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Pulmonary Arterial HypertensionPhase 4Compass-2NCT00303459

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

A Phase 4 study testing bosentan in people with Pulmonary Arterial Hypertension, run by Actelion.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 12 years and older
Conditions the study is for
Pulmonary Arterial Hypertension
What is being tested?
bosentan
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
334 participants
Where
No sites listed yet
Study dates
May 2006to Dec 2013
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
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  • 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):
  • 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

Who cannot join

  • 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)
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  • 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

About this study

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

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.

Being tested
bosentan, placebo
Keywords
sildenafil, Combination Drug Therapy, bosentan, Pulmonary Hypertension, Pulmonary Arterial Hypertension, Multicenter Study, Antihypertensive Agents, Tracleer, endothelin receptor antagonist, Randomized Controlled Trial, Phosphodiesterase type 5 inhibitor (PDE5i), Outcome Assessment
Medical subject headings
Pulmonary Arterial Hypertension, Hypertension, Pulmonary

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • bosentanDrug

    bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.

  • placeboDrug

    Matching bosentan placebo/b.i.d.

Study groups in NCT00303459
Study groupRoleWhat they receive
AExperimentalBosentan
Receives: Drug: bosentan
BPlacebo comparatorPlacebo
Receives: Drug: placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: From baseline to end of study, approximately 86 months

Secondary outcomes (9)

  1. 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.

    Measured: Baseline to end of study, approximately 86 months

  2. 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.

    Measured: From baseline to week 16

  3. 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.

    Measured: From baseline to Week 16

  4. 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.

    Measured: Baseline to End of Study, approximately 86 months

  5. 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.

    Measured: Baseline to Month 20

  6. 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').

    Measured: Baseline to Week 16

  7. 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).

    Measured: From baseline to Week 16

  8. 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.

    Measured: Baseline to Week 16

  9. 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.

    Measured: Week 16

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Mar 2006 (estimated)
  2. Study startMay 2006
  3. Primary completionDec 2013
  4. Study completionDec 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
334 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00303459
Sponsor's protocol ID
AC-052-414
Other IDs
COMPASS-2
Acronym
Compass-2
Status last verified
Jan 2025
First submitted
16 Mar 2006
Last updated
4 Feb 2025
Data monitoring committee
Yes

Publications

  • McLaughlin V, Channick RN, Ghofrani HA, Lemarie JC, Naeije R, Packer M, Souza R, Tapson VF, Tolson J, Al Hiti H, Meyer G, Hoeper MM. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015 Aug;46(2):405-13. doi: 10.1183/13993003.02044-2014. Epub 2015 Jun 25.

    PubMed 26113687

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing bosentan in people with Pulmonary Arterial Hypertension, run by Actelion.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Jan 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Time to First Confirmed Morbidity/Mortality Event up to the End of Study (time frame: From baseline to end of study, approximately 86 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00303459, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Feb 2025.

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