Pulmonary Arterial Hypertension
Conditions
Keywords
pulmonary arterial hypertension, bosentan, sildenafil, combination therapy, Compass 3
Brief summary
An open label, non-comparative study design is appropriate for this Phase 4 study designed to assess whether a core therapy of bosentan, either as monotherapy or with the addition of sildenafil, enables patients with pulmonary arterial hypertension (PAH) to achieve a 6-minute walk distance (6 MWD) of ≥380 meters after 28 weeks of therapy This design is also appropriate to pioneer the utility of cardiac MRI in assessing improved functional capacity in PAH and exploring its correlation with other parameters.
Interventions
DRUGBosentan
Oral bosentan 62.5 mg BID first 4 weeks followed by 24 weeks of 125 mg BID if the 62.5 mg BID dose was well tolerated
DRUGSildenafil
Oral sildenafil 20 mg TID in patients who do not reach the 6-MWT distance threshold at Week 16
Sponsors
Actelion
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent prior to initiation of any study-mandated procedures. 2. Males or females ≥ 12 years of age (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception). 3. Symptomatic patients with the following types of PAH belonging to World Health Organization (WHO) Pulmonary Hypertension Classification Group I: * Idiopathic (IPAH) * Familial (FPAH) * Associated with PAH (APAH): * Collagen vascular disease * Drugs and toxins 4. Patients naïve to treatment with advanced PAH therapies (i.e., endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors or prostacyclins) with a right heart catheterization (RHC) showing all of the following: * Mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg * Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg or left ventricular end diastolic pressure (LVEDP) ≤ 15 mm Hg when PCWP is not accurately obtained * Pulmonary vascular resistance ≥ 3 Wood units 5. 6-MWT distance ≥ 150 meters and \< 360 meters.
Exclusion criteria
1. Patients with Pulmonary Hypertension (PH) belonging to WHO Classification Group II-V. 2. Patients with PAH (WHO PH Classification Group I) other than that listed in the Inclusion Criteria. 3. Pregnant and/or nursing. 4. Women of childbearing potential not using a reliable method of contraception. 5. Patients with known human immunodeficiency virus (HIV) infection. 6. Patients with significant vasoreactivity during right heart catheterization (i.e., a fall in mPAP to \< 40 mm Hg with a decrease of ≥ 10 mm Hg and with a normal cardiac index ≥ 2.5 l/min.m\^2). 7. Patients with restrictive lung disease (i.e., total lung capacity (TLC) \< 60% of normal predicted value). 8. Patients with obstructive lung disease (i.e., forced expiratory volume/ forced vital capacity (FEV1/FVC) \< 0.5). 9. Patients with impaired left ventricular function (LVEF \<50%) or diastolic dysfunction. 10. Patients with portal hypertension, cirrhosis, moderate to severe liver impairment (Child-Pugh Class B or C), or liver enzymes (Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)) \> 3.0 times the upper limit of normal range. 11. Treatment with glibenclamide (glyburide) and calcineurin inhibitors (cyclosporine A, tacrolimus) sirolimus, everolimus up to 1 week prior to Baseline (Day 1). 12. Patients currently receiving or predicted to require treatment, during the course of the study, with nitrates, protease inhibitors, or alpha-blockers. 13. Patients with a hemoglobin concentration \< 75 % of the lower limit of the normal range or \< 8.5 g/dL. 14. Patients currently receiving or predicted to require treatment with a prostanoid during the course of the study. 15. Patients with systolic blood pressure \< 85 mm Hg. 16. Patients with body weight \< 40 kg. 17. Patients who have received any investigational product within 90 days prior to Baseline. 18. Patients who previously received any advanced therapy for PAH (e.g., ERAs, PDE-5 inhibitors or prostacyclins). 19. Patients with hypersensitivity to sildenafil or any excipients of its formulation. 20. Patients with any contraindication to sildenafil treatment (i.e., nitrates). 21. Patients with any recent medical condition limiting the ability to comply with the study requirements (i.e., stroke, myocardial infarction). 22. Patients with unstable PAH whose disease state would prohibit the completion of study procedures, in the opinion of the investigator. 23. Patients unable to complete a MRI scan (e.g., claustrophobia). 24. Patients with permanent cardiac pacemakers, automatic internal cardioverter defibrillators (AICD's), neurostimulators, hearing aides, and other implanted metallic devices that are contraindicated during a MRI study. 25. Patients with conditions that would interfere with proper cardiac gating during MRI, such as atrial fibrillation or multiple premature ventricular contractions (PVCs)/premature atrial contractions (PACs). 26. Patients with conditions that prevent compliance with the protocol or the ability to adhere to therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Reaching a 6-Minute Walk Test (6MWT) Distance ≥ 380 Meters | at 16 weeks and at 28 weeks of a stepped approach to therapy | The 6MWT is a non encouraged test, which measures the walking distance covered over a 6 minute period |
Participant flow
Recruitment details
The study was conducted at 23 centers in the United States. First patient, first visit: 25 April 2007; last patient, last visit: 23 April 2010
Pre-assignment details
The study included a screening phase of 2 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Bosentan/Sildenafil Oral bosentan 62.5 mg twice daily (BID) for 4 week followed by 24 weeks of 125 mg BID with the addition of sildenafil 20 mg thrice daily (TID) in patients who do not reach the 6-MWT distance threshold at Week 16 | 100 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Death | 4 |
| Overall Study | Discontinued sildenafil | 2 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Moved out of state | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrew consent | 3 |
Baseline characteristics
| Characteristic | Bosentan/Sildenafil |
|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 15.99 |
| Age, Customized Between 21 and 84 years | 100 participants |
| Region of Enrollment United States | 100 participants |
| Sex: Female, Male Female | 82 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 88 / 100 |
| serious Total, serious adverse events | 30 / 100 |
Outcome results
Primary
Number of Patients Reaching a 6-Minute Walk Test (6MWT) Distance ≥ 380 Meters
The 6MWT is a non encouraged test, which measures the walking distance covered over a 6 minute period
Time frame: at 16 weeks and at 28 weeks of a stepped approach to therapy
Population: Intention to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosentan/Sildenafil | Number of Patients Reaching a 6-Minute Walk Test (6MWT) Distance ≥ 380 Meters | Week 16 | 16 participants |
| Bosentan/Sildenafil | Number of Patients Reaching a 6-Minute Walk Test (6MWT) Distance ≥ 380 Meters | Week 28 | 24 participants |