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

Pulmonary Arterial Hypertension Clinical Trial

— Compass-2  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00303459
• Other study ID #: AC-052-414
• Secondary ID: COMPASS-2
• Status: Completed
• Phase: Phase 4
• First received: March 16, 2006
• Last updated: October 16, 2015
• Start date: May 2006
• Est. completion date: December 2013

Study information

• Verified date: October 2015
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationEuropean Union: European Medicines AgencyBrazil: National Health Surveillance Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 334
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension

Intervention

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Brazil,  Czech Republic,  Denmark,  Germany,  Greece,  Portugal,  Saudi Arabia,  Slovakia,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to First Confirmed Morbidity/Mortality Event up to the End of Study	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.	From baseline to end of study, approximately 86 months	No
Secondary	Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation	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.	Baseline to end of study, approximately 86 months	No
Secondary	Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT)	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.	From baseline to week 16	No
Secondary	Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class 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.	From baseline to Week 16	No
Secondary	Time to Death of All Causes From Baseline to End of Study	Kaplan-Meier estimate of percentage of participants without a mortality event.Time to death due to any cause.	Baseline to End of Study, approximately 86 months	No
Secondary	Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP)	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.	Baseline to Month 20	No
Secondary	Change From Baseline to Week 16 in Borg Dyspnea Index	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').	Baseline to Week 16	No
Secondary	Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score	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).	From baseline to Week 16	No
Secondary	Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score	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.	Baseline to Week 16	No
Secondary	Patient Global Self Assessment (PGSA) Status at 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.	Week 16	No

External Links

•   Tracleer for PAH approval page at Drugs@FDA.gov