Study of the Efficacy and Safety of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Open Heart Surgery

Study Overview
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Brief Summary
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Endothelin-1 is a powerful substance that may be involved in causing hemodynamic instability (problems related to unstable blood pressure) during and after open heart surgery. Tezosentan is an investigational intravenous drug that blocks the endothelin receptors. This clinical trial will assess the potential benefit of tezosentan compared with placebo in the treatment of patients undergoing open heart surgery with cardiopulmonary bypass (CPB). Treatment time is from the start of surgery up to 24 hours.

Detailed Description
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Endothelin-1 levels are increased during and after cardiac surgery with cardiopulmonary bypass (CPB), and are associated with many deleterious consequences, including increased pulmonary arterial pressure (PAP), increased pulmonary vascular resistance (PVR), reduced myocardial contractility, and ultimately right ventricular failure. Right ventricular failure during weaning from CPB increases the risk of mortality and morbidity, especially in patients with elevated PAP prior to cardiac surgery. Endothelin receptor antagonists (ERAs) have been shown to decrease PVR and pulmonary arterial pressure (PAP), and improve right ventricular function in patients with pulmonary arterial hypertension. In animal models, ERAs have been shown to decrease the incidence of post-bypass pulmonary hypertensive crises. The primary objective of this trial is to demonstrate that tezosentan, a dual ERA, reduces the incidence of clinically relevant right ventricular failure in patients with pre-operative pulmonary hypertension, due to left heart disease, undergoing CPB.

Official Title
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Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Cardiac Surgery

Conditions
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Heart Diseases, Hypertension, Pulmonary

Intervention / Treatment
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* Drug: tezosentan
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years of age Male or female patients (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception). Patients undergoing complex* cardiac surgery on CPB and having systolic PAP > 40 mmHg or mean PAP > 30 mmHg (*surgery on 2 valves, 1 valve and revascularization, or reoperation of a valve) Patients undergoing cardiac surgery on CPB and having pre-operative pulmonary hypertension due to left heart disease with systolic PAP > 60 mmHg Signed written informed consent Exclusion Criteria: Systolic blood pressure < 100 mmHg Significant chronic lung disease Emergency surgery Pregnant/breast-feeding Investigational drug use within 28 days prior to randomization Complex adult congenital heart disease. Severe concomitant illness limiting life expectancy to < 6 months Participation in a device study that will affect the outcome of the study Pre-operative use of balloon pump, inotropes/vasopressors, treatment of pulmonary arterial hypertension Known hypersensitivity to tezosentan or drugs of the same class, or any of their excipients Severe liver impairment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Tezosentan | Drug: tezosentan<br>* Tezosentan (ACT-050089, Ro 61-0612) as a 1% solution in 0.9% NaCl (i.e., normal saline) for i.v. use.<br>|
| Placebo Comparator: 2<br>Placebo | Drug: placebo<br>* Placebo (i.e., normal saline) for i.v. use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective of this trial is to demonstrate that tezosentan, a dual ERA, reduces the incidence of clinically relevant right ventricular failure in patients with pre-operative pulmonary hypertension, due to left heart disease, undergoing CPB. |  | During weaning from CPB | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients w/a major clinical event w/in 28 days after study drug initiation like death/major cardiovascular events/infections that prolong hospital stay or require re-admission/new onset of renal failure requiring renal replacement therapy |  | Within 28 days after study initiation | 
| Time to weaning from cardiopulmonary bypass |  | Defined as time from release of cross-clamp to successful weaning from CPB | 
| Time from end of CPB to final discharge from Intensive Care Unit (ICU) |  | From end of CPB to final discharge from ICU | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Left sided heart disease, Elevated pulmonary arterial pressure, Right ventricular failure, Cardiac surgery, heart-lung machine, cardiopulmonary bypass, tezosentan, Actelion