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

Heart Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00458276
• Other study ID #: AC-051-350
• Status: Terminated
• Phase: Phase 3
• Start date: April 2007
• Est. completion date: March 2008

Study information

• Verified date: July 2018
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 274
• Est. completion date: March 2008
• Est. primary completion date: February 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Diseases
• Hypertension
• Hypertension, Pulmonary

Intervention

Drug:
• tezosentan
Tezosentan (ACT-050089, Ro 61-0612) as a 1% solution in 0.9% NaCl (i.e., normal saline) for i.v. use.
• placebo
Placebo (i.e., normal saline) for i.v. use.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Czechia,  France,  Germany,  India,  Israel,  Italy,  Poland,  Serbia,  Slovakia,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Time to weaning from cardiopulmonary bypass		Defined as time from release of cross-clamp to successful weaning from CPB
Secondary	Time from end of CPB to final discharge from Intensive Care Unit (ICU)		From end of CPB to final discharge from ICU