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

Information source: Actelion
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pulmonary Arterial Hypertension

Intervention: bosentan (Drug); placebo (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Actelion

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.

Clinical Details

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

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

Primary outcome: Time to First Confirmed Morbidity/Mortality Event up to the End of Study

Secondary outcome:

Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation

Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT)

Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16

Time to Death of All Causes From Baseline to End of Study

Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP)

Change From Baseline to Week 16 in Borg Dyspnea Index

Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score

Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score

Patient Global Self Assessment (PGSA) Status at Week 16

Eligibility

Minimum age: 12 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

Hospital Madre Teresa, Belo Horizonte 30430-142, Brazil

CHSCPA, Porto Alegre 90020-090, Brazil

Hospital das Clínicas - FMUSP, Sao Paulo 05403-000, Brazil

Instituto Dante Pazzanese, Sao Paulo 04012-909, Brazil

UNIFESP - Pneumologia, Sao Paulo 04023-062, Brazil

Kardiologicka klinika Videnska, Praha 140 21, Czech Republic

Vseobecna Fakultni Nemocnice, Praha 128 08, Czech Republic

Rigshospitalet, Copenhagen 2100, Denmark

Universitätsklinikum Giessen und Marburg, Standort Giessen Zentrum für Innere Medizin, Giessen 35392, Germany

Medizinische Hochschule Hannover, Hannover 30625, Germany

Medizinische Klinik der Universitat Innere Medizin III, Heidelberg 69120, Germany

Klinik Lowenstein GmbH, Loewenstein 74245, Germany

Universitatsklinikum Regensburg, Regensburg 93053, Germany

General Hospital Alexandra, Athens 11528, Greece

University General Hospital "Attikon", Athens 12462, Greece

Rio University Hospital, Patras, Greece

Universidade de Coimbra, Coimbra 3000-076, Portugal

Hospital de Santa Maria, Lisbon 1649-035, Portugal

Riyadh Military Hospital, Riyadh 11159, Saudi Arabia

NUSCH, a.s., Bratislava, Slovakia

Vychodoslovensky ustav srdcovych a cievnych chorob, a.s., Kosice, Slovakia

Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria 35016, Spain

Hospital Universitario 12 Octubre, Madrid 28041, Spain

Sahlgrenska University Hospital, Gothenburg, Sweden

Royal Hallamshire Hospital, Sheffield S102JF, United Kingdom

Hospital de Messejana, Fortaleza, CE 60864-190, Brazil

UCSD Medical Center, Thornton Hospital, La Jolla, California 92037-7381, United States

Greater Los Angeles VA Medical Center, Los Angeles, California 90073, United States

University of California (UC) Davis Health System, Sacramento, California 95817, United States

UCSF, San Francisco, California 94143, United States

University of Colorado Health Sciences Center, Denver, Colorado 80220, United States

University of Connecticut, Farmington, Connecticut 06030, United States

Yale University School of Medicine, Dept. of Internal Medicine, Pulmonary & Critical Care, New Haven, Connecticut 06520-8057, United States

Hospital Universitário de Brasília, Brasília, DF 70840-050, Brazil

Bay Area Chest Physicians, Clearwater, Florida 33756, United States

Shands Hospital at the University of Florida, Gainesville, Florida 30067, United States

Mayo Clinic Jacksonville, Jacksonville, Florida 32224, United States

University of Florida - Jacksonville, Jacksonville, Florida 32209, United States

Winthrop University Hospital, Mineola, Georgia 30067, United States

University of Iowa Pulmonary Hypertension Program, Iowa City, Iowa 52242, United States

University of Kansas Medical Center, Kansas City, Kansas 66160, United States

UK Medical Center - University of Kentucky, Lexington, Kentucky 40536-0294, United States

Hospital das Clínicas - UFMG, Belo Horizonte, MG 30130-100, Brazil

Johns Hopkins University, Baltimore, Maryland 21205, United States

University of Maryland - School of Medicine, Baltimore, Maryland 21201-1595, United States

Tufts - New England Medical Center, Boston, Massachusetts 02111, United States

University of Michigan Cardiology, Ann Arbor, Michigan 48109, United States

Harper University Hospital - Wayne State University, Detroit, Michigan 48201, United States

Spectrum Health Research Department, Grand Rapids, Michigan 49525, United States

University of Minnesota Department of Medicine - Cardiovascular Division, Minneapolis, Minnesota 55455, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

St. Luke's Hospital, Chesterfield, Missouri 63017, United States

Washington University, St. Louis, Missouri 63110, United States

Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 03756-0001, United States

Duke University Medical Center (DUMC), Durham, North Carolina 27710, United States

Lindner Clinical Trials Center, Cincinnati, Ohio 45219, United States

The Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States

Ohio State University - Pulmonary Clinical Trials Office - Martha Morehouse Medical Plaza, Columbus, Ohio 43210, United States

The Oregon Clinic - Pulmonary and Critical Care Medicine, Portland, Oregon 97220, United States

Allegheny General Hospital, Pittsburgh, Pennsylvania 15212, United States

University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute, Pittsburgh, Pennsylvania 15213, United States

Medical University of South Carolina (MUSC), Charleston, South Carolina 29425, United States

Mid Carolina Internal Medicine, Lexington, South Carolina 29072, United States

South Carolina Pharmaceutical Research, Spartanburg, South Carolina 29303, United States

University of Texas Medical Branch, Galveston, Texas 77555-0561, United States

Baylor Clinic, Houston, Texas 77030, United States

Inova Fairfax Hospital, Falls Church, Virginia 22042-3300, United States

Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin 53226, United States

Additional Information

Tracleer for PAH approval page at Drugs@FDA.gov

Starting date: May 2006
Last updated: January 22, 2015

Page last updated: August 23, 2015

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