Pulmonary Arterial Hypertension
Conditions
Brief summary
To assess the efficacy and safety of sildenafil when added to patients with PAH who are taking bosentan as all or part of their background therapy.
Interventions
DRUGBosentan
Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil)
OTHERPlacebo
Bosentan + Placebo for 12 weeks of the study (double blind), then 12 months open label phase (bosentan + sildenafil)
DRUGSildenafil Citrate
Bosentan + Sildenafil for 12 weeks of the study (double blind), then 12 months open label phase
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects aged 18 and over above with PAH and for which bosentan therapy is indicated according to national license * Subjects with a mean pulmonary artery pressure of \>25mmHg and a pulmonary artery wedge pressure of \<15mmHg at rest via right heart catheterization within 3 years prior to randomization. * Subjects whose baseline 6 Minute Walk Test distance is \>100m and \< 450m.
Exclusion criteria
* PAH secondary to any aetiology including congenital heart disease other than those specified in the inclusion criteria * Subjects whose 6 Minute Walk Test may be limited by conditions other than PAH related dyspnoea or fatigue eg. claudication from vascular insufficiency or arthritis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 | Week 12 | 6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Week 12 | WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class. |
| Clinical Worsening Events | Week 12 | No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead. Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy. |
| Change From Baseline in Borg Dyspnea Score at Week 12 | Week 12 | Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight \[just noticeable\]); 1. (very slight); 2. (slight breathlessness); 3. (moderate); 4 (some what severe); 5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe \[almost maximum\]); and 10 (maximum). |
| One Year Survival Probability From the Start of Sildenafil Treatment. | One year from the time of starting sildenafil | The survival probability of all participants up to 1-year post start of Sildenafil treatment; for participants who were randomized to Sildenafil, this was the week 52 from randomization, and for participants who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these participants). Those participants who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at the time of discontinuation and those who discontinued from the study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil. |
| One Year Survival From the Start of Sildenafil Treatment. | One year from the time of starting sildenafil | The survival status of all participants who discontinued from the study, including those participants who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit. |
Countries
Australia, Czechia, France, Germany, Greece, Israel, Italy, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 29 active centers in 10 countries (10 centers in Germany, 5 centers in the United States of America \[USA\], 3 centers in France, 2 centers in Australia, Czech Republic, Italy, and Israel, and 1 center in Greece, Taiwan and United Kingdom \[UK\])
Pre-assignment details
Participants were on bosentan therapy for 3 months prior. Participants were randomized to sildenafil or placebo. Part A study was double-blind phase (12 weeks) and Part B was 12 months open-label phase. 53 and 51 participants were randomized to placebo and sildenafil arm respectively. One participant in sildenafil arm did not receive any treatment
Participants by arm
| Arm | Count |
|---|---|
| Placebo In Part A of the study: the participants received placebo three times a day (TID), in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study.
In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months | 53 |
| Sildenafil In Part A of the study: the participants received sildenafil 20 mg TID, in addition to their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study.
In Part B of the study: All the participants received sildenafil 20 mg TID for 12 months. | 50 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part A (Double Blind Randomized) | Death | 0 | 1 |
| Part A (Double Blind Randomized) | Protocol Violation | 1 | 3 |
| Part A (Double Blind Randomized) | Reason unspecified | 0 | 1 |
| Part A (Double Blind Randomized) | Related adverse event | 2 | 2 |
| Part A (Double Blind Randomized) | Related and Unrelated adverse event | 1 | 0 |
| Part A (Double Blind Randomized) | Unrelated adverse event | 1 | 0 |
| Part B (Open-label) | Adverse Event | 5 | 5 |
| Part B (Open-label) | Death | 0 | 1 |
| Part B (Open-label) | Lack of Efficacy | 3 | 1 |
| Part B (Open-label) | Protocol Violation | 0 | 1 |
| Part B (Open-label) | Reason unspecified | 0 | 1 |
| Part B (Open-label) | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Sildenafil | Total |
|---|---|---|---|
| Age, Continuous | 56.9 Years STANDARD_DEVIATION 14.14 | 55.2 Years STANDARD_DEVIATION 15.1 | 56.0 Years STANDARD_DEVIATION 14.57 |
| Mean Pulmonary Artery Pressure (mPAP) | 44.9 Millimeter(mm) of mercury(Hg) STANDARD_DEVIATION 13.33 | 46.9 Millimeter(mm) of mercury(Hg) STANDARD_DEVIATION 12.47 | 45.8 Millimeter(mm) of mercury(Hg) STANDARD_DEVIATION 12.89 |
| Sex: Female, Male Female | 41 Participants | 37 Participants | 78 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 25 Participants |
| Six Minute Walk Test (6MWT) | 350.38 Meters STANDARD_DEVIATION 87.587 | 354.44 Meters STANDARD_DEVIATION 73.121 | 352.35 Meters STANDARD_DEVIATION 80.52 |
| World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class I | 0 Participants | 0 Participants | 0 Participants |
| World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class II | 15 Participants | 20 Participants | 35 Participants |
| World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class III | 38 Participants | 29 Participants | 67 Participants |
| World Health Organization Functional Class in Participants with Pulmonary Arterial Hypertension Class IV | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 53 | 33 / 50 |
| serious Total, serious adverse events | 23 / 53 | 22 / 50 |
Outcome results
Primary
Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12
6MWT is the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.
Time frame: Week 12
Population: Intent-to-Treat (ITT) Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward (LOCF) approach. Statistical analysis was carried out on LOCF values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 | Change from baseline at Week 12 (n=46,44) | 17.42 Meters | Standard Deviation 57.27 |
| Placebo | Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 | Change from baseline at Week 12 LOCF (n=53,49) | 14.08 Meters | Standard Deviation 57.557 |
| Sildenafil | Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 | Change from baseline at Week 12 (n=46,44) | 14.08 Meters | Standard Deviation 63.679 |
| Sildenafil | Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12 | Change from baseline at Week 12 LOCF (n=53,49) | 13.62 Meters | Standard Deviation 60.95 |
Comparison: The estimated sample size was based upon the primary endpoint. A sample size of 51 subjects per treatment group was required to detect a difference of 30 meters between treatments with 80% power at a one-sided significance level of 0.05, assuming a standard deviation of 60 meters.~This primary statistical analysis was carried for Week 12 data.p-value: 0.580290% CI: [-21.843, 17.087]ANCOVA
Secondary
Change From Baseline in Borg Dyspnea Score at Week 12
Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight \[just noticeable\]); 1. (very slight); 2. (slight breathlessness); 3. (moderate); 4 (some what severe); 5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe \[almost maximum\]); and 10 (maximum).
Time frame: Week 12
Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Borg Dyspnea Score at Week 12 | Change from Baseline at Week 12 (n=46,43) | 0.16 Units on a scale | Standard Deviation 1.637 |
| Placebo | Change From Baseline in Borg Dyspnea Score at Week 12 | Change from Baseline at Week 12 LOCF (n=53,49) | 0.24 Units on a scale | Standard Deviation 1.709 |
| Sildenafil | Change From Baseline in Borg Dyspnea Score at Week 12 | Change from Baseline at Week 12 (n=46,43) | -0.73 Units on a scale | Standard Deviation 1.656 |
| Sildenafil | Change From Baseline in Borg Dyspnea Score at Week 12 | Change from Baseline at Week 12 LOCF (n=53,49) | -0.62 Units on a scale | Standard Deviation 1.583 |
Secondary
Clinical Worsening Events
No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead. Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy.
Time frame: Week 12
Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Worsening Events | (A) | 0 Participants |
| Placebo | Clinical Worsening Events | (C) | 2 Participants |
| Placebo | Clinical Worsening Events | (B) | 0 Participants |
| Placebo | Clinical Worsening Events | (D) | 0 Participants |
| Placebo | Clinical Worsening Events | None | 51 Participants |
| Sildenafil | Clinical Worsening Events | (D) | 0 Participants |
| Sildenafil | Clinical Worsening Events | None | 47 Participants |
| Sildenafil | Clinical Worsening Events | (A) | 1 Participants |
| Sildenafil | Clinical Worsening Events | (B) | 0 Participants |
| Sildenafil | Clinical Worsening Events | (C) | 2 Participants |
Secondary
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF
WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class.
Time frame: Week 12
Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the LOCF approach.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Worsened 2 Classes | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Worsened 1 Class | 1 Participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | No Change | 45 Participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Improved 1 Class | 7 Participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Improved 2 Classes | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Discontinued | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Died | 0 Participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Missing | 0 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Missing | 0 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Worsened 2 Classes | 0 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Improved 2 Classes | 0 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Worsened 1 Class | 0 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Died | 1 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | No Change | 39 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Discontinued | 0 Participants |
| Sildenafil | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Class in Participants With PAH at Week 12 LOCF | Improved 1 Class | 10 Participants |
Secondary
One Year Survival From the Start of Sildenafil Treatment.
The survival status of all participants who discontinued from the study, including those participants who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit.
Time frame: One year from the time of starting sildenafil
Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The participants in placebo arm have received Sildenafil on or after Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | One Year Survival From the Start of Sildenafil Treatment. | 2 Participants who died |
| Sildenafil | One Year Survival From the Start of Sildenafil Treatment. | 2 Participants who died |
Secondary
One Year Survival Probability From the Start of Sildenafil Treatment.
The survival probability of all participants up to 1-year post start of Sildenafil treatment; for participants who were randomized to Sildenafil, this was the week 52 from randomization, and for participants who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these participants). Those participants who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at the time of discontinuation and those who discontinued from the study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil.
Time frame: One year from the time of starting sildenafil
Population: ITT Population (Full Analysis Set) consisted of all participants who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The participants in placebo arm have received Sildenafil on or after Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | One Year Survival Probability From the Start of Sildenafil Treatment. | 0.042 Probability of death |
| Sildenafil | One Year Survival Probability From the Start of Sildenafil Treatment. | 0.040 Probability of death |