Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)

Inclusion Criteria:

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 pretreatment 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 Intrauterine 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 =< 6-minute walk test (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), 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

- glibenclamide (glyburide)

- both cytochrome P2C9 (CYP2C9) and cytochrome P3A4 (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