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

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ClinicalTrials.gov Identifier: NCT00458276
Recruitment Status : Terminated (6 month vital status report not collected after 28 day follow up analysis indicated no difference between placebo & tezosentan)
First Posted : April 10, 2007
Last Update Posted : February 15, 2010
Sponsor:
Information provided by:

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  (Clinical Trial)
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 : April 2007
Primary Completion Date : February 2008
Study Completion Date : March 2008

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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.


Outcome Measures

Primary Outcome Measures :
  1. 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. [ Time Frame: During weaning from CPB ]

Secondary Outcome Measures :
  1. 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 [ Time Frame: Within 28 days after study initiation ]
  2. Time to weaning from cardiopulmonary bypass [ Time Frame: Defined as time from release of cross-clamp to successful weaning from CPB ]
  3. Time from end of CPB to final discharge from Intensive Care Unit (ICU) [ Time Frame: From end of CPB to final discharge from ICU ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00458276


  Show 33 Study Locations
Sponsors and Collaborators
Actelion
Investigators
Study Chair: Andre Denault, Prof. Montreal Heart Institute
Study Chair: Ronald Pearl, MD Stanford University
Study Chair: Robert Michler, MD Montefiore Medical Center
Study Chair: Steven Tsui Papworth Hospital
Study Chair: Rainald Seitelberger, Prof. AKH University of Vienna
Study Chair: Andrea D'Armini, Prof. San Matteo Hospital
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Elisabet Lindberg, MD, International Clinical Leader, Actelion
ClinicalTrials.gov Identifier: NCT00458276     History of Changes
Other Study ID Numbers: AC-051-350
First Posted: April 10, 2007    Key Record Dates
Last Update Posted: February 15, 2010
Last Verified: February 2010

Keywords provided by Actelion:
Left sided heart disease
Elevated pulmonary arterial pressure
Right ventricular failure
Cardiac surgery
heart-lung machine
cardiopulmonary bypass
tezosentan
Actelion

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Heart Diseases
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Tezosentan
Epoprostenol
Vasodilator Agents
Antihypertensive Agents
Platelet Aggregation Inhibitors