Cyclosporine and Prognosis in Acute Myocardial Infarction (MI) Patients (CIRCUS)

Does Cyclosporine ImpRove Clinical oUtcome in ST Elevation Myocardial Infarction Patients

Infarct size is a major determinant of prognosis after Acute Myocardial Infarction (AMI). The investigators recently reported that cyclosporine A, when administered immediately prior to percutaneous coronary intervention (PCI), can significantly reduce infarct size in STEMI (ST Elevation acute Myocardial Infarction) patients. The objective of the present study is to determine whether cyclosporine can improve STEMI patient clinical outcome. Nine-hundred and seventy two patients with ST elevation MI will be entered into a multicentre, randomized, placebo-controlled, double-blinded study. They will receive one single injection of cyclosporine A (CicloMulsion, verum) or an equivalent volume of placebo prior to reperfusion therapy by PCI. The incidence of the combined endpoint (mortality, hospitalization for heart failure, left ventricular (LV) remodeling) will be assessed at one year and three years after treatment.

Study Overview

• Status: Completed
• Conditions: ST Elevation Acute Myocardial Infarction
• Intervention / Treatment: Drug: Injection of Cyclosporin; Drug: Placebo; Procedure: Echocardiography

• Study Type: Interventional
• Enrollment (Actual): 970
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • Algemeen Ziekenhuis Sint-Jan Brugge
  • Charleroi, Belgium, 6000
    • Chu Charleroi
  • Edegem, Belgium, 2650
    • Hôpital universitaire d'Anvers (UZA)
  • Yvoir, Belgium, 5530
    • CHU Mont-Godinne
• France
  • Agen, France, 47000
    • Clinique ESQUIROL - SAINT-HILAIRE
  • Aix En Provence, France, 13616
    • Centre Hospitalier du Pays d'Aix
  • Angers, France, 49033
    • Centre Hospitalier Universitaire d'Angers
  • Annecy, France, 74011
    • Centre Hospitalier D'annecy
  • Avignon, France, 84000
    • Hôpital Henri Duffaut
  • Bayonne, France, 64100
    • Clinique Lafourcade
  • Brest, France, 29609
    • Centre Hospitalier Universitaire
  • Bron cedex, France, 69677
    • Hôpital Louis Pradel, Hospices Civils de Lyon
  • Caen, France, 14033
    • CHRU- Hôpital de la Côte de Nacre
  • Chartres, France, 28018
    • Centre Hospitalier General
  • Clermont Ferrand, France, 63003
    • CHU - Hôpital Gabriel Montpied
  • Compiegne, France, 60321
    • CH de Compiègne
  • Creteil, France, 94010
    • CH Henri Mondor
  • Dijon, France, 21034
    • Hopital Du Bocage
  • Grenoble, France, 38043
    • Hôpital A. MICHALLON - CHU
  • Hagueneau, France, 67504
    • Centre Hospitalier General
  • Lille, France
    • CHRU - Hôpital Cardiologique Calmette
  • Lyon, France, 69009
    • Clinique de la Sauvegarde
  • Lyon, France, 69365
    • Centre Hospitalier St Luc St Joseph
  • Massy, France, 91300
    • Institut Jacques Cartier
  • Montpellier, France, 34295
    • CHU Arnaud de Villeneuve
  • Montpellier, France, 34960
    • Clinique du Millenaire
  • Mulhouse, France, 68100
    • CHU de Mulhouse
  • Mulhouse, France, 69607
    • Clinique du Diaconat
  • Nantes, France, 44093
    • Hopital Guillaume Et Rene Laennec
  • Nimes, France, 30029
    • CHU de Nimes
  • Ollioules, France, 83192
    • Polyclinique des Fleurs
  • PAU, France, 64011
    • CH de Pau
  • Paris, France, 75018
    • APHP Hôpital Bichat
  • Pessac, France, 33604
    • Hopital Haut Leveque
  • Quincy Sous Senart, France, 91480
    • Hôpital Claude Galien
  • Rennes, France, 35003
    • Hôpital Pontchaillou
  • Rouen, France, 76031
    • Hopital Charles Nicolle
  • Strasbourg, France, 67091
    • Hôpitaux Universitaires, Nouvel Hôpital Civil
  • Tarbes, France, 65000
    • Clinique de l'Ormeau - CCV des Pyrénées
  • Toulouse, France, 31043
    • CHU de Rangueil
  • Tours, France, 37044
    • CHRU de Tours
  • Tours, France, 37042
    • Clinique Saint Gatien
  • Vandoeuvre Les Nancy, France, 54511
    • Hôpital Brabois - CHU Nancy
  • Villeurbanne, France, 69100
    • Clinique du Tonkin
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Eligibility criteria (for screening before hospital admission):

1. All (male and female) patients, aged over 18, without any legal protection measure,
2. Having a health coverage,
3. Presenting within 12 hours of the onset of chest pain,
4. Who have ST segment elevation ≥0.2 mV in two contiguous leads,

5. For whom the clinical decision was made to treat with percutaneous coronary intervention (PCI).

   And (further inclusion criteria to be confirmed by the admission coronary-angiography):

6. The culprit coronary artery has to be the LAD
7. The LAD artery has to be occluded (TIMI flow grade 0-1) at the time of admission coronary angiography.
8. Preliminary oral informed consent followed by signed informed consent as soon as possible.

Patients undergoing either primary PCI or rescue PCI are eligible for the study. Patients with previous AMI, PCI or coronary artery bypass surgery (CABG) are eligible for the study.

Exclusion Criteria:

1. Patients with loss of consciousness or confused
2. Patients with cardiogenic shock
3. Patients with the left circumflex or the right coronary artery (RCA) as the culprit artery, or with evidence of coronary collaterals to the risk region
4. Patients with an opened (TIMI > 1) LAD coronary artery at admission on initial (admission) coronary angiography
5. Patients with 5.2. known hypersensitivity to cyclosporine 5.3. known hypersensitivity to egg, peanut or Soya-bean proteins 5.4. known renal insufficiency (either known creatinin clearance < 30 ml/min/1.73m² or current medical care for severe renal insufficiency) 5.5. known liver insufficiency 5.6. uncontrolled (treated or untreated) hypertension (> 180/110 mmHg)
6. Patients treated with any compound containing Hypericum perforatum (St.-John's-worth) or Stiripentol or Aliskiren or Bosentan or Rosuvastatine
7. Female patients currently pregnant or women of childbearing age who were not using contraception (oral diagnosis).
8. Patients with any disorder associated with immunological dysfunction more recently than 6 months prior to presentation 8.2. cancer, lymphoma 8.3. known positive serology for HIV, or hepatitis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; one single intravenous bolus injection of Placebo Echocardiography	Drug: Placebo; One single intravenous bolus injection of Placebo; Procedure: Echocardiography; 1 year after AMI
Experimental: Cyclosporin; Injection of Cyclosporin A : one single intravenous bolus injection of 2.5 mg/Kg Echocardiography	Drug: Injection of Cyclosporin; one single intravenous bolus injection of 2.5 mg/Kg; Other Names: Cyclosporin A (CicloMulsion, verum); Procedure: Echocardiography; 1 year after AMI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Combined incidence of [total mortality; hospitalization for heart failure; LV remodeling (increase of LV end-diastolic volume > 15%)]	at 1 year post-AMI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ejection fraction	Functional outcome	at 1 year
Left-Ventricular End-Diastolic Volume (LVEDV)	Functional outcome	at 1 year
Left-Ventricular End-Systolic Volume (LVESV)	Functional outcome	at 1 year
Total mortality		at 1 year
Cardiovascular death		at 1 year
Heart failure	In-hospital worsening of heart failure after reperfusion, or rehospitalization for: a)worsening of a heart failure existing at admission, b)appearance of "new" heart failure	at 1 year
Myocardial infarction		at 1 year
Unstable angina		at 1 year
Stroke		at 1 year
Infarct size	Measured by cardiac MRI, only for patients included in participating centers where cardiac MRI is part of the usual post-infarct care	at 1 year
Infarct size: peak Troponin (T or I)	Explorative outcome. Cardiac prognostic factors.	At admission and at 4 hours (+/- 30 minutes) after study treatment administration
Microvascular obstruction (no reflow)	Explorative outcome. Cardiac prognostic factors.	During hospitalization at admission

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Michel OVIZE, MD, Prof, Hospices Civils de Lyon

Publications and helpful links

General Publications

• Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guerin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Rande JL, Unterseeh T, Le Breton H, Beard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M. Cyclosporine before PCI in Patients with Acute Myocardial Infarction. N Engl J Med. 2015 Sep 10;373(11):1021-31. doi: 10.1056/NEJMoa1505489. Epub 2015 Aug 30.
• Bochaton T, Claeys MJ, Garcia-Dorado D, Mewton N, Bergerot C, Jossan C, Amaz C, Boussaha I, Thibault H, Ovize M. Importance of infarct size versus other variables for clinical outcomes after PPCI in STEMI patients. Basic Res Cardiol. 2019 Dec 12;115(1):4. doi: 10.1007/s00395-019-0764-8.
• Mewton N, Cung TT, Morel O, Cayla G, Bonnefoy-Cudraz E, Rioufol G, Angoulvant D, Guerin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, Morice MC, Monassier JP, Ider O, Dubois-Rande JL, Unterseeh T, Lebreton H, Beard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Hansson MJ, Elmer E, Boussaha I, Jossan C, Torner A, Claeys M, Garcia-Dorado D, Ovize M; CIRCUS Study Investigators. Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial). Am Heart J. 2015 Jun;169(6):758-766.e6. doi: 10.1016/j.ahj.2015.02.020. Epub 2015 Mar 13.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: December 28, 2011
• First Submitted That Met QC Criteria: December 29, 2011
• First Posted (Estimate): January 2, 2012

Study Record Updates

• Last Update Posted (Actual): February 26, 2018
• Last Update Submitted That Met QC Criteria: February 23, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: STEMI; cyclosporine; reperfusion injury
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 2009.559