Primary objective: to demonstrate that tezosentan, in patients undergoing cardiac surgery with cardiopulmonary bypass, reduces the incidence of clinically relevant right ventricular failure resulting in difficult separation from bypass or need for…
ID
Source
Brief title
Condition
- Other condition
- Heart failures
- Cardiac therapeutic procedures
Synonym
Health condition
pulmonale hypertensie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of patients during weaning from cardiopulmonary bypass, with
clinically relevant right ventricular failure defined as absence of or
significant reduction of right ventricular wall motion by direct visual
inspection peri-operatively and/or severe reduction of right ventricular
fraction area change (>20%) measured by 2-D echocardiography, requiring the use
of 3 or more inotropic/vasopressor treatments or 2 at high doses, return to
CPB, use of rescue therapy for high PAP, use of ventricular assist device or
with fatal outcome (all causes, up to 24 hours after start of weaning).
Definition of high dose of vasopressor/inotropic drugs:
• Dopamine > 5 µg/kg/min
• Dobutamine > 5µg/kg/min
• Norepinephrine (noradrenalin) > 0.05 µg/kg/min
• Epinephrine (adrenalin) > 0.05 µg/kg/min
• Milrinone bolus >= 50 µg/kg, and > 0.5 µg/kg/min
• Phenylephrine > 2.5 µg/kg/min
• Isoproterenol > 0.01 µg/min
• Vasopressin at a cumulative dose of > 10 units
• Levosimendan > 0.2 µg/kg/min
Secondary outcome
Secondary endpoints
• Proportion of patients with a major clinical event within 28 days after study
drug initiation:
o Death; or
o Major cardiovascular events;* or
o Infections that prolong hospital stay or require re-admission; or
o New onset of renal failure requiring renal replacement therapy.
*Major cardiovascular events: acute pulmonary edema, myocardial infarction,
stroke, ventricular arrhythmia requiring cardioversion, cardiogenic shock or
cardiac arrest.
• 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 ICU.
Background summary
Patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) may
develop high pulmonary pressures that can lead to right ventricular failure
(RVF). RVF is associated with increased post-operative mortality and morbidity.
Patients with pre-operative pulmonary hypertension are at even greater risk of
developing post-operative complications.
Separation from CPB is an important event following cardiac surgery. The
endothelin (ET) system is activated during CPB in patients undergoing cardiac
surgery. Increased ET-1 levels during and after CPB are associated with
pulmonary and systemic vasoconstriction, resulting in increased pulmonary
arterial pressure and vascular resistance, and reduced myocardial
contractility.
Tezosentan is a new potent competitive ET-1 receptor antagonist (ERA).
Pulmonary hypertension is an important factor contributing to the complications
of cardiac surgery, including clinically relevant RVF. Treatment with an ERA
has been shown to decrease PVR, improve RVF, decrease incidence of post-bypass
pulmonary hypertensive crises and improve pulmonary compliance and oxygenation.
Therefore, ERA treatment may prevent clinically relevant RVF associated with
CPB-induced pulmonary hypertension. As an intraveneus ERA, tezosentan could be
suitable for acute conditions such as clinically relevant RVF associated with
pulmonary hypertension during cardiac surgery.
Study objective
Primary objective: to demonstrate that tezosentan, in patients undergoing
cardiac surgery with cardiopulmonary bypass, reduces the incidence of
clinically relevant right ventricular failure resulting in difficult separation
from bypass or need for return to cardiopulmonary bypass or use of ventricular
assist device or death.
Study design
Prospective, multicenter, double-blind, randomized, placebo-controlled,
parallel group, phase III, superiority study.
Intervention
Administration of Tezosentan (ACT-050089, Ro 61-0612) as a 1% solution in 0,9%
NaCl for i.v. use.
Study burden and risks
At screening the following assessments will be done: a full medical examination
and vital parameters. Side effects associated with the use of tezosentan are
headache, nausea, vomiting and hypotension.
Patients may suffer from bruises and/or pain at the location of the
bloodsampling. There is no guarantee that patients will benefit directly from
this research. Information obtained during the course of this clinical research
study may contribute to a better understanding of the disease. Regardless of
any individual benefit, the knowledge gained from this study may contribute to
information that would allow the use of this drug or similar drugs in later
treatment for patients undergoing heart surgery.
Gewerbestrasse 16
4123, Allschwil
Zwitserland
Gewerbestrasse 16
4123, Allschwil
Zwitserland
Listed location countries
Age
Inclusion criteria
- Male or female patients >=18 years of age (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 sPAP > 40 mmHg or mPAP > 30 mmHg (measured by RHC or echocardiography at screening). * Complex cardiac surgery is defined as:
- Surgery on two valves
- Surgery on one valve plus revascularization
- Re-operation of previous valve surgery. ;Or ;Patients undergoing cardiac surgery on CPB and having pre-operative pulmonary hypertension due to left heart disease (measured by RHC or echocardiography at screening) defined as:
- sPAP > 60 mmHg with mPAP/MAP > 0.5
or
- sPAP > 60 mmHg with signs and/or symptoms of right ventricular dysfunction.
- Signed informed consent prior to any study-mandated procedure. ;(MAP = mean arterial pressure; mPAP = mean pulmonary arterial pressure; sPAP = systolic pulmonary arterial pressure; RHC = right heart catheterization.)
Exclusion criteria
- Sitting systolic blood pressure < 100 mmHg (measured at hospital admission).
- Significant chronic lung disease that might interfere with the ability to interpret the study results (e.g., severe chronic obstructive pulmonary disease).
- Emergency surgery.
- Pregnant or breast-feeding females.
- Use of another investigational drug within 28 days prior to randomization.
- Complex adult congenital heart disease.
- Severe concomitant illness limiting life expectancy (< 6 months).
- Participation in a device study that will affect the outcome of the study.
- Pre-operative use of balloon pump.
- Pre-operative use of inotropes/vasopressor drugs.
- Pre-operative treatment of pulmonary arterial hypertension (PAH).
- Known hypersensitivity to tezosentan or drugs of the same class, or any of their excipients.
- Severe liver impairment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-002907-15-NL |
| CCMO | NL16433.100.07 |