CYCLosporinE A in Reperfused Acute Myocardial Infarction (CYCLE)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Heart Care Foundation
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:
NCT01650662
First received: July 24, 2012
Last updated: July 18, 2014
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Acute Myocardial Infarction
Drug: Cyclosporine A
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Mario Negri Institute for Pharmacological Research:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Enrollment: 410
Study Start Date: January 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.

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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01650662

Locations
Italy
Ospedale Regionale Umberto Parini
Aosta, AO, Italy, 11100
Ospedale S. Donato
Arezzo, AR, Italy, 52100
Ospedale San Paolo
Bari, BA, Italy, 70100
Azienda Ospedaliera di Seriate
Seriate, BG, Italy, 24068
Azienda Ospedaliera di Treviglio
Treviglio, BG, Italy, 24047
Policlinico S.Marco
Zingonia - Osio Sotto, BG, Italy, 24040
Ospedale Maggiore
Bologna, BO, Italy, 40100
Istituto Fondazione Poliambulanza
Brescia, BS, Italy, 25100
Azienda Ospedaliera G.Brotzu
Cagliari, CA, Italy, 09100
Azienda Ospedaliera Santa Croce e Carle
Cuneo, CN, Italy, 12100
Ospedale delle Misericordie
Grosseto, GR, Italy, 58100
Ospedale Campo di Marte
Lucca, LU, Italy, 55100
Ospedale di Desio
Desio, MB, Italy, 20832
Policlinico Monza
Monza, MB, Italy, 20900
AOR Villa Sofia - Cervello P.O.
Palermo, PA, Italy, 90100
AOR Villa Sofia - Cervello PO Villa Sofia
Palermo, PA, Italy, 90100
Ospedale Civile dello Spirito Santo
Pescara, PE, Italy, 65100
Ospedale Santa Maria delle Croci
Ravenna, RA, Italy, 48100
Ospedale San Camillo
Roma, RM, Italy, 00100
Ospedale Infermi
Rimini, RN, Italy, 47921
Ospedale Santa Corona
Pietra Ligure, SV, Italy, 17027
Ospedale Santa Chiara
Trento, TN, Italy, 38100
Ospedale degli Infermi
Rivoli, TO, Italy, 10098
Ospedale Maria Vittoria
Torino, TO, Italy, 10100
Azienda Ospedaliera Universitaria - Ospedale Riuniti
Trieste, TS, Italy, 34121
Ospedale S. Giacomo
Castelfranco Veneto, TV, Italy, 31033
Ospedale Ca' Foncello
Treviso, TV, Italy, 31100
Azienda Ospedaliera -Univ. S. Maria delle Misericordie
Udine, UD, Italy, 33200
Ospedale dell'Angelo
Mestre, VE, Italy, 30100
Ospedale Civile San Bortolo
Vicenza, VI, Italy, 36100
Ospedale G.B. Morgani - L. Pierantoni
Forli, Italy, 47100
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
Heart Care Foundation
Investigators
Study Chair: Roberto Latini, MD Mario Negri Institute, Milan, Italy
Study Chair: Filippo Ottani, MD Ospedale G.B. Morgagni, Pierantoni, Forlì, Italy
  More Information

Additional Information:
No publications provided

Responsible Party: Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT01650662     History of Changes
Other Study ID Numbers: CYCLE (IRFMN_5635), 2011-002876-18
Study First Received: July 24, 2012
Last Updated: July 18, 2014
Health Authority: Italy: Ethics Committee

Keywords provided by Mario Negri Institute for Pharmacological Research:
Acute Myocardial Infarction
Cyclosporine A
Reperfusion
Clinical Trial

Additional relevant MeSH terms:
Infarction
Myocardial Infarction
Myocardial Reperfusion Injury
Cardiomyopathies
Cardiovascular Diseases
Heart Diseases
Ischemia
Myocardial Ischemia
Necrosis
Pathologic Processes
Postoperative Complications
Reperfusion Injury
Vascular Diseases
Cyclosporine
Cyclosporins
Anti-Infective Agents
Antifungal Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014