Clinical trial NCT01002859: Effect of Preliminary Administration of Cyclosporine (Sandimmun ®) on Different Markers of Cardiac Ischaemia Induced by Cardiopulmonary Bypass
Official title: Double-Blind Phase II Pilot Monocentric Randomized Clinical Trial Evaluating the Effect of a Preliminary Administration of Cyclosporine on Different Markers of Cardiac Ischemia Led by the Aortic Cross-clamp During Coronary Artery Bypass Surgery With Cardiopulmonary Bypass.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Coronary Artery Bypass Surgery
Cardiopulmonary Bypass
Keywords: Coronary artery bypass graft surgery (CABG)
Cardiopulmonary Bypass (CPB)
Cyclosporine
ischaemia reperfusion
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
First posted: 2009-10-27
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Observe the effect of preliminary cyclosporine administration on different markers of cardiac ischaemia led by the aortic cross-clamp during coronary artery bypass surgery with Cardiopulmonary bypass.

Detailed description: The coronary artery bypass surgery, in spite of substantial improvements during the last years, is still associated to a post-operative mortality and morbidity: myocardial infarction, heart failure, cardiac arrhythmia, renal failure, Stroke.

These complications are often due to ischaemia - reperfusion injury event. Recent studies showed that in case of cellular stress (in particular during the reperfusion after ischaemia) a not specific pore, called Mitochondrial permeability transition Pore (MPTP), could be opened. That caused the loss of ion homeostasis, then cell death as well as by apoptosis as by necrosis.

Prevent the opening of this MPTP during the myocardial reperfusion after coronary bypass, for example, is an important objective to improve the cardioprotection.

The Cyclosporin A, prevents the MPTP from opening. Several studies have shown an cytoprotection led by cyclosporin A, after ischaemia reperfusion in several models as isolated rats heart, in vivo rats heart and ex vivo myocardial ( atrial ) human tissues.

Recently, a multicentric study performed in humans, during the acute phase of myocardial infarction, showed a reduction of infarct size by approximately 40% in the cyclosporine group compared to control group.

Eligibility criteria: Inclusion Criteria:

* Patient hospitalized for a coronary artery bypass surgery
* Not urgent surgery
* Left ventricular ejection fraction (LVEF)\> 40 %
* 18 years and older
* patient who have sign the informed consent form
* Affiliation to the French Social Security.

Exclusion Criteria:

* Beating heart surgery with or without Cardiopulmonary Bypass
* Patient receiving another surgical gesture combined to the CABG
* Myocardial infarction or vascular cerebral attack less than 30 days
* Previous History of cardiac surgery;
* Renal failure (creatinine \> 200 µmol/l)
* Uncontrolled hypertension
* hyperkaliemy;
* hyperuricemy;
* Acute Coronary Syndrome
* Malignant tumor
* Unchecked infection
* Previous intravenous administration of Sandimmun ®;
* allergy to ciclosporin, ethyl alcohol, castor oil or nitrogen
* Pregnant Woman, parturient without contraception, or breast-feeding
* Age \< 18 years
* Patient who have not signed the form of consent;
* Patient Under guardianship or being the object of a legal protective measure

Primary outcomes:
measure: Area under curve and maximal blood level of both troponin-T and Creatine Kinase-MB after cardiopulmonary bypass
timeFrame: at anaesthesia (ti), at the end of the cardiopulmonary bypass (t0), and 6 h, 12 h, 24 h,48h and 72h after the end of the cardiopulmonary bypass.
Secondary outcomes:
measure: Area under curve and maximal blood level of S100β protein
timeFrame: at anaesthesia (ti), at the end of the cardiopulmonary bypass (t0), and 6 h, 12 h, 24 h,48h and 72h after the end of the cardiopulmonary bypass
measure: Spontaneous defibrillation at aorta declamping; Post surgical atrial fibrillation; ECG (new Q wave); Transthoracic Echocardiogram (diastolic and systolic function study, research of paradoxical septal motion, study of cardiac output)....)
timeFrame: until Day 3 after the end of the cardiopulmonary bypass
measure: Levels of inflammatory cytokines (TNF alpha , IL-1 alpha et IL-1 beta, IL-6, IL-8, IL-10). C-reactive protein (CRP) level
timeFrame: until day 8 after the end of the cardiopulmonary bypass
measure: Creatine blood levels
timeFrame: until 3 months after the end of the cardiopulmonary bypass
Other outcomes:
Locations:
city: Grenoble,
country: France
facility: Department of cardiac surgery - University Hospital of Grenoble
Study officials:
affiliation: Cardiac Surgery Department - University Hospital of Grenoble,
name: Vincent BACH, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15;341 ( Pt 2)(Pt 2):233-49.
citation: Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. Cardiovasc Res. 2004 Feb 15;61(3):372-85. doi: 10.1016/S0008-6363(03)00533-9.
citation: Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res. 2003 Dec 1;60(3):617-25. doi: 10.1016/j.cardiores.2003.09.025.
citation: Shanmuganathan S, Hausenloy DJ, Duchen MR, Yellon DM. Mitochondrial permeability transition pore as a target for cardioprotection in the human heart. Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H237-42. doi: 10.1152/ajpheart.01192.2004.
citation: Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008 Jul 31;359(5):473-81. doi: 10.1056/NEJMoa071142.