Official Title: “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”

This study will investigate the effects of the combination of bosentan and sildenafil.

Patients with symptomatic PAH treated with a stable dose of sildenafil equal to or greater tha 20 mg t.i.d. for at least 12 weeks will be randomized to placebo or bosentan 125 mg b.i.d. All randomized patients will be treated with study drug until the predefined target number of morbidity/mortality events is reached.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2009

Intervention(s) in this Clinical Trial

• Drug: bosentan
  • bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.
• Drug: placebo
  • Matching bosentan placebo/b.i.d.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Bosentan
• Placebo Comparator: B
  • Placebo

Primary Measures

• Time from baseline to first adjudicated morbidity/mortality event
  • Time Frame: From baseline to first adjudicated morbidity/mortality event
    Safety Issue?: No

Secondary Measures

• Change from baseline to Week 16 in World Health Organization (WHO) functional class
  • Time Frame: From baseline to Week 16
    Safety Issue?: No
• Change from baseline to Week 16 in Borg dyspnea index
  • Time Frame: From baseline to Week 16
    Safety Issue?: No
• Change from baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) questionnaire
  • Time Frame: From baseline to Week 16
    Safety Issue?: No
• Patient global self assessment at Week 16
  • Time Frame: Week 16
    Safety Issue?: No
• Time to event for the first occurrence of hospitalization for worsening or complication of PAH or initiation of intravenous (I.V.) prostanoids, atrial septostomy, lung transplantation or death from baseline to End of Study
  • Time Frame: Baseline to first hospitalization
    Safety Issue?: No
• Time to death of all causes from baseline to End of Study
  • Time Frame: Baseline to End of Study
    Safety Issue?: No
• Change from baseline to Week 16 in 6 minute walk test (6MWT)
  • Time Frame: From baseline to week 16
    Safety Issue?: No

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 pre-treatment 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 Intra-uterine 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:
• 1. Idiopathic (IPAH)
• 2. Familial (FPAH)
• 3. 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:
• 1. Mean pulmonary arterial pressure (mPAP) >= 25 mm Hg AND
• 2. 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 =< 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 [LFTs]), 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
• immune suppressants (e.g., cyclosporine A and tacrolimus, everolimus, sirolimus)
• inhibitors of CYP2C9 (e.g., voriconazole, metronidazole and miconazole)
• potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin and ritonavir)
• drugs that inhibit both CYP2C9 and CYP3A4 (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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 12 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Actelion

Overall Clinical Trial Officials and Contacts

Overall Contact: Mostafa Chouikh 718-706-6287 mostafa.chouikh@actelion.com

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00303459

Study ID Number: AC-052-414

ClinicalTrials.gov Identifier: NCT00303459

Health Authority: United States: Food and Drug Administration

Tracleer for PAH approval page at Drugs@FDA.gov