Effect of Preliminary Administration of Cyclosporine (Sandimmun ®) on Different Markers of Cardiac Ischaemia Induced by Cardiopulmonary Bypass

Cardiopulmonary Bypass Clinical Trial

— Ciclo et CEC  

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01002859
• Other study ID #: DCIC 08 04
• Status: Terminated
• Phase: Phase 2
• First received: October 26, 2009
• Last updated: September 4, 2014
• Start date: April 2009
• Est. completion date: July 2011

Study information

• Verified date: September 2014
• Source: University Hospital, Grenoble
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 50
• Est. completion date: July 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Cardiopulmonary Bypass
• Coronary Artery Bypass Surgery
• Coronary Artery Disease
• Myocardial Ischemia

Intervention

Drug:
• Sandimmum
Intravenous injection of cyclosporine
• Placebo
Intravenous Injection of NaCl solution

Locations

Country	Name	City	State
France	Department of cardiac surgery - University Hospital of Grenoble	Grenoble,

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Grenoble

Country where clinical trial is conducted

France, 

References & Publications (5)

Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15;341 ( Pt 2):233-49. Review. — View 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. Review. — View 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. — View 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, André-Fouët 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under curve and maximal blood level of both troponin-T and Creatine Kinase-MB after cardiopulmonary bypass		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.	Yes
Secondary	Area under curve and maximal blood level of S100ß protein		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	Yes
Secondary	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)....)		until Day 3 after the end of the cardiopulmonary bypass	Yes
Secondary	Levels of inflammatory cytokines (TNF alpha , IL-1 alpha et IL-1 beta, IL-6, IL-8, IL-10). C-reactive protein (CRP) level		until day 8 after the end of the cardiopulmonary bypass	Yes
Secondary	Creatine blood levels		until 3 months after the end of the cardiopulmonary bypass	Yes