Clinical trial NCT00303459: Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
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
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2006-03-17
Enrollment: 334
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Time to First Confirmed Morbidity/Mortality Event up to the End of Study
timeFrame: From baseline to end of study, approximately 86 months
Secondary outcomes:
measure: Time to First Confirmed Death, Hospitalization for Worsening or Complication of PAH or Initiation of Intravenous Prostanoids, Atrial Septostomy, or Lung Transplantation
timeFrame: Baseline to end of study, approximately 86 months
measure: Change From Baseline to Week 16 in 6 Minute Walk Test (6MWT)
timeFrame: From baseline to week 16
measure: Number of Participants With Improved, No Change, or Worsened World Health Organisation Functional Class From Baseline to Week 16
timeFrame: From baseline to Week 16
measure: Time to Death of All Causes From Baseline to End of Study
timeFrame: Baseline to End of Study, approximately 86 months
measure: Adjusted Percentage Ratio From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-pro-BNP)
timeFrame: Baseline to Month 20
measure: Change From Baseline to Week 16 in Borg Dyspnea Index
timeFrame: Baseline to Week 16
measure: Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Questionnaire Calculated Score
timeFrame: From baseline to Week 16
measure: Change From Baseline to Week 16 in the EuroQol 5 Dimensions (EQ-5D) Visual Analogue Scale Score
timeFrame: Baseline to Week 16
measure: Patient Global Self Assessment (PGSA) Status at Week 16
timeFrame: Week 16
Other outcomes:
Locations:
Study officials:
References:
citation: 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.