Effects of Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Morbidity and Mortality in Symptomatic Patients With Pulmonary Arterial Hypertension - A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Prospective, Event Driven Phase IV Study
Jacksonville, Fla., Rochester, Minn.
Trial status: Open for Enrollment
Why is this study being done?
This study will investigate the effects of the combination of bosentan and sildenafil. Patients with symptomatic PAH treated with a stable dose of sildenafil equal to or greater tha 20 mg t.i.d. for at least 12 weeks will be randomized to placebo or bosentan 125 mg b.i.d. All randomized patients will be treated with study drug until the predefined target number of morbidity/mortality events is reached.
Who is eligible to participate?
1. Signed informed consent prior to initiation of any study-mandated procedure
2. Males or females >=12 years of age (except for countries where this age limit is contrary to specific regulatory requirements).
- Women of childbearing potential must have a negative pre-treatment pregnancy test and must use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.
·Reliable methods of contraception are:
O Barrier type devices (e.g., female condom, diaphragm, contraceptive sponge) only in combination with a spermicide.
O Intra-uterine devices. O Oral, transdermal, injectable or implantable contraceptives only in combination with a barrier method.
- Hormone-based contraceptives alone, regardless of the route of administration, are not considered as reliable methods of contraception.
- Abstention, rhythm method, and contraception by the partner alone are not acceptable methods of contraception.
- Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.
3. Patients with symptomatic PAH
4. Patients with the following types of PAH belonging to WHO Group I:
- Idiopathic (IPAH)
- Familial (FPAH)
- Associated with (APAH):
i. Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%) ii. Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair iii. Drugs and toxins
5. PAH diagnosed by right heart catheter showing:
- Mean pulmonary arterial pressure (mPAP) >= 25 mm Hg AND
- Pulmonary capillary wedge pressure (PCWP) =< 15 mm Hg or left ventricular end diastolic pressure (LVEDP) =< 15 mmHg If both PCWP and LVEDP are available then the LVEDP value is retained for inclusion.
6. Treatment with a stable dose of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to randomization (no sildenafil dosage adjustment should occur in this period) 7)150 m =< 6MWT =< 480 m, documented by 2 tests with second 6MWT within 15% of first 6MWT distance or a third test required
Exclusion Criteria :
1. PAH belonging to WHO group II-V
2. PAH associated with portal hypertension and HIV infection
3. PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
4. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
5. Persistent pulmonary hypertension of the newborn
6. Significant valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e. patients with tricuspid or pulmonary insufficiency secondary to PAH can be included)
7. Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value (see Appendix 3)
8. Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 0.5
9. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
10. Known HIV infection
11. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements or that may interfere with the safety or the evaluation of the study, such as chronic infection, chronic renal failure etc.
12. Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
13. Pregnancy or breast-feeding
14. Condition that prevents compliance with the protocol or adherence to therapy
15. Systolic blood pressure < 85 mmHg
16. Body weight < 40 kg
17. Hemoglobin <75% of the lower limit of the normal range
18. Aspartate aminotransferase (AST) and/or alanine aminotransferase ALT > 1.5 times the upper limit of normal ranges
19. Known hypersensitivity or history of drug-related adverse events with bosentan (e.g. increase in liver function test results [LFTs]), or any of the excipients of its formulation
20. Receipt of an investigational product other than sildenafil within 3 months before start of study treatment
21. Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
22. Concomitant systemic treatment within 1 week prior to randomization with
- calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus
- glibenclamid (glyburide)
- both CYP2C9 and CYP3A4 (e.g., fluconazole, amiodarone, voriconazole)
- combination of drugs that inhibit CYP2C9 and CYP3A4
23. Treatment with nitrates and alpha-blockers at time of randomization
24. In the opinion of the investigator - patients in need for treatment with any prostanoid up to Visit 4
25. Significant left ventricular dysfunction