Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH) (Compass-2)

Actelion Pharmaceuticals

Status and phase

Completed

Phase 4

Conditions

Pulmonary Arterial Hypertension

Treatments

Drug: bosentan

Drug: placebo

Study type

Interventional

Funder types

Industry

Identifiers

NCT00303459

COMPASS-2 (Other Identifier)

AC-052-414

Details and patient eligibility

About

COMPASS-2 is a Phase 4, prospective, randomized, double-blind, placebo-controlled, event-driven study evaluating the effect of bosentan on the time to first confirmed morbidity/mortality event in patients with symptomatic PAH already receiving sildenafil therapy. Patients must have been receiving doses of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to being randomized.

The study continued until the predefined target number of morbidity/mortality events was reached.

Enrollment

334 patients

Sex

All

Ages

12+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

Signed informed consent prior to initiation of any study-mandated procedure
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.
Patients with symptomatic PAH
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
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.
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 :

PAH belonging to WHO group II-V
PAH associated with portal hypertension and HIV infection
PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
Persistent pulmonary hypertension of the newborn
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)
Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value (see Appendix 3)
Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 0.5
Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
Known HIV infection
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.
Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
Pregnancy or breast-feeding
Condition that prevents compliance with the protocol or adherence to therapy
Systolic blood pressure < 85 mmHg
Body weight < 40 kg
Hemoglobin <75% of the lower limit of the normal range
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges
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
Receipt of an investigational product other than sildenafil within 3 months before start of study treatment
Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
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
Treatment with nitrates and alpha-blockers at time of randomization
In the opinion of the investigator - patients in need for treatment with any prostanoid up to Visit 4
Significant left ventricular dysfunction