CYCLosporinE A in Reperfused Acute Myocardial Infarction

Acute Myocardial Infarction Clinical Trial

— CYCLE  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01650662
• Other study ID #: CYCLE (IRFMN_5635)
• Secondary ID: 2011-002876-18
• Status: Completed
• Phase: Phase 3
• First received: July 24, 2012
• Last updated: April 15, 2015
• Start date: January 2012
• Est. completion date: October 2014

Study information

• Verified date: October 2013
• Source: Mario Negri Institute for Pharmacological Research
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 410
• Est. completion date: October 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myocardial Infarction
• Infarction
• Myocardial Infarction
• Myocardial Reperfusion Injury

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
Italy	Ospedale Regionale Umberto Parini	Aosta	AO
Italy	Ospedale S. Donato	Arezzo	AR
Italy	Ospedale San Paolo	Bari	BA
Italy	Ospedale Maggiore	Bologna	BO
Italy	Istituto Fondazione Poliambulanza	Brescia	BS
Italy	Azienda Ospedaliera G.Brotzu	Cagliari	CA
Italy	Ospedale S. Giacomo	Castelfranco Veneto	TV
Italy	Azienda Ospedaliera Santa Croce e Carle	Cuneo	CN
Italy	Ospedale di Desio	Desio	MB
Italy	Ospedale G.B. Morgani - L. Pierantoni	Forli
Italy	Ospedale delle Misericordie	Grosseto	GR
Italy	Ospedale Campo di Marte	Lucca	LU
Italy	Ospedale dell'Angelo	Mestre	VE
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 Corona	Pietra Ligure	SV
Italy	Ospedale Santa Maria delle Croci	Ravenna	RA
Italy	Ospedale Infermi	Rimini	RN
Italy	Ospedale degli Infermi	Rivoli	TO
Italy	Ospedale San Camillo	Roma	RM
Italy	Azienda Ospedaliera di Seriate	Seriate	BG
Italy	Ospedale Maria Vittoria	Torino	TO
Italy	Ospedale Santa Chiara	Trento	TN
Italy	Azienda Ospedaliera di Treviglio	Treviglio	BG
Italy	Ospedale Ca' Foncello	Treviso	TV
Italy	Azienda Ospedaliera Universitaria - Ospedale Riuniti	Trieste	TS
Italy	Azienda Ospedaliera -Univ. S. Maria delle Misericordie	Udine	UD
Italy	Ospedale Civile San Bortolo	Vicenza	VI
Italy	Policlinico S.Marco	Zingonia - Osio Sotto	BG

Sponsors (2)

Lead Sponsor	Collaborator
Mario Negri Institute for Pharmacological Research	Heart Care Foundation

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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.	No
Secondary	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
Secondary	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)	No

External Links

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