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

Sponsor

Idorsia Pharmaceuticals Ltd. (Industry)

Overall Status

Terminated

CT.gov ID

NCT00458276

Collaborator

(none)

274

Enrollment

Locations

Arms

Duration (Months)

8.3

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Diseases Hypertension, Pulmonary	Drug: tezosentan Drug: placebo	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

274 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

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

Study Start Date :

Apr 1, 2007

Actual Primary Completion Date :

Feb 1, 2008

Actual Study Completion Date :

Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Tezosentan	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 Comparator: 2 Placebo	Drug: placebo Placebo (i.e., normal saline) for i.v. use.

Arm

Intervention/Treatment

Experimental: 1

Tezosentan

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 Comparator: 2

Placebo

Drug: placebo

Placebo (i.e., normal saline) for i.v. use.

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305
2	Columbia University Medical Center	New York	New York	United States	10032
3	Montefiore Medical Center/Albert Einstein College of Medicine	New York	New York	United States	10467
4	Duke University Medical Center	Durham	North Carolina	United States	27710
5	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
6	The Cleveland Clinic	Cleveland	Ohio	United States	44195
7	Baylor University Medical Center	Dallas	Texas	United States	75226
8	Texas Heart Institute/St. Luke's Episcopal Hospital/Baylor College	Houston	Texas	United States	77030
9	University of Virginia Health System	Charlottesville	Virginia	United States	22908
10	Medical University of Innsbruck	Innsbruck		Austria
11	AKH University of Vienna	Vienna		Austria
12	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G2B7
13	London Health Sciences Centre-University Hospital	London	Ontario	Canada	N6A5A5
14	Toronto General Hospital	Toronto	Ontario	Canada	M5G2C4
15	Montreal Heart Institute	Montreal	Quebec	Canada	H1T1C8
16	Quebec Heart Institute/Hopital Laval	Quebec		Canada	G1V4G5
17	Institute for Clinical and Experimental Medicine (IKEM)	Prague		Czechia
18	Hopital Pitie Salpetriere	Paris		France
19	Deutches Herzzentrum	Berlin		Germany
20	Dresden Universitatsklinik/Cardiology Center	Dresden		Germany
21	Zentrum der Chirugie-Zchir-des Universitatsklinikums	Frankfurt		Germany	Main 60590
22	Narayana Hrudayalaya	Bangalore		India
23	Nizam's Institute of Medical Sciences	Hyderabaad		India
24	Shaare Zedek Medical Center	Jerusalem		Israel
25	Fondazione IRCCS San Matteo Hospital, Cardiac Surgery	Pavia		Italy	27100
26	Azienda Sanitaria Ospedaliera "San Giovanni Battista", Cardiac Surgery Division	Torino		Italy	10126
27	Medical University of Silesia, 2nd Dept of Cardiac Surgery	Katowice		Poland
28	Klinika Chirurgii Serca, Naczyn I Transplantologii, Szpital Jana Pawla II	Krakow		Poland	31-202
29	Dedinje Cardiovascular Institute	Belgrade		Serbia
30	National Institute of Cardiovascular Diseases, Clinic of Heart Surgery	Bratislava		Slovakia
31	Sahlgrenska University Hospital	Goteborg		Sweden
32	Papworth Hospital	Cambridge		United Kingdom
33	Northern General Hospital	Sheffield		United Kingdom