Cell (RBC) Count at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Change From Baseline in Albumin, Globulin and Total Protein at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Description

Time Frame

Baseline up to Week 24

Title

Mean Change From Baseline in Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid at the Indicated Time Points up to Week 24

Description

Time Frame

Baseline up to Week 24

Title

Description

Time Frame

Baseline up to Week 24

Title

Number of Participants With Urinalysis Data at Baseline and Week 24

Description

Time Frame

Baseline and Week 24

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Signed written informed consent prior to beginning study-related procedures. Subject must be between 18-75 years of age, inclusive, at the Screening Visit. Subjects must weight ≥40 kg at the Screening Visit. Subjects must have symptomatic or severe PAH (WHO functional class II or III) and be categorised as class 1 PAH (defined by the Updated Clinical Classification of Pulmonary Hypertension 2009), due to iPAH, congenital heart disease-congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects or patent ductus arteriosus) or CTD-related PAH (e.g., limited scleroderma, diffuse scleroderma, mixed CTD, systemic lupus erythematosus or overlap syndrome). NOTE: subjects with portopulmonary hypertension and pulmonary venoocclusive disease are NOT eligible for the study. Subjects must have had a right heart catheterisation within 6 months prior to screening and meet all of the following haemodynamic criteria: Mean PAP ≥ 25 mmHg. A PVR ≥ 240 dyn/sec/cm5. A PCWP or left ventricular (LV) end-diastolic pressure of ≤ 15 mmHg. Subjects must be able to walk a distance of at least 150 m but no more than 450 m. In addition, the screening and baseline 6MWT test values must not vary by greater than 10% (calculated using (baseline - screening)/screening with the result to be between -0.1 and 0.1). Subjects must meet both of the following pulmonary function criteria. The tests should have been completed no more than 24 weeks prior to the Screening Visit, if not performed within the previous 24 weeks, the test must be completed at Day 0: Total lung capacity (TLC) ≥ 60% of predicted normal. Forced expiratory volume in one second (FEV1) ≥ 55% of predicted normal. Subjects receiving CCBs must be on stable therapy (i.e., the dose level does not need to change to maintain disease control) for at least 1 month prior to the Screening Visit. Subjects receiving 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) must be on stable therapy (i.e., the dose level does not need to change to maintain disease control) for at least 12 weeks prior to the Screening Visit. Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and Day 0. Female subjects of childbearing potential who are sexually active must agree to use two reliable methods of contraception (as described in Appendix 3 ) from the Screening Visit until study completion and for at least 30 days following the last dose of IP. Subjects who have had a Copper T 380A intrauterine device (IUD) or LNg 20 IUD inserted are not required to use an additional method of contraception. Subject must agree not to participate in a clinical study involving another IP or device throughout this study. Exclusion Criteria: The subject has received PAH therapy (PDE-5 inhibitors, ERA, chronic prostanoid*) within 4 weeks prior to the Screening Visit. *Prostanoid use is classed as chronic when treatment continues for more than 7 days. The subject has received intravenous inotropes (e.g., dopamine, dobutamine) within 2 weeks prior to the Screening Visit. The subject has previously been discontinued from ERA treatment (e.g., bosentan) due to safety or tolerance issues other than those associated with liver function abnormalities. The subject has a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is >2 x the upper limit of normal (ULN) at the Screening Visit. The subject has serum bilirubin value that is >1.5 x ULN at the Screening Visit. The subject has severe hepatic impairment (Child-Pugh class C with or without cirrhosis) at the Screening Visit. The subject has severe renal impairment (creatinine clearance <30 mL/min) at the Screening Visit. The subject has clinically significant anaemia, defined as haemoglobin concentration <10 g/dL or haematocrit <30% at the Screening Visit. The subject has a laboratory result, physical examination finding, medical history incident or other finding, which is a contraindication for treatment with an ERA. Contraindications for treatment include, but are not limited to, evidence of elevated liver functions test or previously experiencing an event that would be defined as a serious AE (SAE) in a clinical trial (see Section 6.3.3.2), which was attributed to treatment with an ERA. The subject has severe hypotension (either diastolic blood pressure <50 mmHg or systolic blood pressure <90 mmHg). The 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 LV dysfunction (defined as LV ejection fraction <45%), LV outflow obstruction, symptomatic coronary artery disease, autonomic hypotension or fluid depletion. The subject has a history of malignancies within the past 5 years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix. The subject has cardiovascular, liver, renal, haematological, gastrointestinal, immunological, 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 study drug or severely limit the lifespan of the subject. A female subject who is pregnant or breastfeeding. The subject has demonstrated non-compliance with previous medical regimens or is unable to comply with the procedures described in this protocol. The subject has a history of abusing alcohol or drugs of abuse (including amphetamines, methamphetamines, opiates, cannabinoids, cocaine, benzodiazepines or barbiturates) within 12 months prior to the Screening Visit. Use of such drugs if prescribed by a Doctor and used according to the prescription would not exclude a subject. The subject has participated in a clinical study involving another IP or device within 4 weeks or five half-lives of an IP, whichever is longer, 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

Harbin

State/Province

Heilongjiang

ZIP/Postal Code

150001

Country

China

Facility Name

GSK Investigational Site

City

Wuhan

State/Province

Hubei

ZIP/Postal Code

430022

Country

China

Facility Name

GSK Investigational Site

City

Hunan

State/Province

Hunan

ZIP/Postal Code

410008

Country

China

Facility Name

GSK Investigational Site

City

Changchun

State/Province

Jilin

ZIP/Postal Code

130021

Country

China

Facility Name

GSK Investigational Site

City

Xian

State/Province

Shaanxi

ZIP/Postal Code

710032

Country

China

Facility Name

GSK Investigational Site

City

Jinan

State/Province

Shandong

ZIP/Postal Code

250012

Country

China

Facility Name

GSK Investigational Site

City

Beijing

ZIP/Postal Code

100032

Country

China

Facility Name

GSK Investigational Site

City

Beijing

ZIP/Postal Code

100034

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

200001

Country

China

Facility Name

GSK Investigational Site

City

Shanghai

ZIP/Postal Code

200433

Country

China

12. IPD Sharing Statement

Citations:

PubMed Identifier

32799568

Citation

Zhao QH, Peng FH, Yu ZX, Zhang GC, Ji QS, Wang Y, Liu JM, Huo Y, Zeng XF, Li JH, Zi L, Jing ZC. Effect of ambrisentan on echocardiographic and Doppler measures from patients in China with pulmonary arterial hypertension. Expert Rev Cardiovasc Ther. 2020 Sep;18(9):643-649. doi: 10.1080/14779072.2020.1807942. Epub 2020 Sep 29.

Results Reference

derived

PubMed Identifier

32680480

Citation

Li M, Jing ZC, Li Y, Huo Y, Yu Z, Zhang G, Zhu P, Liu J, Ji Q, Wu B, Zhong J, Wang P, Zhu W, Zeng X. Efficacy and safety of ambrisentan in Chinese patients with connective tissue disease-pulmonary arterial hypertension: a post-hoc analysis. BMC Cardiovasc Disord. 2020 Jul 17;20(1):339. doi: 10.1186/s12872-020-01591-1.

Results Reference

derived

PubMed Identifier

27770771

Citation

Huo Y, Jing ZC, Zeng XF, Liu JM, Yu ZX, Zhang GC, Li Y, Wang Y, Ji QS, Zhu P, Wu BX, Zheng Y, Wang PP, Li J. Evaluation of efficacy, safety and tolerability of Ambrisentan in Chinese adults with pulmonary arterial hypertension: a prospective open label cohort study. BMC Cardiovasc Disord. 2016 Oct 22;16(1):201. doi: 10.1186/s12872-016-0361-9.

Results Reference

derived

Learn more about this trial

Efficacy Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

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Efficacy Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

Vascular Disease

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

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