Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: bosentan; placebo
Intervention description: bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.; Matching bosentan placebo/b.i.d.
Intervention MeSH terms: Bosentan
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 334.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: sildenafil; Combination Drug Therapy; bosentan; Pulmonary Hypertension; Pulmonary Arterial Hypertension; Multicenter Study; Antihypertensive Agents; Tracleer; endothelin receptor antagonist; Randomized Controlled Trial; Phosphodiesterase type 5 inhibitor (PDE5i); Outcome Assessment

Summary:

      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.
    

Eligibility criteria:

        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