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

Study Overview
=================
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.

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

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: bosentan
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Bosentan | Drug: bosentan<br>* bosentan/62.5 mg tablet/b.i.d. for 4 weeks then bosentan/125 mg tablet/b.i.d.<br>|
| Placebo Comparator: B<br>Placebo | Drug: placebo<br>* Matching bosentan placebo/b.i.d.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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