Pulmonary Hypertension
Conditions
Brief summary
The primary objective of this study was to evaluate the safety and efficacy of ambrisentan in a broad population of participants with pulmonary hypertension (PH). Secondary objectives of this study were to evaluate the effects of ambrisentan on other clinical measures of pulmonary arterial hypertension (PAH), long-term treatment success, and survival.
Detailed description
This study was to enroll up to 200 participants with PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1); 2) PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5). Participants with left heart disease or left heart failure were excluded (WHO Group 2). Participants could be receiving prostacyclin or sildenafil therapy at baseline, and participants who previously discontinued either bosentan, sitaxsentan, or both, due to liver function test abnormalities were eligible.
Interventions
DRUGAmbrisentan
Oral tablets taken once daily.
Sponsors
Gilead Sciences
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
Summarized Inclusion Criteria: 1. 18 years of age or older 2. Current diagnosis of PH associated with an acceptable etiology as outlined in the protocol, including: PH due to the following etiologies: 1) PAH including idiopathic and familial PAH and PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts (including Eisenmenger's syndrome), human immunodeficiency virus (HIV) infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gaucher disease, hemoglobinopathies, and splenectomy (WHO Group 1); 2) PH associated with lung diseases and/or hypoxemia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sleep-disordered breathing, and alveolar hypoventilation disorders (WHO Group 3); 3) PH due to proximal or distal chronic thromboembolic obstruction (WHO Group 4); and 4) PH due to sarcoidosis (WHO Group 5). 3. Stable regimen (within four weeks) of chronic prostanoid, PDE-5 inhibitor, calcium channel blocker, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor therapy 4. Right heart catheterization completed prior to screening must meet pre-specified criteria 5. Female participants of childbearing potential must have a negative serum pregnancy test and must agree to use a reliable double method of contraception until study completion and for at least four weeks following their final study visit. 6. Male participants must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking ambrisentan and queried regarding his understanding of the potential risks as described in the Informed Consent Form. Summarized
Exclusion criteria
1. Participation in a previous clinical study with ambrisentan 2. Bosentan or sitaxsentan use within four weeks prior to the screening visit 3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab value that is greater than 3 times the upper limit of normal at the screening visit 4. Pulmonary function tests not meeting the following pre-specified criteria: 1) mean pulmonary arterial pressure (PAP) \>= 25 mm Hg; 2) PVR \> 3 mm Hg/L/min; 3) pulmonary capillary wedge pressure (PCWP) or left ventricle end diastolic pressure (LVEDP) \< 15 mm Hg; 4) total lung capacity (TLC) \>= 70% of predicted normal for participants without ILD or \>= 60% of predicted normal in participants with ILD; forced expiratory volume in 1 second (FEV1) \>= 65% of predicted normal in participants without COPD or \>= 50% of predicted normal in participants with COPD 5. Contraindication to treatment with endothelin receptor antagonist (ERA) 6. History of malignancies other than basal cell carcinoma of the skin or in situ carcinoma of the cervix within the past five years 7. Female participant who is pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD) | Baseline to Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 48 in Borg Dyspnea Index | Baseline to Week 48 | Change from Baseline to Week 48 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum. |
| Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP) | Baseline to Week 24 | — |
| Percent Change From Baseline to Week 48 in BNP | Baseline to Week 48 | — |
| Change From Baseline to Week 24 in WHO Functional Class | Baseline to Week 24 | Change from baseline in World Health Organization functional class (WHO) at Week 24 is the incidence of participants that improved, had no change, or worsened. WHO categories are 1 to 4 with the worse category at 4. Improvement = a category change from baseline of \<= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0. |
| Change From Baseline to Week 48 in WHO Functional Class | Baseline to Week 48 | Change from baseline in WHO at Week 48 is expressed as the incidence of participants that improved, had no change or worsened. WHO categories range from 1 to 4 with the worse category at 4. Improvement = a category change from baseline of \<= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0. |
| Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale | Baseline to Week 24 | Change from baseline to Week 24 in the SF-36 health survey physical functioning scale. 10 activities rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10. |
| Change From Baseline to Week 24 in Borg Dyspnea Index | Baseline to Week 24 | Change from Baseline to Week 24 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum. |
| Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24 | Baseline to Week 24 | Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents |
| Percent of Participants With no Clinical Worsening of PH at Week 48 | Baseline to Week 48 | Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents |
| Failure-free Treatment Status | Baseline to Week 24 | Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents |
| Monotherapy Treatment Status | Baseline to Week 24 | Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment |
| Long-term Survival | Baseline to Week 24 | Defined as not dying during study participation |
| Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale | Baseline to Week 48 | Change from baseline to Week 48 in the SF-36 health survey physical functioning scale. 10 activities are rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General US population mean and standard deviation. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and standard deviation of 10. |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
Enrollment occurred between September 2006 and January 2008 and the study was conducted between August 2006 and May 2009 in 39 centers in the United States, Australia and Canada
Pre-assignment details
The screening period was 4 weeks. Participants who received bosentan or sitaxsentan within 4 weeks prior to the screening visit were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Ambrisentan Eligible participants received 5 mg ambrisentan once daily for the first 24 weeks. One dose reduction to 2.5 mg was permitted during the 24-week fixed-dose treatment period if the participant did not tolerate the study drug. After the initial 24-week treatment period, investigators could adjust the study drug dose as clinically indicated (available doses were 2.5, 5, and 10 mg). | 224 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Addition of other PAH therapeutic agent | 1 |
| Overall Study | Adverse Event | 40 |
| Overall Study | Lack of Efficacy | 5 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Lung transplant | 3 |
| Overall Study | Not compliant | 6 |
| Overall Study | Partipant moved away | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 10 |
Baseline characteristics
| Characteristic | Ambrisentan |
|---|---|
| Age Continuous | 55 years STANDARD_DEVIATION 16 |
| Sex: Female, Male Female | 156 Participants |
| Sex: Female, Male Male | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 203 / 224 |
| serious Total, serious adverse events | 97 / 224 |
Outcome results
Primary
Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD)
Time frame: Baseline to Week 24
Population: Full Analysis Set. Last Observation Carried forward. 4 participants were excluded from the analysis due to lack of post-baseline 6MWD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change From Baseline to Week 24 in 6 Minute Walk Distance (6MWD) | 20.5 meters | Standard Deviation 65.64 |
p-value: <0.00195% CI: [11.8, 29.3]t-test, 2 sided
Secondary
Change From Baseline to Week 24 in Borg Dyspnea Index
Change from Baseline to Week 24 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.
Time frame: Baseline to Week 24
Population: Full Analysis Set. Last Observation Carried forward. 4 participants were excluded from the analysis due to lack of post-baseline Borg Dyspnea Index data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change From Baseline to Week 24 in Borg Dyspnea Index | -0.5 Units on a scale | Standard Deviation 2.18 |
p-value: <0.00195% CI: [-0.8, -0.3]t-test, 2 sided
Secondary
Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale
Change from baseline to Week 24 in the SF-36 health survey physical functioning scale. 10 activities rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.
Time frame: Baseline to Week 24
Population: Full Analysis Set. Last Observation Carried forward. 26 participants were excluded from the analysis due to lack of baseline or post-baseline SF-36 data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change From Baseline to Week 24 in SF-36 Health Survey Physical Functioning Scale | 2.88 Units on a scale | Standard Deviation 7.943 |
p-value: <0.001t-test, 2 sided
Secondary
Change From Baseline to Week 24 in WHO Functional Class
Change from baseline in World Health Organization functional class (WHO) at Week 24 is the incidence of participants that improved, had no change, or worsened. WHO categories are 1 to 4 with the worse category at 4. Improvement = a category change from baseline of \<= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.
Time frame: Baseline to Week 24
Population: Full Analysis Set. Last Observation Carried Forward. 3 participants were not analyzed due to lack of post-baseline WHO functional class data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan | Change From Baseline to Week 24 in WHO Functional Class | -3 | 0 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 24 in WHO Functional Class | -2 | 0.9 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 24 in WHO Functional Class | -1 | 22.2 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 24 in WHO Functional Class | 0 | 70.1 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 24 in WHO Functional Class | 1 | 6.8 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 24 in WHO Functional Class | 2 | 0 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 24 in WHO Functional Class | 3 | 0 Percentage of participants |
p-value: <0.001Wilcoxon signed-rank test
Secondary
Change From Baseline to Week 48 in Borg Dyspnea Index
Change from Baseline to Week 48 in Borg Dyspnea Index. The Borg Dyspnea Index of Perceived Exertion Scores range from 0 to 10. Best and Worst values are: 0 (Best) to 10 (Worst). Scales are described as rating of breathlessness and its description: 0= none; 0.5= very,very slight (just noticeable); 1= very slight; 2=slight; 3= moderate; 4= somewhat severe; 5= severe; 6 (in between severe and very severe); 7= very severe; 8 (in between very, very severe and maximum); 9= very, very severe; and 10= maximum.
Time frame: Baseline to Week 48
Population: Full Analysis Set. Observed data. 114 participants were excluded from the analysis due to lack of Week 48 Borg Dyspnea Index data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change From Baseline to Week 48 in Borg Dyspnea Index | -0.6 Units on a scale | Standard Deviation 1.91 |
p-value: 0.00195% CI: [-1, -0.2]t-test, 2 sided
Secondary
Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale
Change from baseline to Week 48 in the SF-36 health survey physical functioning scale. 10 activities are rated by health limitations using 3 categories (1= Yes, limited a lot; 2= Yes, limited a little; and 3= No, not limited at all). The best score is 3 and the worst score is 1. Scores are transformed by subtracting the unit by the lowest raw score and dividing by the raw score range. The scores are then standardized with the 1998 General US population mean and standard deviation. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and standard deviation of 10.
Time frame: Baseline to Week 48
Population: Full Analysis Set. Last Observation Carried forward. 25 participants were excluded from the analysis due to lack of baseline or post-baseline SF-36 data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan | Change From Baseline to Week 48 in SF-36 Health Survey Physical Functioning Scale | 2.80 Units on a scale | Standard Deviation 8.634 |
p-value: <0.001t-test, 2 sided
Secondary
Change From Baseline to Week 48 in WHO Functional Class
Change from baseline in WHO at Week 48 is expressed as the incidence of participants that improved, had no change or worsened. WHO categories range from 1 to 4 with the worse category at 4. Improvement = a category change from baseline of \<= -1: change of -3 (eg, WHO from 4 to 1), change of -2 (eg, WHO from 3 to 1), change of -1 (eg, WHO from 2 to 1). Inversely, participants worsening are those with a category change from baseline of at least +1. No change in WHO functional class represents the percentage of participants with a change in category from baseline of 0.
Time frame: Baseline to Week 48
Population: Full Analysis Set. Observed Data. 3 participants were not analyzed due to lack of post-baseline WHO functional class data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan | Change From Baseline to Week 48 in WHO Functional Class | -3 | 0 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 48 in WHO Functional Class | -2 | 1.7 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 48 in WHO Functional Class | -1 | 34.5 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 48 in WHO Functional Class | 0 | 57.1 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 48 in WHO Functional Class | 1 | 6.7 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 48 in WHO Functional Class | 2 | 0 Percentage of participants |
| Ambrisentan | Change From Baseline to Week 48 in WHO Functional Class | 3 | 0 Percentage of participants |
p-value: <0.001Wilcoxon signed-rank test
Secondary
Failure-free Treatment Status
Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents
Time frame: Baseline to Week 24
Population: Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Failure-free Treatment Status | 95.3 Percentage of participants |
95% CI: [91.4, 97.4]
Secondary
Failure-free Treatment Status
Defined by occurrence of death, lung transplantation, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents
Time frame: Baseline to Week 48
Population: Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Failure-free Treatment Status | 92.9 Percentage of participants |
95% CI: [88.3, 95.8]
Secondary
Long-term Survival
Defined as not dying during study participation
Time frame: Baseline to Week 24
Population: Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Long-term Survival | 97.1 Percentage of participants |
95% CI: [93.6, 98.7]
Secondary
Long-term Survival
Defined as not dying during study participation
Time frame: Baseline to Week 48
Population: Full Analysis Set. Participants who were lost to follow-up were censored at the date of last contact.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Long-term Survival | 95.3 Percentage of participants |
95% CI: [91.2, 97.6]
Secondary
Monotherapy Treatment Status
Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment
Time frame: Baseline to Week 24
Population: Full Analysis Set - Subset of participants who were not receiving other PH therapy at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Monotherapy Treatment Status | 95.0 Percentage of participants |
95% CI: [88.5, 97.9]
Secondary
Monotherapy Treatment Status
Defined by no addition of sildenafil, iloprost, treprostinil, or epoprostenol to ongoing ambrisentan treatment
Time frame: Baseline to Week 48
Population: Full Analysis Set - Subset of participants who were not receiving other PH therapy at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Monotherapy Treatment Status | 90.0 Percentage of participants |
95% CI: [81.6, 94.7]
Secondary
Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP)
Time frame: Baseline to Week 24
Population: Full Analysis Set. Last Observation Carried forward. 10 participants were excluded from the analysis due to lack of baseline or post-baseline BNP data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ambrisentan | Percent Change From Baseline to Week 24 in B-type Natriuretic Peptide (BNP) | -25.5 Percent change in BNP |
95% CI: [-33.6, -16.3]
Secondary
Percent Change From Baseline to Week 48 in BNP
Time frame: Baseline to Week 48
Population: Full Analysis Set. Observed data. 111 participants were excluded from the analysis due to lack of baseline or Week 48 BNP data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ambrisentan | Percent Change From Baseline to Week 48 in BNP | -29.2 Percent change in BNP |
95% CI: [-39.8, -16.6]
Secondary
Percent of Participants With no Clinical Worsening of PH at Week 48
Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents
Time frame: Baseline to Week 48
Population: Full analysis set. Participants who were lost to follow-up were censored at the date of last contact.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Percent of Participants With no Clinical Worsening of PH at Week 48 | 84.1 Percentage of participants |
95% CI: [78.2, 88.6]
Secondary
Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24
Clinical worsening: occurrence of death, lung transplantation, hospitalization for PH, atrial septostomy, a change to chronic prostanoid or sildenafil treatment due to protocol-defined worsening criteria, or study withdrawal due to the addition of other clinically approved PH therapeutic agents
Time frame: Baseline to Week 24
Population: Full analysis set. Participants who were lost to follow-up were censored at the date of last contact.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ambrisentan | Percent of Participants With no Clinical Worsening of Pulmonary Hypertension (PH) at Week 24 | 89.4 Percentage of participants |
95% CI: [84.4, 92.8]