CYCLosporinE A in Reperfused Acute Myocardial Infarction

Study Overview
=================
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.

Official Title
-----------------
CYCLosporinE A in Reperfused Acute Myocardial Infarction Prospective, Controlled, Randomized, Multicentre Trial to Examine Whether a Single i.v. Bolus of Cyclosporine A Before PCI Can Reduce Myocardial Reperfusion Injury in Patients With STEMI.

Conditions
-----------------
Acute Myocardial Infarction

Intervention / Treatment
-----------------
* Drug: Cyclosporine A


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclosporine A<br>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. | Drug: Cyclosporine A<br>* 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.<br>|
| Experimental: Control group<br>The control group received on the top of recommended standard care for acute myocardial infarction. | Drug: Cyclosporine A<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of myocardial reperfusion, measured with ST-segment resolution >=70% | Improvement of myocardial reperfusion, measured with ST-segment resolution >=70% 1 hour after PCI | 1 hour after percutaneous coronary intervention (PCI) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High sensitive cardiac troponin T (hs-cTnt). | High sensitive cardiac troponin T (hs-cTnt) at day 4 after PCI; ; this will be the most relevant among secondary endpoints given its value as readout of cardiac protection. | at day 4 after percutaneous coronary intervention (PCI) | 
| Clinical events: all-cause mortality, HF or shock; rehospitalization for CV reasons | Clinical events within 6 months of randomization: all-cause mortality, HF or shock; rehospitalization for CV reasons. | within 6 months of randomization | 
| Infarct size: Troponin curve (T or I, assayed locally) | Infarct size: Troponin curve (T or I, assayed locally); The time course of troponin release during the first 72 hours after the visualization of the antegrade flow, will be studied. | Time course of troponin release during the first 72 hours after the visualization of the antegrade flow. | 
| LV remodeling and function as assessed by echocardiography; | LV remodeling and function at 6 months, as assessed by echocardiography; | at 6 months after randomization | 
| No reflow, as assessed by myocardial blush | No reflow, as assessed by myocardial blush after the visualization of the antegrade flow | 1 day (after the visualization of the antegrade flow) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Myocardial Infarction, Cyclosporine A, Reperfusion, Clinical Trial