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

Phase 3

Terminated

Conditions: Hypertension, Pulmonary
Heart Diseases

Interventions: Drug: placebo
Drug: tezosentan

Registration Number: NCT00458276

Lead Sponsor: Idorsia Pharmaceuticals Ltd.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 274

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	placebo	Placebo
1	tezosentan	Tezosentan

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (33): University of Alberta Hospital
🇨🇦
Edmonton, Alberta, Canada
London Health Sciences Centre-University Hospital
🇨🇦
London, Ontario, Canada
Columbia University Medical Center
🇺🇸
New York, New York, United States
University of Virginia Health System
🇺🇸
Charlottesville, Virginia, United States
Toronto General Hospital
🇨🇦
Toronto, Ontario, Canada
Papworth Hospital
🇬🇧
Cambridge, United Kingdom
AKH University of Vienna
🇦🇹
Vienna, Austria
The Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
Medical University of Silesia, 2nd Dept of Cardiac Surgery
🇵🇱
Katowice, Poland
Medical University of Innsbruck
🇦🇹
Innsbruck, Austria
Texas Heart Institute/St. Luke's Episcopal Hospital/Baylor College
🇺🇸
Houston, Texas, United States
Montefiore Medical Center/Albert Einstein College of Medicine
🇺🇸
New York, New York, United States
Institute for Clinical and Experimental Medicine (IKEM)
🇨🇿
Prague, Czechia
National Institute of Cardiovascular Diseases, Clinic of Heart Surgery
🇸🇰
Bratislava, Slovakia
Klinika Chirurgii Serca, Naczyn I Transplantologii, Szpital Jana Pawla II
🇵🇱
Krakow, Poland
Quebec Heart Institute/Hopital Laval
🇨🇦
Quebec, Canada
Azienda Sanitaria Ospedaliera "San Giovanni Battista", Cardiac Surgery Division
🇮🇹
Torino, Italy
Dresden Universitatsklinik/Cardiology Center
🇩🇪
Dresden, Germany
Sahlgrenska University Hospital
🇸🇪
Goteborg, Sweden
Fondazione IRCCS San Matteo Hospital, Cardiac Surgery
🇮🇹
Pavia, Italy
Hopital Pitie Salpetriere
🇫🇷
Paris, France
Nizam's Institute of Medical Sciences
🇮🇳
Hyderabaad, India
Dedinje Cardiovascular Institute
🇷🇸
Belgrade, Serbia
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Shaare Zedek Medical Center
🇮🇱
Jerusalem, Israel
Stanford University School of Medicine
🇺🇸
Stanford, California, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Baylor University Medical Center
🇺🇸
Dallas, Texas, United States
Zentrum der Chirugie-Zchir-des Universitatsklinikums
🇩🇪
Frankfurt, Germany
Montreal Heart Institute
🇨🇦
Montreal, Quebec, Canada
Narayana Hrudayalaya
🇮🇳
Bangalore, India
Deutches Herzzentrum
🇩🇪
Berlin, Germany
Northern General Hospital
🇬🇧
Sheffield, United Kingdom