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