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 - COMPASS 2

Conditions: Patients to be included must have PAH belonging to WHO Group I, in agreement with the approved indications for sildenafil in PAH by the US FDA:a.Idiopathic (IPAH)b.Familial (FPAH)c.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 repairiii.Drugs and toxins
MedDRA version: 9.1Level: LLTClassification code 10064908Term: Associated with (APAH)
MedDRA version: 9.1Level: LLTClassification code 10064910Term: Familial (FPAH)
MedDRA version: 9.1Level: LLTClassification code 10064909Term: Idiopathic (IPAH)

Registration Number: EUCTR2005-005068-97-GR

Lead Sponsor: Actelion Pharmaceuticals Ltd.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 180

Inclusion Criteria

1)Signed informed consent prior to initiation of any study-mandated procedure
2)Males or females >= 18 years of age
•Women of childbearing potential must have a negative pre-treatment pregnancy test and must use reliable 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:
a.Idiopathic (IPAH)
b.Familial (FPAH)
c.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:
a.Mean pulmonary arterial pressure
(mPAP) >= 25 mmHg
AND
b.Pulmonary capillary wedge pressure
(PCWP) <= 15 mmHg 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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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
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 prior to randomization
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
•immune suppressants (e.g., cyclosporine A and tacrolimus, everolimus, sirolimus)
•inhibitors of CYP2C9 (e.g., voriconazole, metronidazole, miconazole)
•potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin and ritonavir)
•drugs that inhibit both CYP2C9 and CYP 3A4 (e.g., fluconazole, amiodarone), ,
•protease inhibitors (e.g., ritonavir)
•glibenclamide (glyburide)
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