Hypertension, Pulmonary
Conditions
Keywords
Pulmonary Arterial Hypertension, Ambrisentan, Sponsor Rest of World: GSK, Tadalafil, PAH, Sponsor US: Gilead
Brief summary
The purpose of this study is to compare the two treatment strategies; first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in subjects with Pulmonary Arterial Hypertension. This will be assessed by time to the first clinical failure event.
Interventions
DRUGambrisentan
ambrisentan (target dose: 10mg)
DRUGtadalafil
tadalafil (target dose: 40mg)
Sponsors
Gilead Sciences
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subjects must have a diagnosis of Pulmonary Arterial Hypertension (PAH) due to the following: a. idiopathic or heritable PAH b. PAH associated with: i. connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed connective tissue disease, systemic lupus erythematosus, or overlap syndrome) ii. drugs or toxins iii. Human Immunodeficiency Virus (HIV) infection iv. congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus) NB: subjects with portopulmonary hypertension and pulmonary veno-occlusive disease are NOT eligible for the study * Subject must have a current diagnosis of being in World Health Organisation (WHO) Functional Class II or III. * Subject must meet all of the following haemodynamic criteria by means of a right heart catheterization prior to screening: i. mPAP of ≥25 mmHg ii. PVR ≥ 300 dynes/sec/cm5 iii. PCWP or LVEDP of ≤12 mmHg if PVR ≥300 to \<500 dyne/sec/cm5 , or PCWP/LVEDP ≤ 15 mmHg if PVR ≥500 dynes/sec/cm5 * Subject must walk a distance of ≥125m and ≤500m at the screening visit
Exclusion criteria
* Subject received previous PAH therapy (phosphodiesterase type 5 inhibitor (PDE5i), endothelin receptor antagonist (ERA), chronic prostanoid\*) within 4 weeks prior to the screening visit (\*Chronic prostanoid use is considered \>7 days of treatment) * Subject received ERA treatment (e.g., bosentan or sitaxentan) or PDE5i treatment (e.g. Sildenafil) at any time AND discontinued due to tolerance issues other than those associated with liver function abnormalities * Subjects who have previously discontinued ambrisentan or tadalafil in either another clinical study or commercial product (Volibris/Letairis or Adcirca) for safety or tolerability reasons.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | From Baseline up to the Final Assessment Visit (FAV) (average of 609 days) | Time to the first adjudicated CF event (death, hospitalization for worsening pulmonary arterial hypertension \[PAH\], disease progression, or unsatisfactory long-term clinical response) after initiating either first-line combination therapy with AMB and TAD or first-line monotherapy with either drug (AMB or TAD) in par. with PAH was assessed. If data was not available for some par. following a loss to follow-up, their event times were treated as censored at their last assessment time for the statistical analyses. FAV occurred approximately 4 weeks after the predicted 105th adjudicated first CF event was reached. Par. who had an FAV, and who had no adjudicated events or whose first adjudicated event occurred after their FAV, were censored at their individual FAV. Modified Intent-to-Treat (mITT) Population: all randomized par. who met the PAH diagnosis and inclusion/exclusion criteria defined in protocol amendment 2 and who also received at least one dose of investigational product (IP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24 | Baseline and Week 24 | N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate marker of heart failure. The data were log-transformed. The geometric mean was calculated (based on the log-transformed data). The geometric mean ratio was calculated as the ratio between the Week 24 value and the Baseline value (based on the log-transformed data) and presented as percent change = 100 \* (geometric mean ratio - 1). The Baseline value is the last value prior to administration of study drug; this may be prior to or on the day of study drug initiation. No imputation was performed for missing data. The secondary endpoints were analyzed according to a pre-specified hierarchical testing procedure. |
| Percentage of Participants With a Satisfactory Clinical Response at Week 24 | Baseline and Week 24 | A satisfactory clinical response at Week 24 is defined as a participant who meets all of the following criteria: 10% improvement in 6MWD compared with Baseline; improvement to or maintenance of World Health Organization (WHO) class I or II symptoms; no events of clinical worsening prior to or at the Week 24 visit. Clinical worsening events included: death, hospitalization for pulmonary arterial hypertension (PAH), and disease progression. Participants without an event of clinical worsening prior to or at the Week 24 visit who did not have a 6MWD value or a WHO functional class value at Week 24 were excluded from the analysis. |
| Change From Baseline in the 6 Minute Walk Distance Test at Week 24 | Baseline and Week 24 | The 6-minute walk distance (6MWD) test measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned a rank reflecting the relative order of the actual event times. Baseline 6MWD comprised of an average of the last two consecutive measurements prior to randomization that varied by no greater than 10%. If only one measurement was available, that measurement was used. If no two consecutive measures vary by no greater than 10% then Baseline was based on the last two consecutive measures for a participant. |
| Change From Baseline in the World Health Organization Functional Class at Week 24 | Baseline and Week 24 | The WHO Functional Class (FC) indicates the severity of PAH and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. There are four grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). Baseline WHO FC is the latest assessment prior to dosing (i.e., at Randomization or Screening). Change from Baseline at Week 24 was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observations was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times. |
| Change From Baseline in Borg Dyspnea Index at Week 24 | Baseline (BL) and Week 24 | Borg Dyspnea Index (BDI) indicates the degree of breathlessness after completion of the 6 minute walk test. The BDI was calculated by using the Borg category (C) ratio (R) CR10 scale which starts at 0 (nothing at all) and has no upper limit (extremely strong). Change from BL was calculated as the Week 24 values minus the BL value. The BDI scale was assessed by each participant. The BL BDI score is the average of the two BDI values obtained following the two 6MWD tests used in determining the BL 6MWD. A negative change from BL in the BDI score represented an improvement for the participant. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times. |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Greece, Italy, Japan, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
500 participants (par.) in the ITT Population were also included in the modified ITT Population (those who also met the modified inclusion/exclusion criteria defined in the protocol amendment 2). Disposition results below have been presented for the ITT Population.
Pre-assignment details
A total of 610 par. were randomized; however, only 605 were included in the Intent-to-Treat (ITT) Population (randomized par. who received at least one dose of IP). All par. received a minimum of 24 weeks of therapy unless they died or withdrew.
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy: Ambrisentan + Tadalafil Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. | 302 |
| Ambrisentan Monotherapy Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg. | 152 |
| Tadalafil Monotherapy Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks. | 151 |
| Total | 605 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 34 | 27 | 24 |
| Overall Study | Lost to Follow-up | 2 | 0 | 3 |
| Overall Study | Missing Completion Status | 1 | 0 | 0 |
| Overall Study | Physician Decision | 14 | 10 | 10 |
| Overall Study | Protocol Violation | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 6 | 8 |
Baseline characteristics
| Characteristic | Combination Therapy: Ambrisentan + Tadalafil | Ambrisentan Monotherapy | Tadalafil Monotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 55.9 Years STANDARD_DEVIATION 13.86 | 55.2 Years STANDARD_DEVIATION 14.41 | 55.9 Years STANDARD_DEVIATION 14.75 | 55.7 Years STANDARD_DEVIATION 14.21 |
| Race/Ethnicity, Customized African American/African Heritage | 11 Participants | 14 Participants | 13 Participants | 38 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 3 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Mixed Race | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White - Arabic /North African Heritage | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 280 Participants | 131 Participants | 133 Participants | 544 Participants |
| Sex: Female, Male Female | 223 Participants | 117 Participants | 121 Participants | 461 Participants |
| Sex: Female, Male Male | 79 Participants | 35 Participants | 30 Participants | 144 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 | 279 / 302 | 140 / 152 | 135 / 151 |
| serious Total, serious adverse events | 124 / 302 | 63 / 152 | 68 / 151 |
Outcome results
Primary
Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV
Time to the first adjudicated CF event (death, hospitalization for worsening pulmonary arterial hypertension \[PAH\], disease progression, or unsatisfactory long-term clinical response) after initiating either first-line combination therapy with AMB and TAD or first-line monotherapy with either drug (AMB or TAD) in par. with PAH was assessed. If data was not available for some par. following a loss to follow-up, their event times were treated as censored at their last assessment time for the statistical analyses. FAV occurred approximately 4 weeks after the predicted 105th adjudicated first CF event was reached. Par. who had an FAV, and who had no adjudicated events or whose first adjudicated event occurred after their FAV, were censored at their individual FAV. Modified Intent-to-Treat (mITT) Population: all randomized par. who met the PAH diagnosis and inclusion/exclusion criteria defined in protocol amendment 2 and who also received at least one dose of investigational product (IP).
Time frame: From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)
Population: mITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Therapy: Ambrisentan + Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Disease progression | 10 Participants |
| Combination Therapy: Ambrisentan + Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Death (all-cause) | 9 Participants |
| Combination Therapy: Ambrisentan + Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Unsatisfactory long-term clinical response | 17 Participants |
| Combination Therapy: Ambrisentan + Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Hospitalization for worsening PAH | 10 Participants |
| Combination Therapy: Ambrisentan + Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | First adjudicated clinical failure event | 46 Participants |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Hospitalization for worsening PAH | 30 Participants |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Disease progression | 16 Participants |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Unsatisfactory long-term clinical response | 23 Participants |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Death (all-cause) | 8 Participants |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | First adjudicated clinical failure event | 77 Participants |
| Ambrisentan Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Hospitalization for worsening PAH | 18 Participants |
| Ambrisentan Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | First adjudicated clinical failure event | 43 Participants |
| Ambrisentan Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Death (all-cause) | 2 Participants |
| Ambrisentan Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Disease progression | 12 Participants |
| Ambrisentan Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Unsatisfactory long-term clinical response | 11 Participants |
| Tadalafil Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Disease progression | 4 Participants |
| Tadalafil Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Death (all-cause) | 6 Participants |
| Tadalafil Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | First adjudicated clinical failure event | 34 Participants |
| Tadalafil Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Hospitalization for worsening PAH | 12 Participants |
| Tadalafil Monotherapy | Number of Participants With First Adjudicated Clinical Failure (CF) Event, Death, Hospitalisation for Worsening PAH, Disease Progression, Unsatisfactory Long-term Clinical Response, All Through FAV | Unsatisfactory long-term clinical response | 12 Participants |
p-value: 0.000295% CI: [0.348, 0.724]Stratified Log Rank
p-value: 0.000495% CI: [0.314, 0.723]Stratified Log Rank
p-value: 0.004595% CI: [0.338, 0.827]Stratified Log Rank
Secondary
Change From Baseline in Borg Dyspnea Index at Week 24
Borg Dyspnea Index (BDI) indicates the degree of breathlessness after completion of the 6 minute walk test. The BDI was calculated by using the Borg category (C) ratio (R) CR10 scale which starts at 0 (nothing at all) and has no upper limit (extremely strong). Change from BL was calculated as the Week 24 values minus the BL value. The BDI scale was assessed by each participant. The BL BDI score is the average of the two BDI values obtained following the two 6MWD tests used in determining the BL 6MWD. A negative change from BL in the BDI score represented an improvement for the participant. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
Time frame: Baseline (BL) and Week 24
Population: mITT Population. Only participants with Baseline data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy: Ambrisentan + Tadalafil | Change From Baseline in Borg Dyspnea Index at Week 24 | -1.00 Scores on a scale |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Change From Baseline in Borg Dyspnea Index at Week 24 | -0.50 Scores on a scale |
| Ambrisentan Monotherapy | Change From Baseline in Borg Dyspnea Index at Week 24 | -0.50 Scores on a scale |
| Tadalafil Monotherapy | Change From Baseline in Borg Dyspnea Index at Week 24 | -0.50 Scores on a scale |
95% CI: [-0.75, 0]Stratified Wilcoxon Rank Sum Test
95% CI: [-1, 0]Stratified Wilcoxon Rank Sum Test
95% CI: [-1, 0]Stratified Wilcoxon Rank Sum Test
Secondary
Change From Baseline in the 6 Minute Walk Distance Test at Week 24
The 6-minute walk distance (6MWD) test measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned a rank reflecting the relative order of the actual event times. Baseline 6MWD comprised of an average of the last two consecutive measurements prior to randomization that varied by no greater than 10%. If only one measurement was available, that measurement was used. If no two consecutive measures vary by no greater than 10% then Baseline was based on the last two consecutive measures for a participant.
Time frame: Baseline and Week 24
Population: mITT Population. Only participants with Baseline data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy: Ambrisentan + Tadalafil | Change From Baseline in the 6 Minute Walk Distance Test at Week 24 | 48.98 Meters |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Change From Baseline in the 6 Minute Walk Distance Test at Week 24 | 23.80 Meters |
| Ambrisentan Monotherapy | Change From Baseline in the 6 Minute Walk Distance Test at Week 24 | 27.00 Meters |
| Tadalafil Monotherapy | Change From Baseline in the 6 Minute Walk Distance Test at Week 24 | 22.70 Meters |
p-value: <0.000195% CI: [12, 33.5]Stratified Wilcoxon Rank Sum Test
p-value: 0.000595% CI: [11, 38.5]Stratified Wilcoxon Rank Sum Test
p-value: 0.00395% CI: [8, 33.7]Stratified Wilcoxon Rank Sum Test
Secondary
Change From Baseline in the World Health Organization Functional Class at Week 24
The WHO Functional Class (FC) indicates the severity of PAH and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. There are four grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). Baseline WHO FC is the latest assessment prior to dosing (i.e., at Randomization or Screening). Change from Baseline at Week 24 was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observations was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
Time frame: Baseline and Week 24
Population: mITT Population. Only participants with Baseline data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy: Ambrisentan + Tadalafil | Change From Baseline in the World Health Organization Functional Class at Week 24 | 0.0 Scores on a scale |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Change From Baseline in the World Health Organization Functional Class at Week 24 | 0.0 Scores on a scale |
| Ambrisentan Monotherapy | Change From Baseline in the World Health Organization Functional Class at Week 24 | 0.0 Scores on a scale |
| Tadalafil Monotherapy | Change From Baseline in the World Health Organization Functional Class at Week 24 | 0.0 Scores on a scale |
p-value: 0.228795% CI: [0, 0]Stratified Wilcoxon Rank Sum Test
95% CI: [0, 0]Stratified Wilcoxon Rank Sum Test
95% CI: [0, 0]Stratified Wilcoxon Rank Sum Test
Secondary
Percentage of Participants With a Satisfactory Clinical Response at Week 24
A satisfactory clinical response at Week 24 is defined as a participant who meets all of the following criteria: 10% improvement in 6MWD compared with Baseline; improvement to or maintenance of World Health Organization (WHO) class I or II symptoms; no events of clinical worsening prior to or at the Week 24 visit. Clinical worsening events included: death, hospitalization for pulmonary arterial hypertension (PAH), and disease progression. Participants without an event of clinical worsening prior to or at the Week 24 visit who did not have a 6MWD value or a WHO functional class value at Week 24 were excluded from the analysis.
Time frame: Baseline and Week 24
Population: mITT Population. Only those participants who had a Yes/No response were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Ambrisentan + Tadalafil | Percentage of Participants With a Satisfactory Clinical Response at Week 24 | 39 Percentage of participants |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Percentage of Participants With a Satisfactory Clinical Response at Week 24 | 29 Percentage of participants |
| Ambrisentan Monotherapy | Percentage of Participants With a Satisfactory Clinical Response at Week 24 | 31 Percentage of participants |
| Tadalafil Monotherapy | Percentage of Participants With a Satisfactory Clinical Response at Week 24 | 27 Percentage of participants |
p-value: 0.026495% CI: [1.054, 2.319]Regression, Logistic
p-value: 0.151895% CI: [0.878, 2.308]Regression, Logistic
p-value: 0.032195% CI: [1.047, 2.833]Regression, Logistic
Secondary
Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24
N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate marker of heart failure. The data were log-transformed. The geometric mean was calculated (based on the log-transformed data). The geometric mean ratio was calculated as the ratio between the Week 24 value and the Baseline value (based on the log-transformed data) and presented as percent change = 100 \* (geometric mean ratio - 1). The Baseline value is the last value prior to administration of study drug; this may be prior to or on the day of study drug initiation. No imputation was performed for missing data. The secondary endpoints were analyzed according to a pre-specified hierarchical testing procedure.
Time frame: Baseline and Week 24
Population: mITT Population. Only participants with data available at the specified time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Ambrisentan + Tadalafil | Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24 | -67.15 Percent change | Standard Error 0.069 |
| Monotherapy Pooled: Ambrisentan or Tadalafil | Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24 | -50.37 Percent change | Standard Error 0.07 |
| Ambrisentan Monotherapy | Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24 | -56.15 Percent change | Standard Error 0.096 |
| Tadalafil Monotherapy | Percent Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24 | -43.83 Percent change | Standard Error 0.095 |
p-value: <0.000195% CI: [-44.78, -20.66]ANCOVA
p-value: 0.011195% CI: [-40.04, -6.4]ANCOVA
p-value: <0.000195% CI: [-53.16, -26.97]ANCOVA