Hypertension, Pulmonary
Conditions
Keywords
Ambrisentan, Pulmonary Arterial Hypertension, 6MWD
Brief summary
The primary objective of this study is to evaluate the effect of GSK1325760A on improvement in exercise capacity in subjects with pulmonary arterial hypertension (PAH). The secondary objectives of this study are to evaluate administration of GSK1325760A on: * The safety and tolerability * Improvement of PAH * The steady-state plasma pharmacokinetics of GSK1325760A
Interventions
DRUGGSK1325760A
Primary evaluation period: 5 mg/day, po, 12 weeks. Dose adjustment period: 2.5 mg, 5 mg or 10 mg/day, po, 12 weeks.
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have a diagnosis of Pulmonary Arterial Hypertension (PAH) in clinical classification of Pulmonary Hypertension Group1 * The mean right heart catheterization parameters measured from 6 months prior to the administration of the investigational drug must meet the criteria below: * Mean pulmonary arterial pressure (mPAP) of \>25 mmHg * Pulmonary vascular resistance (PVR) of \>3 mmHg/L/min * Mean pulmonary capillary wedge pressure or left ventricular end diastolic pressure of \<15 mmHg (if measurable) * The measured six minutes walk distance (6MWD) at screening visit is in the range of =\>150m and \<=450m
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Week 12 | Baseline and Week 12 | Mean change from baseline was calculated as the Week 12 value minus the baseline value. 6MWD was measured by a 6 minute walk test. This test measures the distance that a subject can walk in a period of 6 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Borg Dyspnea Index (BDI) at Weeks 12 and 24 | Baseline and 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 breathlessness after completion of the 6 minute walk test. The BDI scale was assessed by each participant. Imputation technique was last observation carried forward. |
| Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 | Weeks 12 and 24 | There are four grades for WHO FC (class I = none, Class IV = most severe). The WHO FC indicates the severity of Pulmonary Arterial Hypertension and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. Imputation technique was last observation carried forward. |
| Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) at Week 24, Assessed as the First Occurrence of a Particular Event | Week 24 | 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 study discontinuation due to change to other PAH treatment. Time to clinical worsening is measured as the number of participants who experienced these events during 24 weeks. |
| Mean Change From Baseline in Mean Pulmonary Atery Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) at Weeks 12 and 24 | Baseline and Weeks 12 and 24 | mPAP and mRAP are measures of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques). |
| Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Week 24/Withdrawal | Baseline and Week 24/Withdrawal | Change from baseline was calculated as the Week 24/Withdrawal value minus the basline value. 6MWD was measured by a 6 minute walk test. This test measures the distance that a subject can walk in a period of 6 minutes. Imputation technique was last observation carried forward. |
| Mean Change From Baseline in Cardiac Output (CO) at Weeks 12 and 24 | Baseline and Weeks 12 and 24 | CO is a measure of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques). |
| Mean Change From Baseline in Pulmonary Vascular Resistance (PVR) at Weeks 12 and 24 | Baseline and Weeks 12 and 24 | PVR is a measure of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques). |
| Mean Change From Baseline in B-type Natriuretic Peptide (BNP) Values at Weeks 12 and 24 | Baseline and Weeks 12 and 24 | Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. BNP is a surrogate maker of heart failure and was measured by a central laboratory. Observed data analysis (no imputation techniques). |
| Mean Change From Baseline in Cardiac Index (CI) at Weeks 12 and 24 | Baseline and Weeks 12 and 24 | CI is a measure of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GSK1325760A GSK1325760A 5 mg once a day by Week 12. After Week 12, GSK1325760A 10 mg once a day (the dosage could be increased or decreased appropriately according to a participant's condition). | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| First 12-Week Treatment Period | Adverse Event | 1 |
| First 12-Week Treatment Period | Initiation of prohibited medication | 1 |
| First 12-Week Treatment Period | Withdrawal by Subject | 1 |
| Second 12-Week Treatment Period | Adverse Event | 1 |
Baseline characteristics
| Characteristic | GSK1325760A |
|---|---|
| Age Continuous | 45.5 years STANDARD_DEVIATION 13.66 |
| Race/Ethnicity, Customized Asian-Japanese Heritage | 25 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / — |
| serious Total, serious adverse events | 4 / — |
Outcome results
Primary
Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Week 12
Mean change from baseline was calculated as the Week 12 value minus the baseline value. 6MWD was measured by a 6 minute walk test. This test measures the distance that a subject can walk in a period of 6 minutes.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS): all participants registered, with the exception of those who had not received any dose of the investigational product and those who had no efficacy assessment after administration of the investigational product. Imputation technique was last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Week 12 | 33.49 Meters | Standard Deviation 43.236 |
95% CI: [15.231, 51.744]
Secondary
Mean Change From Baseline in B-type Natriuretic Peptide (BNP) Values at Weeks 12 and 24
Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. BNP is a surrogate maker of heart failure and was measured by a central laboratory. Observed data analysis (no imputation techniques).
Time frame: Baseline and Weeks 12 and 24
Population: Full Analysis Set: Analysis was conducted using observed data only. Some participants were withdrawn before Week 24, or some participants could not be measured at Week 24 in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in B-type Natriuretic Peptide (BNP) Values at Weeks 12 and 24 | Week 12, n=21 | -76.86 Nanograms/Liter (ng/L) | Standard Deviation 160.942 |
| GSK1325760A | Mean Change From Baseline in B-type Natriuretic Peptide (BNP) Values at Weeks 12 and 24 | Week 24, n=24 | -60.15 Nanograms/Liter (ng/L) | Standard Deviation 248.345 |
Secondary
Mean Change From Baseline in Cardiac Index (CI) at Weeks 12 and 24
CI is a measure of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques).
Time frame: Baseline and Weeks 12 and 24
Population: Full Analysis Set: Analysis was conducted using observed data only. Some participants were withdrawn before Week 24, or some participants could not be measured at Week 24 in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in Cardiac Index (CI) at Weeks 12 and 24 | Week 12, n=21 | 0.623 L/min/m2 | Standard Deviation 0.598 |
| GSK1325760A | Mean Change From Baseline in Cardiac Index (CI) at Weeks 12 and 24 | Week 24, n=16 | 0.598 L/min/m2 | Standard Deviation 0.6115 |
Secondary
Mean Change From Baseline in Cardiac Output (CO) at Weeks 12 and 24
CO is a measure of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques).
Time frame: Baseline and Weeks 12 and 24
Population: Full Analysis Set: Analysis was conducted using observed data only. Some participants were withdrawn before Week 24, or some participants could not be measured at Week 24 in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in Cardiac Output (CO) at Weeks 12 and 24 | Week 12, n=21 | 1.033 L/min | Standard Deviation 0.8783 |
| GSK1325760A | Mean Change From Baseline in Cardiac Output (CO) at Weeks 12 and 24 | Week 24, n=16 | 1.035 L/min | Standard Deviation 0.9968 |
Secondary
Mean Change From Baseline in Mean Pulmonary Atery Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) at Weeks 12 and 24
mPAP and mRAP are measures of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques).
Time frame: Baseline and Weeks 12 and 24
Population: Full Analysis Set: Analysis was conducted using observed data only. Some participants were withdrawn before Week 24, or some participants could not be measured at Week 24 in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in Mean Pulmonary Atery Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) at Weeks 12 and 24 | mPAP (mmHg) at Week 24, n=16 | -8.69 mmHg | Standard Deviation 13.903 |
| GSK1325760A | Mean Change From Baseline in Mean Pulmonary Atery Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) at Weeks 12 and 24 | mPAP (mmHg) at Week 12, n=21 | -6.29 mmHg | Standard Deviation 11.201 |
| GSK1325760A | Mean Change From Baseline in Mean Pulmonary Atery Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) at Weeks 12 and 24 | mRAP (mmHg) at Week 12, n=21 | -1.12 mmHg | Standard Deviation 3.761 |
| GSK1325760A | Mean Change From Baseline in Mean Pulmonary Atery Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) at Weeks 12 and 24 | mRAP (mmHg) at Week 24, n=16 | -0.69 mmHg | Standard Deviation 3.683 |
Secondary
Mean Change From Baseline in Pulmonary Vascular Resistance (PVR) at Weeks 12 and 24
PVR is a measure of cardiopulmonary hemodynamics. Change from baseline was calculated as the Week 12 and 24 values minus the baseline value. Observed data analysis (no imputation techniques).
Time frame: Baseline and Weeks 12 and 24
Population: Full Analysis Set: Analysis was conducted using observed data only. Some participants were withdrawn before Week 24, or some participants could not be measured at Week 24 in this study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in Pulmonary Vascular Resistance (PVR) at Weeks 12 and 24 | Week 12, n=21 | -7.257 mmHg/L/min | Standard Deviation 7.4344 |
| GSK1325760A | Mean Change From Baseline in Pulmonary Vascular Resistance (PVR) at Weeks 12 and 24 | Week 24, n=16 | -8.349 mmHg/L/min | Standard Deviation 7.6391 |
Secondary
Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Week 24/Withdrawal
Change from baseline was calculated as the Week 24/Withdrawal value minus the basline value. 6MWD was measured by a 6 minute walk test. This test measures the distance that a subject can walk in a period of 6 minutes. Imputation technique was last observation carried forward.
Time frame: Baseline and Week 24/Withdrawal
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in Six Minutes Walk Distance (6MWD) at Week 24/Withdrawal | 46.82 Meters | Standard Deviation 52.705 |
95% CI: [24.566, 69.076]
Secondary
Mean 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 breathlessness after completion of the 6 minute walk test. The BDI scale was assessed by each participant. Imputation technique was last observation carried forward.
Time frame: Baseline and Weeks 12 and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GSK1325760A | Mean Change From Baseline in the Borg Dyspnea Index (BDI) at Weeks 12 and 24 | Week 12 | -0.60 Points on a scale | Standard Deviation 2.157 |
| GSK1325760A | Mean Change From Baseline in the Borg Dyspnea Index (BDI) at Weeks 12 and 24 | Week 24 | -0.69 Points on a scale | Standard Deviation 1.904 |
Secondary
Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24
There are four grades for WHO FC (class I = none, Class IV = most severe). The WHO FC indicates the severity of Pulmonary Arterial Hypertension and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. Imputation technique was last observation carried forward.
Time frame: Weeks 12 and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1325760A | Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 | Improved at Week 12 | 9 Participants |
| GSK1325760A | Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 | No change at Week 12 | 16 Participants |
| GSK1325760A | Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 | Deteriorated at Week 12 | 0 Participants |
| GSK1325760A | Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 | Improved at Week 24 | 10 Participants |
| GSK1325760A | Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 | No change at Week 24 | 14 Participants |
| GSK1325760A | Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 | Deteriorated at Week 24 | 1 Participants |
Secondary
Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) at 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 study discontinuation due to change to other PAH treatment. Time to clinical worsening is measured as the number of participants who experienced these events during 24 weeks.
Time frame: Week 24
Population: Full Analysis Set: : all participants registered, with the exception of those who had not received any dose of the investigational product and those who had no efficacy assessment after administration of the investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1325760A | Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) at Week 24, Assessed as the First Occurrence of a Particular Event | Death | 0 Participants |
| GSK1325760A | Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) at Week 24, Assessed as the First Occurrence of a Particular Event | Lung transplantation | 0 Participants |
| GSK1325760A | Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) at Week 24, Assessed as the First Occurrence of a Particular Event | Hospitalization for PAH treatment | 0 Participants |
| GSK1325760A | Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) at Week 24, Assessed as the First Occurrence of a Particular Event | Atrial Septostomy | 0 Participants |
| GSK1325760A | Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) at Week 24, Assessed as the First Occurrence of a Particular Event | Study discontinuation (additional medication) | 1 Participants |