Clinical trial NCT01650662: CYCLosporinE A in Reperfused Acute Myocardial Infarction
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myocardial Infarction
Keywords: Acute Myocardial Infarction
Cyclosporine A
Reperfusion
Clinical Trial
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
Collaborators: name: Heart Care Foundation
First posted: 2012-07-26
Enrollment: 410
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Improvement of myocardial reperfusion, measured with ST-segment resolution >=70%
timeFrame: 1 hour after percutaneous coronary intervention (PCI)
Secondary outcomes:
measure: High sensitive cardiac troponin T (hs-cTnt).
timeFrame: at day 4 after percutaneous coronary intervention (PCI)
measure: Clinical events: all-cause mortality, HF or shock; rehospitalization for CV reasons
timeFrame: within 6 months of randomization
measure: Infarct size: Troponin curve (T or I, assayed locally)
timeFrame: Time course of troponin release during the first 72 hours after the visualization of the antegrade flow.
measure: LV remodeling and function as assessed by echocardiography;
timeFrame: at 6 months after randomization
measure: No reflow, as assessed by myocardial blush
timeFrame: 1 day (after the visualization of the antegrade flow)
Other outcomes:
Locations:
city: Aosta
country: Italy
facility: Ospedale Regionale Umberto Parini
state: AO
city: Arezzo
country: Italy
facility: Ospedale S. Donato
state: AR
city: Bari
country: Italy
facility: Ospedale San Paolo
state: BA
city: Seriate
country: Italy
facility: Azienda Ospedaliera di Seriate
state: BG
city: Treviglio
country: Italy
facility: Azienda Ospedaliera di Treviglio
state: BG
city: Zingonia - Osio Sotto
country: Italy
facility: Policlinico S.Marco
state: BG
city: Bologna
country: Italy
facility: Ospedale Maggiore
state: BO
city: Brescia
country: Italy
facility: Istituto Fondazione Poliambulanza
state: BS
city: Cagliari
country: Italy
facility: Azienda Ospedaliera G.Brotzu
state: CA
city: Cuneo
country: Italy
facility: Azienda Ospedaliera Santa Croce e Carle
state: CN
city: Grosseto
country: Italy
facility: Ospedale delle Misericordie
state: GR
city: Lucca
country: Italy
facility: Ospedale Campo di Marte
state: LU
city: Desio
country: Italy
facility: Ospedale di Desio
state: MB
city: Monza
country: Italy
facility: Policlinico Monza
state: MB
city: Palermo
country: Italy
facility: AOR Villa Sofia - Cervello P.O.
state: PA
city: Palermo
country: Italy
facility: AOR Villa Sofia - Cervello PO Villa Sofia
state: PA
city: Pescara
country: Italy
facility: Ospedale Civile dello Spirito Santo
state: PE
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
state: RA
city: Roma
country: Italy
facility: Ospedale San Camillo
state: RM
city: Rimini
country: Italy
facility: Ospedale Infermi
state: RN
city: Pietra Ligure
country: Italy
facility: Ospedale Santa Corona
state: SV
city: Trento
country: Italy
facility: Ospedale Santa Chiara
state: TN
city: Rivoli
country: Italy
facility: Ospedale degli Infermi
state: TO
city: Torino
country: Italy
facility: Ospedale Maria Vittoria
state: TO
city: Trieste
country: Italy
facility: Azienda Ospedaliera Universitaria - Ospedale Riuniti
state: TS
city: Castelfranco Veneto
country: Italy
facility: Ospedale S. Giacomo
state: TV
city: Treviso
country: Italy
facility: Ospedale Ca' Foncello
state: TV
city: Udine
country: Italy
facility: Azienda Ospedaliera -Univ. S. Maria delle Misericordie
state: UD
city: Mestre
country: Italy
facility: Ospedale dell'Angelo
state: VE
city: Vicenza
country: Italy
facility: Ospedale Civile San Bortolo
state: VI
city: Forli
country: Italy
facility: Ospedale G.B. Morgani - L. Pierantoni
Study officials:
affiliation: Mario Negri Institute, Milan, Italy
name: Roberto Latini, MD
role: STUDY_CHAIR
affiliation: Ospedale G.B. Morgagni, Pierantoni, Forlì, Italy
name: Filippo Ottani, MD
role: STUDY_CHAIR
References:
citation: 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.