CYCLosporinE A in Reperfused Acute Myocardial Infarction (CYCLE)

• Improvement of myocardial reperfusion, measured with ST-segment resolution >=70% [ Time Frame: 1 hour after percutaneous coronary intervention (PCI) ] [ Designated as safety issue: No ]
  Improvement of myocardial reperfusion, measured with ST-segment resolution >=70% 1 hour after PCI
  
  

• High sensitive cardiac troponin T (hs-cTnt). [ Time Frame: at day 4 after percutaneous coronary intervention (PCI) ] [ Designated as safety issue: No ]
  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.
  
  
• Clinical events: all-cause mortality, HF or shock; rehospitalization for CV reasons [ Time Frame: within 6 months of randomization ] [ Designated as safety issue: No ]
  Clinical events within 6 months of randomization: all-cause mortality, HF or shock; rehospitalization for CV reasons.
  
  
• Infarct size: Troponin curve (T or I, assayed locally) [ Time Frame: Time course of troponin release during the first 72 hours after the visualization of the antegrade flow. ] [ Designated as safety issue: No ]
  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.
  
  
• LV remodeling and function as assessed by echocardiography; [ Time Frame: at 6 months after randomization ] [ Designated as safety issue: No ]
  LV remodeling and function at 6 months, as assessed by echocardiography;
  
  
• No reflow, as assessed by myocardial blush [ Time Frame: 1 day (after the visualization of the antegrade flow) ] [ Designated as safety issue: No ]
  No reflow, as assessed by myocardial blush after the visualization of the antegrade flow
  
  

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.