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

Phase 4

Completed

Conditions: Pulmonary Arterial Hypertension

Interventions: Drug: placebo
Drug: bosentan

Registration Number: NCT00303459

Lead Sponsor: Actelion

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 334

Inclusion Criteria

Signed informed consent prior to initiation of any study-mandated procedure
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.
Patients with symptomatic PAH
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
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.
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 :

PAH belonging to WHO group II-V
PAH associated with portal hypertension and HIV infection
PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
Persistent pulmonary hypertension of the newborn
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)
Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value (see Appendix 3)
Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 0.5
Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
Known HIV infection
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.
Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
Pregnancy or breast-feeding
Condition that prevents compliance with the protocol or adherence to therapy
Systolic blood pressure < 85 mmHg
Body weight < 40 kg
Hemoglobin <75% of the lower limit of the normal range
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges
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
Receipt of an investigational product other than sildenafil within 3 months before start of study treatment
Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
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
Treatment with nitrates and alpha-blockers at time of randomization
In the opinion of the investigator - patients in need for treatment with any prostanoid up to Visit 4
Significant left ventricular dysfunction

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
B	placebo	Placebo
A	bosentan	Bosentan

Primary Outcome Measures

Name	Time	Method
Time to First Confirmed Morbidity/Mortality Event up to the End of Study	From baseline to end of study, approximately 86 months	Kaplan-Meier estimate of percentage of participants without a morbidity/mortality event. A morbidity/mortality event is defined as the occurrence of a) death, b) hospitalization for worsening or complication of PAH or intravenous prostanoid initiation, c) atrial septostomy, d) lung transplantation, or e) worsening PAH, defined as "moderately" or "markedly" worsened PAH symptoms using a patient global self-assessment (PGSA) scale AND initiation of inhaled or subcutaneous prostanoids or the disease progression package (open-label bosentan). If a patient replied "no change" or "mildly worse" on the PGSA, a decrease in 6MWT of 20% versus last visit or 30% versus baseline is also required to confirm the event.

Secondary Outcome Measures

Name	Time	Method
Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation	Baseline to end of study, approximately 86 months	Kaplan-Meier estimate of percentage of participants without an event of death, hospitalization (for worsening or complication of PAH or initiation of intravenous prostanoids), atrial septostomy or lung transplantation. Time to first confirmed death, hospitalization (for worsening or complication of PAH or initiation of intravenous prostanoids), atrial septostomy or lung transplantation from baseline to end of study was confirmed by an independent Clinical Endpoint Committee.
Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT)	From baseline to week 16	The 6MWT is a non-encouraged test, which measures the distance covered over a 6 minute walk; the patient is instructed to walk as far as possible in a 30 m long flat corridor, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Areas were to be well ventilated with air temperature controlled between 20 °C and 23 °C (68 °F to 76 °F). The test was to be administered at the same time of day and by the same tester throughout the study. The tester measured the distance walked by non-encouraged patients during the timed 6 minute period.
Time to Death of All Causes From Baseline to End of Study	Baseline to End of Study, approximately 86 months	Kaplan-Meier estimate of percentage of participants without a mortality event.Time to death due to any cause.
Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16	From baseline to Week 16	Class I: no limitation of usual physical activity (PA) which does not increase dyspnea, fatigue, chest pain, or presyncope. Class II: mild limitation of PA. No discomfort at rest. Normal PA increases dyspnea, fatigue, chest pain, or presyncope. Class III: marked limitation of PA. No discomfort at rest. Less than ordinary activity increases dyspnea, fatigue, chest pain, or presyncope. Class IV: unable to perform any PA and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any PA.
Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP)	Baseline to Month 20	Blood sampling for the measurement of NT-pro-BNP was performed and the plasma concentrations of NT-pro-BNP were determined by a certified centralized laboratory.
Change From Baseline to Week 16 in Borg Dyspnea Index	Baseline to Week 16	The Borg dyspnea index was evaluated immediately after the 6MWT to obtain a rating of dyspnea at the end of the exercise using a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal').
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score	Baseline to Week 16	The EQ-5D questionnaire is a patient-reported outcome consisting of a 5 dimensional descriptive system and a visual analog scale (VAS) together with brief demographic questions. EQ-5D VAS asks respondents to rate their perception of their overall health on a vertical visual analogue scale with 'best imaginable health state' set at 100 and 'worst imaginable health state' set at 0.
Patient Global Self Assessment (PGSA) Status at Week 16	Week 16	The PGSA is a questionnaire that allows the patient to compare his/her PAH status in response to the question "How do you feel about your PAH today compared with your last visit?" asked by the investigator. Patients use a seven-point scale to respond: markedly better, moderately better, mildly better, no change, markedly worse, moderately worse, or mildly worse.
Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score	From baseline to Week 16	The EQ-5D questionnaire is a patient-reported outcome consisting of a 5 dimensional descriptive system and a visual analog scale (VAS). The descriptive system asks respondents to describe their health status. Health is defined in 5 dimensions: (1) mobility, (2) self care, (3) usual activities, (4) pain or discomfort, and (5) anxiety or depression. Each dimension is divided into 3 levels, indicating (a) no problem, (b) some or moderate problems, or (c) extreme problems. Respondents record their problem(s) in each of the 5 dimensions. Combinations of these levels define a total of 243 health states. A health state defined by the descriptive system of EQ-5D can be described by a 5-digit number with full health is indicated by 11111 and poorest health state by 33333. The EQ-5D calculated score was derived by re-assigning local scores for answers to each question and combining these local scores into a global score with ranges from 0 (worst possible outcome) to 1 (best possible outcome).

Trial Locations

Locations (68): Greater Los Angeles VA Medical Center
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Los Angeles, California, United States
Johns Hopkins University
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Baltimore, Maryland, United States
South Carolina Pharmaceutical Research
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Spartanburg, South Carolina, United States
Tufts - New England Medical Center
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Boston, Massachusetts, United States
UCSD Medical Center, Thornton Hospital
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La Jolla, California, United States
University of California (UC) Davis Health System
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Sacramento, California, United States
Bay Area Chest Physicians
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Clearwater, Florida, United States
Mayo Clinic Jacksonville
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Jacksonville, Florida, United States
Shands Hospital at the University of Florida
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Gainesville, Florida, United States
University of Florida - Jacksonville
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Jacksonville, Florida, United States
Winthrop University Hospital
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Mineola, Georgia, United States
University of Iowa Pulmonary Hypertension Program
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Iowa City, Iowa, United States
UK Medical Center - University of Kentucky
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Lexington, Kentucky, United States
University of Maryland - School of Medicine
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Baltimore, Maryland, United States
University of Michigan Cardiology
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Ann Arbor, Michigan, United States
Spectrum Health Research Department
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Grand Rapids, Michigan, United States
Washington University
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St. Louis, Missouri, United States
Dartmouth Hitchcock Medical Center
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Lebanon, New Hampshire, United States
The Cleveland Clinic Foundation
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Cleveland, Ohio, United States
St. Luke's Hospital
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Chesterfield, Missouri, United States
Ohio State University - Pulmonary Clinical Trials Office - Martha Morehouse Medical Plaza
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Columbus, Ohio, United States
University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute
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Pittsburgh, Pennsylvania, United States
Baylor Clinic
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Houston, Texas, United States
Medical University of South Carolina (MUSC)
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Charleston, South Carolina, United States
University of Texas Medical Branch
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Galveston, Texas, United States
Inova Fairfax Hospital
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Falls Church, Virginia, United States
Hospital das Clínicas - UFMG
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Belo Horizonte, MG, Brazil
Hospital Madre Teresa
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Belo Horizonte, Brazil
CHSCPA
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Porto Alegre, Brazil
Instituto Dante Pazzanese
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Sao Paulo, Brazil
UNIFESP - Pneumologia
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Sao Paulo, Brazil
Hospital das Clínicas - FMUSP
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Sao Paulo, Brazil
Kardiologicka klinika Videnska
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Praha, Czech Republic
Universitätsklinikum Giessen und Marburg, Standort Giessen Zentrum für Innere Medizin
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Giessen, Germany
Medizinische Klinik der Universitat Innere Medizin III
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Heidelberg, Germany
Klinik Lowenstein GmbH
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Loewenstein, Germany
Universitatsklinikum Regensburg
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Regensburg, Germany
Rio University Hospital
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Patras, Greece
University General Hospital "Attikon"
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Athens, Greece
Riyadh Military Hospital
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Riyadh, Saudi Arabia
Hospital Universitario Insular de Gran Canaria
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Las Palmas de Gran Canaria, Spain
Hospital Universitario 12 Octubre
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Madrid, Spain
Sahlgrenska University Hospital
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Gothenburg, Sweden
Royal Hallamshire Hospital
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Sheffield, United Kingdom
Rigshospitalet
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Copenhagen, Denmark
Hospital de Messejana
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Fortaleza, CE, Brazil
Hospital Universitário de Brasília
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Brasília, DF, Brazil
UCSF
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San Francisco, California, United States
University of Colorado Health Sciences Center
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Denver, Colorado, United States
Harper University Hospital - Wayne State University
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Detroit, Michigan, United States
University of Minnesota Department of Medicine - Cardiovascular Division
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Minneapolis, Minnesota, United States
Duke University Medical Center (DUMC)
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Durham, North Carolina, United States
The Oregon Clinic - Pulmonary and Critical Care Medicine
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Portland, Oregon, United States
Lindner Clinical Trials Center
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Cincinnati, Ohio, United States
Froedtert Memorial Lutheran Hospital
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Milwaukee, Wisconsin, United States
Medizinische Hochschule Hannover
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Hannover, Germany
Allegheny General Hospital
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Pittsburgh, Pennsylvania, United States
Universidade de Coimbra
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Coimbra, Portugal
NUSCH, a.s.
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Bratislava, Slovakia
Hospital de Santa Maria
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Lisbon, Portugal
Mayo Clinic
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Rochester, Minnesota, United States
Yale University School of Medicine, Dept. of Internal Medicine, Pulmonary & Critical Care
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New Haven, Connecticut, United States
Vseobecna Fakultni Nemocnice
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Praha, Czech Republic
General Hospital Alexandra
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Athens, Greece
Vychodoslovensky ustav srdcovych a cievnych chorob, a.s.
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Kosice, Slovakia
University of Connecticut
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Farmington, Connecticut, United States
Mid Carolina Internal Medicine
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Lexington, South Carolina, United States
University of Kansas Medical Center
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Kansas City, Kansas, United States