Confirming The Sitaxsentan Dose In Patients Undergoing Heart Surgery

Study Overview
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Brief Summary
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This is a multi-center, randomized study of sitaxsentan administered intravenously to subjects who are undergoing elective CABG, cardiac valve replacement, or combined CABG and cardiac valve replacement procedures that require CPB.

Official Title
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SELECTIVE ENDOTHELIN TYPE A RECEPTOR INHIBITION IN CARDIAC SURGERY SUBJECTS WITH PRE-EXISTING CARDIOVASCULAR RISK FACTORS: A DOSE CONFIRMATION STUDY

Conditions
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Cardiac Surgery Subjects, Subjects Undergoing CABG and/or Cardiac Valve Replacement

Intervention / Treatment
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* Drug: sitaxsentan (Thelin)
* Drug: sitaxsentan (Thelin)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has been identified for coronary artery bypass grafting (CABG), aortic and/or mitral valve replacement, or combined CABG and cardiac valve replacement procedures that require cardiopulmonary bypass (CPB). Exclusion Criteria: Requires an emergent or emergency CABG and/or cardiac valve replacement.

Ages Eligible for Study
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Minimum Age: 48 Years
Maximum Age: 82 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sitaxsentan (1.0 mg/kg)<br> | Drug: sitaxsentan (Thelin)<br>* sitaxsentan (1.0 mg/kg) will begin immediately following cross-clamp release and 12 hours post-CPB.<br>* Other names: sitaxsentan, Thelin;|
| Experimental: sitaxsentan (2.0 mg/kg)<br> | Drug: sitaxsentan (Thelin)<br>* Sitaxsentan (2.0 mg/kg) will begin immediately following cross-clamp release and 12 hours post-CPB.<br>* Other names: sitaxsentan, Thelin;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo will begin immediately following cross-clamp release and 12 hours post-CPB.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From 0 Hour in Pulmonary Vascular Resistance (PVR) at 0.5 Hour Post-separation From Cardiopulmonary Bypass (CPB) | PVR in participants was derived from mean pulmonary artery pressure (PAP) (millimeter of mercury [mmHg]), pulmonary capillary wedge pressure (PCWP [mmHg]) and cardiac output (CO [litres per minute]). It was calculated using the following formula: ([mean PAP-PCWP] divided by CO)*80, where CO= stroke volume (SV)*heart rate (HR). Post-separation from CPB was the time immediately following cross-clamp release in CPB. Percent change in PVR at 0.5 hour post-separation from CPB in participants were summarized and reported. | 0 hour, 0.5 hour post-separation from CPB | 
| Percent Change From 0 Hour in Pulmonary Vascular Resistance (PVR) at 6 Hour Post-separation From Cardiopulmonary Bypass (CPB) | PVR in participants was derived from mean PAP (mmHg), PCWP (mmHg) and CO (litres per minute). It was calculated using the following formula: ([mean PAP-PCWP] divided by CO)*80, where CO= SV * HR. Percent change in PVR at 6 hour in participants were summarized and reported. | 0 hour, 6 hour post-separation from CPB | 
| Percent Change From 0 Hour in Pulmonary Vascular Resistance (PVR) at 12 Hour Post-separation From Cardiopulmonary Bypass (CPB) | PVR in participants was derived from mean PAP (mmHg), PCWP (mmHg) and CO (litres per minute). It was calculated using the following formula: ([mean PAP-PCWP] divided by CO)*80, where CO= SV * HR. Percent change in PVR at 12 hour in participants were summarized and reported. | 0 hour, 12 hour post-separation from CPB | 
| Percent Change From 0 Hour in Pulmonary Vascular Resistance (PVR) at 24 Hour Post-separation From Cardiopulmonary Bypass (CPB) | PVR in participants was derived from mean PAP (mmHg), PCWP (mmHg) and CO (litres per minute). It was calculated using the following formula: ([mean PAP-PCWP] divided by CO)*80, where CO= SV * HR. Percent change in PVR at 24 hour in participants were summarized and reported. | 0 hour, 24 hour post-separation from CPB | 
| Mortality: Number of Participants Died During Surgery and Initial Hospitalization | Number of participants who died during surgery or during initial hospitalization are reported here. | During surgery, initial hospitalization period (up to 29 days for 1 mg/kg group, up to 44 days for 2 mg/kg dose group, up to 19 days for placebo group) | 
| Number of Participants With Myocardial Infarction, Cerebrovascular Event, Hemodynamic Collapse and Re-operation | Number of participants with following incidents: myocardial infarction (Q and non-Q wave); stroke or cerebrovascular event (acute ischemia, hemorrhagic stroke or infarction, or a transient ischemia attack); hemodynamic collapse (requiring ventricular assistance devices) and re-operation (participants who returned to the operating room) during the initial hospitalization were reported. | Initial hospitalization period (up to 44 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Inotropic Requirements During the 24 Hours Postoperative Period | Participants were considered for inotropic requirements/therapy in case of either severe right ventricular failure or high pulmonary artery pressure, or if cardiac output was not maintained with epinephrine. | Immediately after cross-clamp removal up to 24 hours post-separation from CPB | 
| Change From 0 Hour in Cardiac Output (CO) at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) | CO was calculated by multiplying stroke volume (SV) with heart rate (HR). It was used to evaluate the hemodynamic profile of each participant. | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Central Venous Pressure (CVP) at 0.5, 6, 12, and 24 Hours Post-separation From Cardiopulmonary Bypass (CPB) |  | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Hematocrit at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) | The hematocrit is percentage of the volume of whole blood that is made up of red blood cells (RBCs). | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Heart Rate at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) | Heart rate was assessed as one of the hemodynamic profile assessments at the specified time points. | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Mean Pulmonary Artery Pressure (MPAP) at 0.5, 6, 12, and 24 Hours Post-separation From Cardiopulmonary Bypass (CPB) | mPAP was measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position. It was used to evaluate the hemodynamic profile of each participant. | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Pulmonary Capillary Wedge Pressure (PCWP) at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) | PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure. It was used to evaluate the hemodynamic profile of each participant. | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Pulmonary Vascular Resistance (PVR) at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) | PVR in participants was derived from mean PAP (mmHg), PCWP (mmHg) and CO (litres per minute). It was calculated using the following formula: ([mean PAP-PCWP] divided by CO)*80, where CO= SV * HR. | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Venous Oxygen Saturation (SV02/02) at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) | Venous oxygen saturation is the percentage of oxygen bound to hemoglobin in blood returning to the right side of the heart. It reflects the amount of oxygen left over after the tissues consumption. | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Systemic Vascular Resistance (SVR) at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) | SVR was calculated using formula: ([mean systemic arterial pressure - mean right atrial pressure] divided by CO)*80, where CO= SV * HR. | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Mean Systemic Blood Pressure (MSBP) at 0.5, 6, 12, and 24 Hours Post-Separation From Cardiopulmonary Bypass (CPB) |  | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Change From 0 Hour in Urine Output at 0.5, 6, 12, and 24 Hours Post-separation From Cardiopulmonary Bypass (CPB) |  | 0, 0.5, 6, 12, 24 hours post-separation from CPB | 
| Number of Participants With Unanticipated Perioperative and Postoperative Blood Requirements | Number of participants with unanticipated perioperative (occurring at or around the time of the surgery) and postoperative (period following the surgery) blood requirements were recorded on case report forms, summarized and reported in this outcome measure. | 0 to 24 hours post-separation from CPB | 
| Duration of Assisted Ventilation | Assisted Ventilation time was the time (in hours) between intubation and extubation. | 0 hour up to 24 hours post-separation from CPB | 
| Duration of Intensive Care Unit (ICU) Stay |  | 0 hour post-separation from CPB up to 44 days | 
| Duration of Initial Postoperative Hospitalization | The duration of initial postoperative hospitalization had been reported. | 0 hour post-separation from CPB up to 44 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multi-center, placebo-controlled, randomized study of sitaxsentan administered to subjects post-cross-clamp release and 12 hours post-CPB