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 repair iii.Drugs and toxins MedDRA version: 9.1 Level: LLT Classification code 10064908 Term: Associated with (APAH)
Conditions
Sponsors
Actelion Pharmaceuticals Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
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) =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
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) 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 • calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus • glibenclamide (glyburide) • inhibitors of 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To demonstrate that the combination of bosentan and sildenafil prolongs the time to the first adjudicated morbidity/mortality event compared with sildenafil monotherapy in symptomatic patients with pulmonary arterial hypertension (PAH);Secondary Objective: To assess: - the effects of the combination of bosentan and sildenafil compared with sildenafil monotherapy: ·on the 6-minute walk test (6MWT) ·on the modified WHO functional class in the patient population investigated, ·on the Borg dyspnea index in the patient population investigated, ·on the change in Patient Global Self Assessment in the patient population investigated ·on the time to event for the first occurrence of hospitalization for worsening or complication of PAH (including initiation of i.v. prostanoids), atrial septostomy, lung transplantation or death in the patient population investigated ·on the time to death of all causes in the patient population investigated ·on the quality of life in the patient population investigated and to assess the safety and tolerability of the combination of bosentan and sildenafil in the patient population investigated;Primary end point(s): Primary Endpoint •Time from baseline to first adjudicated morbidity/mortality event, defined as follows: a.Death b.Hospitalization for worsening or complications of PAH or initiation of i.v. prostanoids c.Atrial septostomy d.Lung transplantation e.Worsening PAH defined by fulfillment of both of the following criteria: 1) The recognition that the patient’s symptoms are worse using a 7-item Patient Global Self Assessment Scale: •If the Patient Global Self Assessment is “moderately worse” or “markedly worse,” confirmatory examinations of worsening PAH may be performed if deemed necessary by the investigator. These examinations include (but are not limited to): right heart catheterization (RHC), 6MWT. However, none of these examinations are mandatory and the investigator can choose the method of evaluation. •If the P | — |
Countries
Belgium, Czech Republic, Denmark, Germany, Greece, Portugal, Spain, Sweden, United Kingdom
Outcome results
None listed