CYCLosporinE A in Reperfused Acute Myocardial Infarction

NCT ID: NCT01650662

Last Updated: 2015-04-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 410 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-01-31
• Study Completion Date: 2014-10-31

Brief Summary

Infarct size is a major determinant of prognosis after myocardial infarction (MI). It has been reported that Cyclosporine A (CsA) administered immediately prior to percutaneous coronary intervention (PCI) significantly could reduce reperfusion injury and consequently infarct size in ST elevation MI (STEMI) patients.

CYCLE trial is a multicenter, controlled, randomized open label study, with blind assessment of endpoint measures. The objective is to determine whether a single i.v. dose of CsA within 6 hour onset of symptoms of STEMI in 444 patients, improves outcomes after successful primary PCI, by reducing myocardial injury associated to reperfusion.

Detailed Description

The possibility of optimizing the results of an early and effective reopening of the occluded artery by reducing/avoiding the impact of the so-called reperfusion injury has been for many years one of the most elusive objectives of pharmacological research, with evolving hypothesis and targets.

A recently published trial has provided support to a line of investigation focused on the role of mitochondrial dysfunction, the so-called permeability transition, as cause of irreversible myocardial injury associated to reperfusion. In fact, a single dose of the widely used immunosuppressant agent, CsA, a potent inhibitor of mitochondrial permeability transition pore opening, was reported to limit ischemia-reperfusion injury in 50 patients with anterior MI who underwent primary PCI.

Since infarct size and left ventricular function are the main determinants of long-term morbidity and mortality, a single measure to limit infarct size is of potential clinical benefit. Therefore the results of the previously mentioned trial should be replicated in a larger sample size, before going on to a trial with clinical endpoints.

• Sample size

Assuming an incidence of the primary endpoint of 55% in the control group, we calculated that 444 patients (222 patients per group) will be required for the study to have 80% power to detect a 25% relative improvement (resulting in an endpoint frequency of 68.7% in the CsA group) with a 5% drop-out rate and a two-sided alpha level of 5%. The size of the trial will allow to investigate treatment benefit for the secondary endpoint hsTnT: assuming a concentration of 2.7 ng/mL on day 4 (common SD=2.1) in the control group, the study will have a 90% power to show a 25% reduction with CsA at a two-sided alpha level of 5%.

• Safety

Adverse events with intravenous CsA (i.e. anaphylactoid reactions/anaphylactic shock, acute renal failure, or hypertensive crisis) are reported to be very rare. In this trial, patients will receive only one iv dose of CsA, therefore we expect a low probability of adverse effects related to repeated administrations, i.e. acute renal failure or hypertensive crisis. Nonetheless a close monitoring of the safety of the single dose of CsA is foreseen with monthly examination of data of safety by the Steering Committee.

Conditions

Acute Myocardial Infarction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cyclosporine A

The investigational active treatment is CsA, an immunosuppressant indicated for the prevention of acute rejection after organ transplant, including cardiac transplantation.

The preparation used in the trial will be Sandimmun IV, containing CsA 50 mg/ml, Cremophor® EL and 94% ethyl alcohol in a 5 ml vial.

Patients will received Cyclosporine A on the top of recommended standard care for acute myocardial infarction.

Group Type: EXPERIMENTAL

Cyclosporine A

Intervention Type: DRUG

In the CsA group, at least 5 min before balloon inflation and stenting, patients will receive an intravenous bolus injection of 2.5 mg/kg of CsA. In the control group, patients will receive only recommended treatments. CsA will be dissolved in normal NaCl 0.9% solution (final concentration 25 mg/ml) and injected slowly (over 20-30 seconds) via a catheter positioned in an antecubital vein at least 5 min before PCI, to allow for distribution of the drug.

Control group

The control group received on the top of recommended standard care for acute myocardial infarction.

Group Type: EXPERIMENTAL

Cyclosporine A

Intervention Type: DRUG

In the CsA group, at least 5 min before balloon inflation and stenting, patients will receive an intravenous bolus injection of 2.5 mg/kg of CsA. In the control group, patients will receive only recommended treatments. CsA will be dissolved in normal NaCl 0.9% solution (final concentration 25 mg/ml) and injected slowly (over 20-30 seconds) via a catheter positioned in an antecubital vein at least 5 min before PCI, to allow for distribution of the drug.

Interventions

Cyclosporine A

In the CsA group, at least 5 min before balloon inflation and stenting, patients will receive an intravenous bolus injection of 2.5 mg/kg of CsA. In the control group, patients will receive only recommended treatments. CsA will be dissolved in normal NaCl 0.9% solution (final concentration 25 mg/ml) and injected slowly (over 20-30 seconds) via a catheter positioned in an antecubital vein at least 5 min before PCI, to allow for distribution of the drug.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male and female patients with large STEMI not older than 6 hours, defined as
• angina pectoris or equivalent symptoms of more than 20 minutes duration within last 6 hours, and
• ST elevation in at least 3 leads in anterior MI and/or a deviation in at least 4 leads in inferior MI,
• TIMI flow 0 or 1 in identified culprit artery
• Intended acute primary PCI
• Age ≥ 18 years
• Ability to understand the nature, scope, and possible consequences of the study participation/legal capacity
• Written informed consent

Exclusion Criteria

• Left bundle branch block
• TIMI flow > 1 in the identified culprit artery
• Treatment with CsA within last 10 days
• Contraindication to CsA or history of allergic reaction to CsA
• Coronary anatomy not suitable for PCI
• Thrombolytic therapy within 24 h. before randomization
• Previous MI
• Previous CABG
• Severe renal or hepatic insufficiency
• Malignant tumor, not curatively treated
• Women with childbearing potential, esp. pregnant or nursing women
• Participation in another clinical or device trial within the previous 30 days

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Heart Care Foundation

OTHER

Sponsor Role: collaborator

Mario Negri Institute for Pharmacological Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roberto Latini, MD

Role: STUDY_CHAIR

Mario Negri Institute, Milan, Italy

Filippo Ottani, MD

Role: STUDY_CHAIR

Ospedale G.B. Morgagni, Pierantoni, Forlì, Italy

Locations

Ospedale Regionale Umberto Parini

Aosta, AO, Italy

Ospedale S. Donato

Arezzo, AR, Italy

Ospedale San Paolo

Bari, BA, Italy

Azienda Ospedaliera di Seriate

Seriate, BG, Italy

Azienda Ospedaliera di Treviglio

Treviglio, BG, Italy

Policlinico S.Marco

Zingonia - Osio Sotto, BG, Italy

Ospedale Maggiore

Bologna, BO, Italy

Istituto Fondazione Poliambulanza

Brescia, BS, Italy

Azienda Ospedaliera G.Brotzu

Cagliari, CA, Italy

Azienda Ospedaliera Santa Croce e Carle

Cuneo, CN, Italy

Ospedale G.B. Morgani - L. Pierantoni

Forlì, Forli, Italy

Ospedale delle Misericordie

Grosseto, GR, Italy

Ospedale Campo di Marte

Lucca, LU, Italy

Ospedale di Desio

Desio, MB, Italy

Policlinico Monza

Monza, MB, Italy

AOR Villa Sofia - Cervello P.O.

Palermo, PA, Italy

AOR Villa Sofia - Cervello PO Villa Sofia

Palermo, PA, Italy

Ospedale Civile dello Spirito Santo

Pescara, PE, Italy

Ospedale Santa Maria delle Croci

Ravenna, RA, Italy

Ospedale San Camillo

Roma, RM, Italy

Ospedale Infermi

Rimini, RN, Italy

Ospedale Santa Corona

Pietra Ligure, SV, Italy

Ospedale Santa Chiara

Trento, TN, Italy

Ospedale degli Infermi

Rivoli, TO, Italy

Ospedale Maria Vittoria

Torino, TO, Italy

Azienda Ospedaliera Universitaria - Ospedale Riuniti

Trieste, TS, Italy

Ospedale S. Giacomo

Castelfranco Veneto, TV, Italy

Ospedale Ca' Foncello

Treviso, TV, Italy

Azienda Ospedaliera -Univ. S. Maria delle Misericordie

Udine, UD, Italy

Ospedale dell'Angelo

Mestre, VE, Italy

Ospedale Civile San Bortolo

Vicenza, VI, Italy

Countries

Italy

References

Ottani F, Latini R, Staszewsky L, La Vecchia L, Locuratolo N, Sicuro M, Masson S, Barlera S, Milani V, Lombardi M, Costalunga A, Mollichelli N, Santarelli A, De Cesare N, Sganzerla P, Boi A, Maggioni AP, Limbruno U; CYCLE Investigators. Cyclosporine A in Reperfused Myocardial Infarction: The Multicenter, Controlled, Open-Label CYCLE Trial. J Am Coll Cardiol. 2016 Feb 2;67(4):365-374. doi: 10.1016/j.jacc.2015.10.081.

Reference Type: DERIVED

PMID: 26821623 (View on PubMed)

Related Links

http://www.anmco.it

The protocol presentation, can be found in the window of CYCLE Study.

Other Identifiers

2011-002876-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CYCLE (IRFMN_5635)

Identifier Type: -

Identifier Source: org_study_id