Pulmonary Arterial Hypertension, Pulmonary Hypertension
Conditions
Keywords
Sitaxsentan, endothelin receptor antagonist
Brief summary
This protocol is for subjects with pulmonary arterial hypertension and is the first of 3 studies forming the Sitaxsentan efficacy and safety trial with Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) program.
Interventions
DRUGSitaxsentan
Sitaxsentan = 100 mg tablet administered orally, once daily
DRUGPlacebo
Sitaxsentan Placebo = 1 tablet administered orally, once daily
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Current diagnosis of symptomatic pulmonary arterial hypertension (PAH) classified by one of the following: idiopathic arterial hypertension (IPAH), primary pulmonary hypertension (PPH), familial pulmonary arterial hypertension (FPAH) or pulmonary arterial hypertension (PAH) associated with connective tissue diseases. Has WHO functional class III symptoms.
Exclusion criteria
* Previous exposure to an endothelin receptor antagonist (ETRA) such as sitaxsentan, bosentan or ambrisentan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12 | Baseline/Day 1 and Week 12 | 6 MWD was 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. Change is Week 12 results minus baseline results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Baseline, Weeks 4, 8 and 12 or Early Termination (ET) | WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (cannot 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 to Clinical Worsening (TTCW) | Baseline, Weeks 4, 8 and 12 or ET | TTCW defined as the number of days between first dose of study drug and the occurrence of a predefined clinical worsening event. Predefined clinical worsening events included: hospitalization for worsening PAH, on-study death, heart-lung or lung transplant, atrial septostomy or withdrawal due to the addition of any chronic medications for the treatment of worsening PAH. |
Countries
Argentina, Bulgaria, Chile, China, Colombia, Costa Rica, Czechia, Dominican Republic, Guatemala, India, Malaysia, Mexico, Peru, Philippines, Romania, Russia, Saudi Arabia, Serbia, Slovakia, South Africa, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitaxsentan Sitaxsentan 100 milligrams (mg) tablet orally once a day | 91 |
| Placebo Matching placebo tablet once a day | 91 |
| Total | 182 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Death | 1 | 6 |
| Overall Study | Other | 0 | 2 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Randomized and not treated | 0 | 1 |
| Overall Study | Terminated by sponsor | 13 | 12 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Sitaxsentan | Total | Placebo |
|---|---|---|---|
| Age, Customized 18 to 44 years | 53 participants | 106 participants | 53 participants |
| Age, Customized 45 to 64 years | 30 participants | 56 participants | 26 participants |
| Age, Customized greater than or equal to 65 years | 8 participants | 17 participants | 9 participants |
| Age, Customized less than 18 years | 0 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 71 Participants | 139 Participants | 68 Participants |
| Sex: Female, Male Male | 20 Participants | 43 Participants | 23 Participants |
| World Health Organization (WHO) Functional Class Functional Class I | 0 Participants | 0 Participants | 0 Participants |
| World Health Organization (WHO) Functional Class Functional Class II | 2 Participants | 2 Participants | 0 Participants |
| World Health Organization (WHO) Functional Class Functional Class III | 88 Participants | 175 Participants | 87 Participants |
| World Health Organization (WHO) Functional Class Functional Class IV | 0 Participants | 0 Participants | 0 Participants |
| World Health Organization (WHO) Functional Class Functional Class Unknown | 1 Participants | 5 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 91 | 24 / 91 |
| serious Total, serious adverse events | 9 / 91 | 12 / 91 |
Outcome results
Primary
Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12
6 MWD was 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. Change is Week 12 results minus baseline results.
Time frame: Baseline/Day 1 and Week 12
Population: Intent to treat population (ITT): all participants who were randomized; missing value at Week 12 imputed with last non-missing value, including the non-missing value obtained at early termination based on last observation carried forward (LOCF)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sitaxsentan | Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12 | Change at Week 12 | 13.0 Meters (m) |
| Sitaxsentan | Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12 | Baseline | 343.0 Meters (m) |
| Placebo | Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12 | Baseline | 330.5 Meters (m) |
| Placebo | Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12 | Change at Week 12 | 3.0 Meters (m) |
p-value: 0.010495% CI: [3, 26]ANCOVA
Secondary
Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12
WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (cannot 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: Baseline, Weeks 4, 8 and 12 or Early Termination (ET)
Population: ITT; N=number of participants with analyzable data; n=number of participants with analyzable data at the specific time point
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 4 - No Change (n=90, 87) | 83 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 8 - Deterioration (n=86, 81) | 1 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 8 - Improvement (n=86, 81) | 13 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 12 - Improvement (n=80, 72) | 17 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 4 - Deterioration (n=90, 87) | 1 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 12 - No Change (n=80, 72) | 63 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 8 - No Change (n=86, 81) | 72 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 12 - Deterioration (n=80, 72) | 0 participants |
| Sitaxsentan | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 4 - Improvement (n=90, 87) | 6 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 12 - Deterioration (n=80, 72) | 1 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 4 - Improvement (n=90, 87) | 2 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 4 - No Change (n=90, 87) | 84 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 4 - Deterioration (n=90, 87) | 1 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 8 - Improvement (n=86, 81) | 6 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 8 - No Change (n=86, 81) | 73 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 8 - Deterioration (n=86, 81) | 2 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 12 - Improvement (n=80, 72) | 7 participants |
| Placebo | Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 | Week 12 - No Change (n=80, 72) | 64 participants |
Comparison: Week 12p-value: 0.2908Cochran-Mantel-Haenszel
Secondary
Time to Clinical Worsening (TTCW)
TTCW defined as the number of days between first dose of study drug and the occurrence of a predefined clinical worsening event. Predefined clinical worsening events included: hospitalization for worsening PAH, on-study death, heart-lung or lung transplant, atrial septostomy or withdrawal due to the addition of any chronic medications for the treatment of worsening PAH.
Time frame: Baseline, Weeks 4, 8 and 12 or ET
Population: ITT; N=number of participants with analyzable data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitaxsentan | Time to Clinical Worsening (TTCW) | NA days |
| Placebo | Time to Clinical Worsening (TTCW) | NA days |