Pulmonary Arterial Hypertension
Conditions
Brief summary
AMB-320/321-E was designed to provide long-term, controlled monitoring of pulmonary arterial hypertension (PAH) patients treated with ambrisentan (AMB) in order to properly define the adverse event profile associated with this endothelin receptor antagonist (ERA), including the incidence and severity of elevated serum liver function tests (LFTs). In addition, this study continued the efficacy assessments of the previous studies, examined long-term AMB treatment success, and compared long-term survival of subjects treated with AMB to the NIH registry of patients with PAH.
Detailed description
AMB-320 (ARIES-1; NCT00423748) and AMB-321 (ARIES-2; NCT00423202) were 12-week, Phase 3, randomized, double-blind, placebo-controlled, multicenter, efficacy studies of AMB in subjects with PAH. The objectives of these studies were to determine the effect of three doses of AMB (2.5, 5.0, and 10.0 mg) on exercise capacity, as well as several clinical measures of PAH. The current study (NCT00578786) was unblinded (by design) prior to completion. The ARIES studies were identical except for the dose groups assessed and the geographic locations where the studies were conducted. Both studies evaluated placebo and 5.0-mg AMB dose groups; however, AMB-320 (NCT00423748) also examined an AMB dose of 10.0 mg, while AMB-321 (NCT00423202) included an AMB dose of 2.5 mg. AMB-320/321-E was an optional study for subjects who had participated in AMB-320 (NCT00423748) or AMB-321 (NCT00423202) that allowed continued long-term treatment with AMB.
Interventions
DRUGambrisentan
2.5, 5.0 or 10.0 mg ambrisentan po, qd, long-term
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject must have completed Week 12 of AMB-320 (NCT00423748) or AMB-321 (NCT00423202) or must have received placebo during AMB-320 (NCT00423748) or AMB-321 (NCT00423202) and met two or more early escape criteria; 2. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form and must sign the form prior to the initiation of any study procedures. 3. Female subject of childbearing potential must agree to use two reliable methods of contraception until study completion and for at least four weeks following their final study visit. Reliable methods include: birth control pills/implants/injections, intrauterine devices (IUDs), spermicide, diaphragms, or condoms.
Exclusion criteria
* Subjects must have met the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequently Reported (15% or More Overall) Adverse Events by Severity | Baseline to Week 295 | The primary endpoint of this study is the incidence and severity of adverse events associated with long-term exposure to AMB in participants with PAH. The most frequently occurring adverse events (occurring in 15% or more of the participants in the combined group) are presented, by severity, that began after entering this extension study. Adverse events that were serious are included. Adverse events are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 6.1 and are presented by MedDRA preferred term. Severity was graded as follows: mild (AE did not interfere with routine activities; subject may have experienced slight discomfort), moderate (AE interfered with routine activities; subject may have experienced significant discomfort), and severe (AE made it impossible to perform routine activities; subject may have experienced intolerable discomfort or pain). |
| Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | Baseline to Week 295 | The number of participants with serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) falling into the following categories: \>3.0 and \</= 5.0 x ULN, \>5.0 and \</= 8.0 x ULN, and \>8.0 x ULN. Includes the highest value per participant across all visits as well as values from early termination visits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | Baseline to Week 48 | The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies. |
| Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | Baseline to Year 2 | The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies. |
| Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | Baseline to Year 3 | Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies. |
| Baseline Borg Dyspnea Index | Baseline | Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). |
| Change From Baseline to Year 1 in Borg Dyspnea Index | Baseline to Year 1 | Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies. |
| Change From Baseline to Year 2 in Borg Dyspnea Index | Baseline to Year 2 | Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies. |
| Change From Baseline to Year 3 in Borg Dyspnea Index | Baseline to Year 3 | Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies. |
| Baseline World Health Organization (WHO) Functional Class | Baseline | WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest. |
| Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Baseline to Year 1 | WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest. |
| Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test | Baseline | The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). |
| Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Baseline to Year 3 | WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest. |
| Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Baseline | The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). 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 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Baseline to Week 12 | The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and 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 SF-36 Health Survey Scales for the Combined Ambrisentan Group | Baseline to Week 24 | The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and 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 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Baseline to Week 36 | The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and SD. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10. |
| Percentage of Participants With No Clinical Worsening of PAH | Baseline to Year 3 | Clinical worsening of PAH was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to AMB in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having clinical worsening after a given time. |
| Percentage of Participants With Failure-Free Treatment Status | Baseline to Year 4 | Treatment failure was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to ambrisentan in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having treatment failure after a given time. |
| Long-term Survival | Baseline to Year 4 | Long-term survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of survival after a given time. |
| Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Baseline to Year 2 | WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest. |
| Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | Baseline to Week 24 | The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). Missing values were imputed using LOCF method based on post-baseline observations. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies. |
Countries
Argentina, Brazil, Chile, Mexico
Participant flow
Recruitment details
Participants completing Week 12 of NCT00423748 or NCT00423202 could enroll in extension (E) study. Participants on placebo in parent study and d/c treatment due to \>/=2 early escape criteria were eligible. Total randomized: 361 (completed/early escape in prior study), 19 (d/c prior study), and 3 (completed prior study, did not enroll in E study).
Pre-assignment details
Participants on active treatment in NCT00423748 or NCT00423202 continued to receive their last assigned blinded ambrisentan (AMB) dose from the prior study. Those on placebo in NCT00423748 were randomized to receive either 5 or 10 mg of AMB in the extension study. Those on placebo in NCT00423202 were randomized to either 2.5 or 5 mg of AMB.
Participants by arm
| Arm | Count |
|---|---|
| Ambrisentan 2.5 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, almost half of those randomized to AMB 2.5 mg were titrated to 5 mg and 10 mg. | 96 |
| Ambrisentan 5 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). Analysis included those not enrolling in this study but received AMB in 1 of the 2 parent studies. It should be noted that by Year 3, a third starting at 5 mg were titrated to 10 mg. | 190 |
| Ambrisentan 10 mg Original randomized dose group in the prior study (NCT00423748 and NCT00423202) or in the current study (for subjects originally randomized to placebo in one of the prior studies). | 97 |
| Total | 383 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 27 | 37 | 17 |
| Overall Study | Early Escape from Prior Study | 2 | 1 | 2 |
| Overall Study | Lack of Efficacy | 2 | 5 | 2 |
| Overall Study | Lost to Follow-up | 0 | 4 | 0 |
| Overall Study | Not Otherwise Specified | 0 | 4 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Pregnancy | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 3 | 1 |
| Overall Study | Qualified but Not Enrolled in Extension | 0 | 3 | 0 |
| Overall Study | Sponsor Decision | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 8 | 5 |
Baseline characteristics
| Characteristic | Ambrisentan 2.5 mg | Ambrisentan 5 mg | Ambrisentan 10 mg | Total |
|---|---|---|---|---|
| 6-Minute Walk Distance (6MWD) | 350.3 meters STANDARD_DEVIATION 86.64 | 347.7 meters STANDARD_DEVIATION 87.333 | 342.3 meters STANDARD_DEVIATION 80.84 | 347.0 meters STANDARD_DEVIATION 85.389 |
| Age Continuous | 52.27 years STANDARD_DEVIATION 14.968 | 51.46 years STANDARD_DEVIATION 14.429 | 49.09 years STANDARD_DEVIATION 16.572 | 51.06 years STANDARD_DEVIATION 15.139 |
| Body Mass Index (BMI) | 26.68 kg/m^2 STANDARD_DEVIATION 5.038 | 26.86 kg/m^2 STANDARD_DEVIATION 5.632 | 28.26 kg/m^2 STANDARD_DEVIATION 7.212 | 27.17 kg/m^2 STANDARD_DEVIATION 5.958 |
| Borg Dyspnea Index (BDI) | 4.14 units on a scale STANDARD_DEVIATION 2.684 | 3.80 units on a scale STANDARD_DEVIATION 2.332 | 3.78 units on a scale STANDARD_DEVIATION 2.133 | 3.88 units on a scale STANDARD_DEVIATION 2.377 |
| Pulmonary Arterial Hypertension Stratification Idiopathic PAH (IPAH) | 63 participants | 119 participants | 59 participants | 241 participants |
| Pulmonary Arterial Hypertension Stratification Non-IPAH | 33 participants | 71 participants | 38 participants | 142 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 6 participants | 2 participants | 9 participants |
| Race/Ethnicity, Customized Black | 0 participants | 5 participants | 6 participants | 11 participants |
| Race/Ethnicity, Customized Caucasian | 81 participants | 148 participants | 65 participants | 294 participants |
| Race/Ethnicity, Customized Hispanic | 14 participants | 29 participants | 22 participants | 65 participants |
| Race/Ethnicity, Customized Other | 0 participants | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 69 Participants | 154 Participants | 79 Participants | 302 Participants |
| Sex: Female, Male Male | 27 Participants | 36 Participants | 18 Participants | 81 Participants |
| World Heath Organization (WHO) Class WHO Class I | 1 participants | 7 participants | 4 participants | 12 participants |
| World Heath Organization (WHO) Class WHO Class II | 51 participants | 77 participants | 35 participants | 163 participants |
| World Heath Organization (WHO) Class WHO Class III | 39 participants | 91 participants | 48 participants | 178 participants |
| World Heath Organization (WHO) Class WHO Class IV | 5 participants | 15 participants | 10 participants | 30 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 36 / 43 | 131 / 146 | 190 / 194 |
| serious Total, serious adverse events | 26 / 43 | 76 / 146 | 103 / 194 |
Outcome results
Primary
Frequently Reported (15% or More Overall) Adverse Events by Severity
The primary endpoint of this study is the incidence and severity of adverse events associated with long-term exposure to AMB in participants with PAH. The most frequently occurring adverse events (occurring in 15% or more of the participants in the combined group) are presented, by severity, that began after entering this extension study. Adverse events that were serious are included. Adverse events are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 6.1 and are presented by MedDRA preferred term. Severity was graded as follows: mild (AE did not interfere with routine activities; subject may have experienced slight discomfort), moderate (AE interfered with routine activities; subject may have experienced significant discomfort), and severe (AE made it impossible to perform routine activities; subject may have experienced intolerable discomfort or pain).
Time frame: Baseline to Week 295
Population: Safety Analysis Set: Includes all participants who received at least 1 dose of AMB in one of the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study. Treatment group assignments for the safety analysis set were based upon the highest dose of AMB received at any time during the parent or extension studies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Moderate | 2 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Moderate | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Moderate | 2 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Mild | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Severe | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Mild | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Severe | 6 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Mild | 6 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Severe | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Moderate | 4 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Moderate | 6 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Moderate | 2 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Mild | 2 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Severe | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Mild | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Severe | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Mild | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Mild | 3 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Moderate | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Severe | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Severe | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Severe | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Mild | 2 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Moderate | 3 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Moderate | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Moderate | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Moderate | 3 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Mild | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Severe | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Severe | 0 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Severe | 5 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Mild | 1 participants |
| Ambrisentan 2.5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Mild | 1 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Mild | 13 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Moderate | 7 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Mild | 5 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Moderate | 14 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Severe | 2 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Severe | 0 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Mild | 4 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Moderate | 11 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Severe | 2 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Mild | 12 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Moderate | 10 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Severe | 2 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Mild | 14 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Moderate | 8 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Severe | 0 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Mild | 31 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Moderate | 19 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Severe | 3 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Mild | 20 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Moderate | 14 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Severe | 0 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Mild | 2 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Moderate | 10 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Severe | 6 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Mild | 2 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Moderate | 7 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Severe | 12 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Mild | 23 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Moderate | 2 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Severe | 1 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Moderate | 4 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Severe | 0 participants |
| Ambrisentan 5 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Mild | 8 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Severe | 19 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Moderate | 15 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Moderate | 26 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Mild | 6 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Mild | 19 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Severe | 7 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Moderate | 14 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Severe | 1 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Moderate | 14 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Right ventricular failure - Severe | 26 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Moderate | 15 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Severe | 1 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Mild | 24 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Diarrhoea - Mild | 17 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Mild | 19 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Moderate | 22 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Severe | 1 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Moderate | 22 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Cough - Severe | 0 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Mild | 36 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Arthralgia - Moderate | 18 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Moderate | 17 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Severe | 4 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dyspnoea exacerbated - Mild | 8 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Headache - Severe | 8 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Moderate | 50 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Upper respiratory tract infection - Mild | 23 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Mild | 7 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Oedema peripheral - Mild | 48 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Severe | 3 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Pulmonary hypertension (worsening) - Moderate | 29 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Nasopharyngitis - Severe | 0 participants |
| Ambrisentan 10 mg | Frequently Reported (15% or More Overall) Adverse Events by Severity | Dizziness - Mild | 31 participants |
Primary
Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN)
The number of participants with serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) falling into the following categories: \>3.0 and \</= 5.0 x ULN, \>5.0 and \</= 8.0 x ULN, and \>8.0 x ULN. Includes the highest value per participant across all visits as well as values from early termination visits.
Time frame: Baseline to Week 295
Population: Safety Analysis Set: Includes all participants who received at least 1 blinded dose of AMB in one of the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >3.0 and </=5.0 x ULN | 0 participants |
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >5.0 and </= 8.0 x ULN | 0 participants |
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >8.0 x ULN | 0 participants |
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | Total ALT results >3.0 x ULN | 0 participants |
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >3.0 and </=5.0 x ULN | 1 participants |
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >5.0 and </= 8.0 x ULN | 0 participants |
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >8.0 x ULN | 0 participants |
| Ambrisentan 2.5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | Total AST results >3.0 x ULN | 1 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >8.0 x ULN | 3 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >8.0 x ULN | 0 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | Total ALT results >3.0 x ULN | 0 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >3.0 and </=5.0 x ULN | 3 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >5.0 and </= 8.0 x ULN | 1 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >3.0 and </=5.0 x ULN | 2 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >5.0 and </= 8.0 x ULN | 1 participants |
| Ambrisentan 5 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | Total AST results >3.0 x ULN | 4 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >8.0 x ULN | 5 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >5.0 and </= 8.0 x ULN | 0 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | ALT >3.0 and </=5.0 x ULN | 4 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | Total ALT results >3.0 x ULN | 1 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >8.0 x ULN | 1 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >5.0 and </= 8.0 x ULN | 0 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | AST >3.0 and </=5.0 x ULN | 7 participants |
| Ambrisentan 10 mg | Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) | Total AST results >3.0 x ULN | 8 participants |
Secondary
Baseline Borg Dyspnea Index
Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time frame: Baseline
Population: All assessments of efficacy were performed using the randomized analysis set, such that subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Baseline Borg Dyspnea Index | 4.14 units on a scale | Standard Deviation 2.684 |
| Ambrisentan 5 mg | Baseline Borg Dyspnea Index | 3.80 units on a scale | Standard Deviation 2.332 |
| Ambrisentan 10 mg | Baseline Borg Dyspnea Index | 3.78 units on a scale | Standard Deviation 2.133 |
| Combined Ambrisentan Group | Baseline Borg Dyspnea Index | 3.88 units on a scale | Standard Deviation 2.377 |
Secondary
Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test
The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.).
Time frame: Baseline
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 350.3 Meters | Standard Deviation 86.64 |
| Ambrisentan 5 mg | Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 347.7 Meters | Standard Deviation 87.33 |
| Ambrisentan 10 mg | Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 342.3 Meters | Standard Deviation 80.84 |
| Combined Ambrisentan Group | Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 347.0 Meters | Standard Deviation 85.39 |
Secondary
Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group
The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). 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
Population: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Functioning | 30.0 units on a scale | Standard Deviation 9.02 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Physical | 35.2 units on a scale | Standard Deviation 10.21 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Bodily Pain | 46.3 units on a scale | Standard Deviation 11.93 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | General Health | 36.0 units on a scale | Standard Deviation 8.65 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Vitality | 42.1 units on a scale | Standard Deviation 10.23 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Social Functioning | 39.6 units on a scale | Standard Deviation 11.8 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Emotional | 39.2 units on a scale | Standard Deviation 13.47 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Health | 43.3 units on a scale | Standard Deviation 12.12 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Component Summary | 35.1 units on a scale | Standard Deviation 8.52 |
| Ambrisentan 2.5 mg | Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Component Summary | 44.5 units on a scale | Standard Deviation 11.98 |
Secondary
Baseline World Health Organization (WHO) Functional Class
WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.
Time frame: Baseline
Population: All assessments of efficacy were performed using the randomized analysis set, such that subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan 2.5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class I | 1 participants |
| Ambrisentan 2.5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class II | 51 participants |
| Ambrisentan 2.5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class III | 39 participants |
| Ambrisentan 2.5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class IV | 5 participants |
| Ambrisentan 5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class II | 77 participants |
| Ambrisentan 5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class III | 91 participants |
| Ambrisentan 5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class IV | 15 participants |
| Ambrisentan 5 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class I | 7 participants |
| Ambrisentan 10 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class III | 48 participants |
| Ambrisentan 10 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class II | 35 participants |
| Ambrisentan 10 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class IV | 10 participants |
| Ambrisentan 10 mg | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class I | 4 participants |
| Combined Ambrisentan Group | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class IV | 30 participants |
| Combined Ambrisentan Group | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class II | 163 participants |
| Combined Ambrisentan Group | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class I | 12 participants |
| Combined Ambrisentan Group | Baseline World Health Organization (WHO) Functional Class | WHO Functional Class III | 178 participants |
Secondary
Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and 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 12
Population: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Functioning (n=299) | 3.9 units on a scale | Standard Deviation 7.4 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Physical (n=298) | 5.6 units on a scale | Standard Deviation 10.81 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Bodily Pain (n=303) | 1.8 units on a scale | Standard Deviation 11.27 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | General Health (n=297) | 3.1 units on a scale | Standard Deviation 7.85 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Vitality (n=301) | 4.6 units on a scale | Standard Deviation 9.12 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Social Functioning (n=303) | 3.9 units on a scale | Standard Deviation 10.63 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Emotional (n=286) | 3.9 units on a scale | Standard Deviation 14.69 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Health (n=301) | 3.2 units on a scale | Standard Deviation 9.72 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Component Summary (n=276) | 3.8 units on a scale | Standard Deviation 7.59 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Component Summary (n=276) | 3.4 units on a scale | Standard Deviation 10.77 |
Secondary
Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). Missing values were imputed using LOCF method based on post-baseline observations. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.
Time frame: Baseline to Week 24
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 38.0 Meters | Standard Deviation 74.28 |
| Ambrisentan 5 mg | Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 32.5 Meters | Standard Deviation 78.55 |
| Ambrisentan 10 mg | Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 40.9 Meters | Standard Deviation 72.85 |
| Combined Ambrisentan Group | Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 36.0 Meters | Standard Deviation 75.97 |
95% CI: [22.7, 53.3]
95% CI: [21.1, 43.8]
95% CI: [26.1, 55.7]
95% CI: [28.3, 43.7]
Secondary
Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and 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: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Functioning (n=226) | 4.7 units on a scale | Standard Deviation 8.75 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Physical (n=227) | 5.7 units on a scale | Standard Deviation 13.37 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Bodily Pain (n=230) | 1.0 units on a scale | Standard Deviation 13.28 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | General Health (n=223) | 3.2 units on a scale | Standard Deviation 8.11 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Vitality (n=227) | 4.5 units on a scale | Standard Deviation 9.55 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Social Functioning (n=230) | 3.5 units on a scale | Standard Deviation 11.5 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Emotional (n=220) | 4.3 units on a scale | Standard Deviation 14.45 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Health (n=227) | 2.6 units on a scale | Standard Deviation 10.57 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Component Summary (n=212) | 3.8 units on a scale | Standard Deviation 9.06 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Component Summary (n=212) | 3.2 units on a scale | Standard Deviation 11.06 |
Secondary
Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and 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 36
Population: All participants were combined into one group for this analysis (all doses) and an observed-case approach was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Functioning (n=183) | 4.9 units on a scale | Standard Deviation 8.27 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Physical (n=181) | 4.5 units on a scale | Standard Deviation 12.34 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Bodily Pain (n=186) | 1.9 units on a scale | Standard Deviation 13.16 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | General Health (n=181) | 4.5 units on a scale | Standard Deviation 12.34 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Vitality (n=185) | 4.6 units on a scale | Standard Deviation 9.16 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Social Functioning (n=186) | 3.7 units on a scale | Standard Deviation 12.26 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Role Emotional (n=178) | 3.6 units on a scale | Standard Deviation 15.17 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Health (n=185) | 2.9 units on a scale | Standard Deviation 11 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Physical Component Summary (n=169) | 3.9 units on a scale | Standard Deviation 8.79 |
| Ambrisentan 2.5 mg | Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group | Mental Component Summary (n=169) | 2.9 units on a scale | Standard Deviation 11.34 |
Secondary
Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.
Time frame: Baseline to Week 48
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 24.9 Meters | Standard Deviation 96.14 |
| Ambrisentan 5 mg | Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 27.9 Meters | Standard Deviation 94.5 |
| Ambrisentan 10 mg | Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 37.2 Meters | Standard Deviation 72.97 |
| Combined Ambrisentan Group | Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 29.5 Meters | Standard Deviation 89.81 |
95% CI: [5.1, 44.7]
95% CI: [14.2, 41.6]
95% CI: [22.4, 52]
95% CI: [20.4, 38.7]
Secondary
Change From Baseline to Year 1 in Borg Dyspnea Index
Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.
Time frame: Baseline to Year 1
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 1 in Borg Dyspnea Index | -0.08 units on a scale | Standard Deviation 2.254 |
| Ambrisentan 5 mg | Change From Baseline to Year 1 in Borg Dyspnea Index | -0.59 units on a scale | Standard Deviation 2.45 |
| Ambrisentan 10 mg | Change From Baseline to Year 1 in Borg Dyspnea Index | -0.51 units on a scale | Standard Deviation 2.4 |
| Combined Ambrisentan Group | Change From Baseline to Year 1 in Borg Dyspnea Index | -0.44 units on a scale | Standard Deviation 2.393 |
95% CI: [-0.55, 0.38]
95% CI: [-0.94, -0.23]
95% CI: [-1, -0.03]
95% CI: [-0.69, -0.2]
Secondary
Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class
WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.
Time frame: Baseline to Year 1
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in extension study. Missing values imputed using LOCF based on post-baseline observations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Improved | 16 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | No Change | 68 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Deteriorated | 10 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Missing | 2 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | No Change | 122 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Deteriorated | 9 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Missing | 3 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Improved | 56 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Deteriorated | 14 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | No Change | 46 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Missing | 1 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Improved | 36 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Missing | 6 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | No Change | 236 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Improved | 108 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class | Deteriorated | 33 participants |
Secondary
Change From Baseline to Year 2 in Borg Dyspnea Index
Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.
Time frame: Baseline to Year 2
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 2 in Borg Dyspnea Index | 0.23 units on a scale | Standard Deviation 2.603 |
| Ambrisentan 5 mg | Change From Baseline to Year 2 in Borg Dyspnea Index | -0.33 units on a scale | Standard Deviation 2.477 |
| Ambrisentan 10 mg | Change From Baseline to Year 2 in Borg Dyspnea Index | -0.65 units on a scale | Standard Deviation 2.305 |
| Combined Ambrisentan Group | Change From Baseline to Year 2 in Borg Dyspnea Index | -0.27 units on a scale | Standard Deviation 2.48 |
95% CI: [-0.31, 0.76]
95% CI: [-0.68, 0.03]
95% CI: [-1.12, -0.18]
95% CI: [-0.52, -0.02]
Secondary
Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.
Time frame: Baseline to Year 2
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 6.7 Meters | Standard Deviation 97.48 |
| Ambrisentan 5 mg | Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 23.2 Meters | Standard Deviation 100.69 |
| Ambrisentan 10 mg | Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 28.0 Meters | Standard Deviation 84.38 |
| Combined Ambrisentan Group | Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 20.3 Meters | Standard Deviation 96.05 |
95% CI: [-13.4, 26.8]
95% CI: [8.7, 37.8]
95% CI: [10.9, 45.1]
95% CI: [10.6, 30.1]
Secondary
Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class
WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.
Time frame: Baseline to Year 2
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in extension study. Missing values were imputed using LOCF based on post-baseline observations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | No Change | 58 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Improved | 16 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Missing | 2 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Deteriorated | 20 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Improved | 58 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | No Change | 109 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Deteriorated | 20 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Missing | 3 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Improved | 39 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Deteriorated | 14 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | No Change | 43 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Missing | 1 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | No Change | 210 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Deteriorated | 54 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Missing | 6 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class | Improved | 113 participants |
Secondary
Change From Baseline to Year 3 in Borg Dyspnea Index
Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.
Time frame: Baseline to Year 3
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 3 in Borg Dyspnea Index | 0.20 units on a scale | Standard Deviation 2.593 |
| Ambrisentan 5 mg | Change From Baseline to Year 3 in Borg Dyspnea Index | -0.14 units on a scale | Standard Deviation 2.514 |
| Ambrisentan 10 mg | Change From Baseline to Year 3 in Borg Dyspnea Index | -0.48 units on a scale | Standard Deviation 2.215 |
| Combined Ambrisentan Group | Change From Baseline to Year 3 in Borg Dyspnea Index | -0.14 units on a scale | Standard Deviation 2.467 |
95% CI: [-0.33, 0.74]
95% CI: [-0.51, 0.22]
95% CI: [-0.93, -0.03]
95% CI: [-0.39, 0.11]
Secondary
Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.
Time frame: Baseline to Year 3
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. The LOCF method of imputation was used; only postbaseline observations were carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 0.7 Meters | Standard Deviation 95.21 |
| Ambrisentan 5 mg | Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 18.8 Meters | Standard Deviation 101.22 |
| Ambrisentan 10 mg | Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 27.8 Meters | Standard Deviation 87.07 |
| Combined Ambrisentan Group | Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test | 16.6 Meters | Standard Deviation 96.54 |
95% CI: [-18.9, 20.3]
95% CI: [4.2, 33.5]
95% CI: [10.1, 45.4]
95% CI: [6.8, 26.4]
Secondary
Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class
WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.
Time frame: Baseline to Year 3
Population: All assessments of efficacy were performed using the randomized analysis set; subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the extension study. Missing values were imputed using LOCF based on post-baseline observations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ambrisentan 2.5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Improved | 17 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | No Change | 57 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Deteriorated | 20 participants |
| Ambrisentan 2.5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Missing | 2 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | No Change | 109 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Deteriorated | 17 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Missing | 3 participants |
| Ambrisentan 5 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Improved | 61 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Deteriorated | 15 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | No Change | 49 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Missing | 1 participants |
| Ambrisentan 10 mg | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Improved | 32 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Missing | 6 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | No Change | 215 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Improved | 110 participants |
| Combined Ambrisentan Group | Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class | Deteriorated | 52 participants |
Secondary
Long-term Survival
Long-term survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of survival after a given time.
Time frame: Baseline to Year 4
Population: All assessments of efficacy were performed using the randomized analysis set, such that subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Ambrisentan 2.5 mg | Long-term Survival | Survival after 1 year of treatment | 96.8 percent probability (KM estimate) | 95% Confidence Interval 1.8 |
| Ambrisentan 2.5 mg | Long-term Survival | Survival after 2 years of treatment | 84.7 percent probability (KM estimate) | 95% Confidence Interval 3.9 |
| Ambrisentan 2.5 mg | Long-term Survival | Survival after 3 years of treatment | 78.4 percent probability (KM estimate) | 95% Confidence Interval 4.5 |
| Ambrisentan 2.5 mg | Long-term Survival | Survival After 4 Years of Treatment | 71.1 percent probability (KM estimate) | 95% Confidence Interval 5.2 |
| Ambrisentan 5 mg | Long-term Survival | Survival after 2 years of treatment | 87.3 percent probability (KM estimate) | 95% Confidence Interval 2.6 |
| Ambrisentan 5 mg | Long-term Survival | Survival after 3 years of treatment | 84.2 percent probability (KM estimate) | 95% Confidence Interval 2.9 |
| Ambrisentan 5 mg | Long-term Survival | Survival After 4 Years of Treatment | 78.1 percent probability (KM estimate) | 95% Confidence Interval 3.8 |
| Ambrisentan 5 mg | Long-term Survival | Survival after 1 year of treatment | 93.1 percent probability (KM estimate) | 95% Confidence Interval 1.9 |
| Ambrisentan 10 mg | Long-term Survival | Survival after 3 years of treatment | 82.7 percent probability (KM estimate) | 95% Confidence Interval 4.5 |
| Ambrisentan 10 mg | Long-term Survival | Survival after 2 years of treatment | 90.7 percent probability (KM estimate) | 95% Confidence Interval 3.1 |
| Ambrisentan 10 mg | Long-term Survival | Survival After 4 Years of Treatment | 82.7 percent probability (KM estimate) | 95% Confidence Interval 4.5 |
| Ambrisentan 10 mg | Long-term Survival | Survival after 1 year of treatment | 94.5 percent probability (KM estimate) | 95% Confidence Interval 2.4 |
| Combined Ambrisentan Group | Long-term Survival | Survival After 4 Years of Treatment | 76.5 percent probability (KM estimate) | 95% Confidence Interval 2.7 |
| Combined Ambrisentan Group | Long-term Survival | Survival after 2 years of treatment | 87.5 percent probability (KM estimate) | 95% Confidence Interval 1.8 |
| Combined Ambrisentan Group | Long-term Survival | Survival after 1 year of treatment | 94.4 percent probability (KM estimate) | 95% Confidence Interval 1.2 |
| Combined Ambrisentan Group | Long-term Survival | Survival after 3 years of treatment | 82.2 percent probability (KM estimate) | 95% Confidence Interval 2.2 |
Secondary
Percentage of Participants With Failure-Free Treatment Status
Treatment failure was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to ambrisentan in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having treatment failure after a given time.
Time frame: Baseline to Year 4
Population: All assessments of efficacy were performed using the randomized analysis set, such that subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Ambrisentan 2.5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 1 year of treatment | 86.8 percent probability (KM estimate) | 95% Confidence Interval 3.6 |
| Ambrisentan 2.5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 2 years of treatment | 77.6 percent probability (KM estimate) | 95% Confidence Interval 4.4 |
| Ambrisentan 2.5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 3 years of treatment | 69.1 percent probability (KM estimate) | 95% Confidence Interval 5 |
| Ambrisentan 2.5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 4 years of treatment | 60.8 percent probability (KM estimate) | 95% Confidence Interval 5.4 |
| Ambrisentan 5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 2 years of treatment | 79.8 percent probability (KM estimate) | 95% Confidence Interval 3.1 |
| Ambrisentan 5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 3 years of treatment | 73.8 percent probability (KM estimate) | 95% Confidence Interval 3.5 |
| Ambrisentan 5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 4 years of treatment | 69.0 percent probability (KM estimate) | 95% Confidence Interval 4 |
| Ambrisentan 5 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 1 year of treatment | 89.0 percent probability (KM estimate) | 95% Confidence Interval 2.4 |
| Ambrisentan 10 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 3 years of treatment | 67.9 percent probability (KM estimate) | 95% Confidence Interval 5.7 |
| Ambrisentan 10 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 2 years of treatment | 81.4 percent probability (KM estimate) | 95% Confidence Interval 4.2 |
| Ambrisentan 10 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 4 years of treatment | 63.2 percent probability (KM estimate) | 95% Confidence Interval 6.2 |
| Ambrisentan 10 mg | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 1 year of treatment | 90.1 percent probability (KM estimate) | 95% Confidence Interval 3.1 |
| Combined Ambrisentan Group | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 4 years of treatment | 66.4 percent probability (KM estimate) | 95% Confidence Interval 2.8 |
| Combined Ambrisentan Group | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 2 years of treatment | 79.6 percent probability (KM estimate) | 95% Confidence Interval 2.2 |
| Combined Ambrisentan Group | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 1 year of treatment | 88.7 percent probability (KM estimate) | 95% Confidence Interval 1.7 |
| Combined Ambrisentan Group | Percentage of Participants With Failure-Free Treatment Status | No treatment failure after 3 years of treatment | 71.3 percent probability (KM estimate) | 95% Confidence Interval 2.6 |
Secondary
Percentage of Participants With No Clinical Worsening of PAH
Clinical worsening of PAH was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to AMB in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having clinical worsening after a given time.
Time frame: Baseline to Year 3
Population: All assessments of efficacy were performed using the randomized analysis set, such that subjects were allotted to an individual dose group based upon their randomized treatment assignment in the 2 prior studies (NCT00423748 or NCT00423202) or in the current extension study.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Ambrisentan 2.5 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 1 year of treatment | 80.4 percent probability (KM estimate) | 95% Confidence Interval 4.2 |
| Ambrisentan 2.5 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 3 years of treatment | 60.7 percent probability (KM estimate) | 95% Confidence Interval 5.2 |
| Ambrisentan 2.5 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 2 years of treatment | 67.8 percent probability (KM estimate) | 95% Confidence Interval 4.9 |
| Ambrisentan 5 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 1 year of treatment | 83.9 percent probability (KM estimate) | 95% Confidence Interval 2.7 |
| Ambrisentan 5 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 3 years of treatment | 67.4 percent probability (KM estimate) | 95% Confidence Interval 3.7 |
| Ambrisentan 5 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 2 years of treatment | 72.4 percent probability (KM estimate) | 95% Confidence Interval 3.4 |
| Ambrisentan 10 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 2 years of treatment | 72.2 percent probability (KM estimate) | 95% Confidence Interval 4.8 |
| Ambrisentan 10 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 1 year of treatment | 82.8 percent probability (KM estimate) | 95% Confidence Interval 3.9 |
| Ambrisentan 10 mg | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 3 years of treatment | 59.9 percent probability (KM estimate) | 95% Confidence Interval 5.6 |
| Combined Ambrisentan Group | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 1 year of treatment | 82.7 percent probability (KM estimate) | 95% Confidence Interval 2 |
| Combined Ambrisentan Group | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 3 years of treatment | 63.8 percent probability (KM estimate) | 95% Confidence Interval 2.7 |
| Combined Ambrisentan Group | Percentage of Participants With No Clinical Worsening of PAH | No clinical worsening after 2 years of treatment | 71.1 percent probability (KM estimate) | 95% Confidence Interval 2.4 |