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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Actelion
ClinicalTrials.gov Identifier:
NCT00303459
First received: March 16, 2006
Last updated: February 11, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: bosentan
Drug: placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Actelion:

Primary Outcome Measures:
  • Time from baseline to first adjudicated morbidity/mortality event [ Time Frame: From baseline to end of study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change from baseline to Week 16 in 6 minute walk test (6MWT) [ Time Frame: From baseline to week 16 ] [ Designated as safety issue: No ]
  • Change from baseline to Week 16 in WHO functional [ Time Frame: From baseline to Week 16 ] [ Designated as safety issue: No ]
  • Change from baseline to Week 16 in Borg dyspnea index [ Time Frame: From baseline to Week 16 ] [ Designated as safety issue: No ]
  • Change from baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) questionnaire [ Time Frame: From baseline to Week 16 ] [ Designated as safety issue: No ]
  • Patient Global Self Assessment at Week 16 [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
  • Time to event for the first occurrence of Death, hospitalization for worsening or complication of PAH or initiation of IV prostanoids, Atrial Septostomy, or Lun Transplantation [ Time Frame: Baseline to end of study ] [ Designated as safety issue: No ]
  • Time to death of all causes from baseline to EOS [ Time Frame: Baseline to End of Study ] [ Designated as safety issue: No ]

Enrollment: 334
Study Start Date: May 2006
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
Bosentan
Drug: bosentan
bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.
Placebo Comparator: B
Placebo
Drug: placebo
Matching bosentan placebo/b.i.d.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 =< 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

    • calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus
    • glibenclamide (glyburide)
    • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00303459

  Show 60 Study Locations
Sponsors and Collaborators
Actelion
  More Information

Additional Information:
No publications provided

Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT00303459     History of Changes
Other Study ID Numbers: AC-052-414, COMPASS-2
Study First Received: March 16, 2006
Last Updated: February 11, 2014
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency
Brazil: National Health Surveillance Agency

Keywords provided by Actelion:
Pulmonary Arterial Hypertension
Pulmonary Hypertension
Antihypertensive Agents
bosentan
Tracleer
sildenafil
endothelin receptor antagonist
Combination Drug Therapy
Outcome Assessment
Randomized Controlled Trial
Multicenter Study
PDE5i

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Sildenafil
Bosentan
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Antihypertensive Agents

ClinicalTrials.gov processed this record on September 18, 2014