cycle protocollo emendato3 versione finale 08012014 · director: prof. silvio garattini via la...

CYCLE-Trial - Clinical Trial Protocol EudraCT-No.: 2011-002876-18 DRAFT 5.0 08/01/2014

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CYCLE-Trial

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 Protocol DRAFT – Version 5.0, January 8, 2014

Clinical Phase: III

Sponsors: Istituto di Ricerche Farmacologiche Mario Negri Director: Prof. Silvio Garattini Via La Masa, 19 20156 Milano

AND

Fondazione per il Tuo cuore – Centro Studi ANMCO Director: Prof. Attilio Maseri Via Lamarmora, 36 Firenze Protocol-code: EudraCT number 2011-002876-18

Working Protocol 2 - March 14, 2012 Including Final Version (Version V2.0, June 20, 2011) Amendment No. 1 (September 14, 2012) Amendment No. 2 (March 4, 2013) Amendment No. 3 (January 8, 2014)


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Steering Committee: Roberto Latini (Chair) Dipartimento di Ricerca Cardiovascolare Istituto di Ricerche Farmacologiche Mario Negri Via Giuseppe La Masa 19 20156 Milano Filippo Ottani (co-Chair) U.O. Cardiologia Emodinamica Osp. G.B. Morgagni - L.Pierantoni Via Carlo Forlanini 34 47100 Forlì Aldo Pietro Maggioni ANMCO Research Center Via La Marmora 34 50121 Firenze Gianni Tognoni Consorzio Mario Negri Sud Via Nazionale 8/A 66030 Santa Maria Imbaro Giuseppe Steffenino SSD Emodinamica, Dipartimento Cardiovascolare Osp. Santa Croce Via Michele Coppino 25 12100 Cuneo Guglielmo Bernardi Cardiologia Osp. Santa Maria della Misericordia Piazza Santa Maria della Misericordia 32100 Udine Zoran Olivari Cardiologia Osp. Santa Maria di Ca' Foncello Piazza Ospedale 1 31100 Treviso

Marco Sicuro SC Cardiologia Ospedale Regionale Umbero Parini Viale Ginevra 3 11100 Aosta


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Ugo Limbruno Laboratorio di Emodinamica Ospedale delle Misericordie Via Senesi, 161 58100 Grosseto Luigi La Vecchia

U.O. Cardiologia Ospedale Civile San Bortolo Via Rodolfi, 37 36100 Vicenza Data Safety & Monitoring Board (DSMB)

Luigi Tavazzi Villa Maria Cecilia Hospital Via Corriera, 1 48010 Cotignola Stefano De Servi UTIC – Cardiologia Ospedale Civile Corso Sempione, 82 20025 Legnano Renato Urso Università degli Studi di Siena Via Banchi di Sotto, 55 53100 Siena Claudio Rapezzi Università di Bologna Via Zamboni, 33 40126 Bologna Fabio Ciceri Fondazione San Raffaele del Monte Tabor OncoEmatologia Clinica Via Olgettina, 60 20132 Milano

Primary Event Committee: Alberto Volpi Via Vetta D’Italia 3 20144 Milano Andrea Finzi Cardiologia Ospedale Maggiore Policlinico Via Francesco Sforza 35 20122 Milano


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Grazia Foti Cardiologia Ospedale Niguarda Ca’ Granda Piazza Ospedale Maggiore 3 20162 Milano Gianna Fabbri Centro Studi ANMCO Via Lamarmora, 34 50121 Firenze Coordinating centers: Centro Studi ANMCO Director: Aldo P Maggioni Via Lamarmora, 34 50121 Firenze Statistical analysis: Simona Barlera Istituto di Ricerche Farmacologiche “Mario Negri” Via La Masa, 19 20156 Milano

Valentina Milani Istituto di Ricerche Farmacologiche Mario Negri

Via La Masa, 19 20156 Milano Data management: Donatella Corrado

Consorzio Mario Negri Sud Via Nazionale 8/A 66030 Santa Maria Imbaro

Project administration: Andrea Lorimer Centro Studi ANMCO Via Lamarmora, 34 50121 Firenze Core laboratories: 1. ECG Dott. Andrea Finzi Cardiologia Ospedale Maggiore Policlinico Via Francesco Sforza 35 20122 Milano Dott.ssa Irina Suliman Centro Studi ANMCO Via Lamarmora, 34 50121 Firenze


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2. Coronary Angiography U.O. Cardiologia Emodinamica Osp. G.B. Morgagni - L.Pierantoni Via Carlo Forlanini 34 47100 Forlì 3. Echocardiography Lidia Staszewsky Istituto di Ricerche Farmacologiche "Mario Negri" Via La Masa, 19 20156 Milano

4. Biomarkers Serge Masson Istituto di Ricerche Farmacologiche "Mario Negri" Via La Masa, 19 20156 Milano


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Signature page for Principal Investigators

Dott. Roberto Latini (Chair) _________________ _________ signature date

Dott. Filippo Ottani (Co-Chair) _________________ _________ signature date

Signature page for Investigators I have read this protocol and agree to conduct this trial in accordance with all stipulations of the protocol and in accordance with the Declaration of Helsinki. ___________________ ___________________ _________ Investigator signature date


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1. ABBREVIATIONS

AMI: acute myocardial infarction

CABG: coronary artery bypass grafting

CHF: congestive heart failure

CK: creatine kinase

CRF: case report form

CsA: cyclosporin A

DSMB: data safety monitoring board

ECG: electrocardiogram

ICU: intensive care unit

IEC: independent ethics committee

IRB: institutional review board

ITT: intention-to-treat

LV: left ventricle

PCI: percutaneous coronary intervention

RR: relative risk

SD: standard deviation

STEMI: ST elevation myocardial infarction

TIMI: score thrombolysis and myocardial infarction

TnT: troponin T; hsTnT: high sensitive TnT

URL: upper reference limit


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Index

Steering Committees and core laboratories .............................................................. 2

Signature page for Principal Investigators .............................................................. 5

1 Abbreviations ...................................................................................................... 6

Index ................................................................................................................... 7

2 Summary ............................................................................................................. 9

3 Background and rationale ................................................................................ 11

4 Study design ..................................................................................................... 12

5 Objective and trial endpoints ........................................................................... 12

6 Study population .............................................................................................. 13

6.1 Inclusion criteria .......................................................................................... 13

6.2 Exclusion criteria ........................................................................................ 13

6.3 Participation in other research ...................................................................... 14

7 Operational aspects ........................................................................................ 14

7.1 Randomization ........................................................................................... 14

7.2 Study treatments ...................................................................................... 15

7.2.1 Delivery ................................................................................................ 15

7.2.2 Pharmaceutical preparation .................................................................15

7.2.3 Dose regimen of the study treatment .................................................. 15

7.3 Study discontinuation ................................................................................ 16

7.4 Concomitant treatments ............................................................................ 16

7.5 Coronary angiography / angioplasty ......................................................... 16

8 Data collection and follow-up schedule ............................................................ 17

8.1 Follow-up visits and study plan .................................................................... 17

8.2 Data collection ............................................................................................ 19

8.2.1 Clinical record forms (CRF) ............................................................... 19

8.2.2 Endpoints ........................................................................................... 19

8.2.3 Safety ............................................................................................... 19

8.3 Database management and quality control ................................................ 19

8.4 Study committees ..................................................................................... 19

8.4.1 ECG Core Lab .................................................................................... 20

8.4.2 Endpoint Committee ........................................................................... 20

8.4.3 Data and Safety Monitoring Board (DSMB) ................................. 20

8.5 Collection of biological samples ................................................................. 20


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8.6 Instrumental examinations ......................................................................... 20

9 Statistical Plan ................................................................................................... 21

9.1 Study Population and Randomization .......................................................... 21

9.2 Endpoints .................................................................................................... 21

9.3 Statistical Analyses .............................................................................. 21

9.4 Sample size calculations ........................................................................... 23

9.5 Subgroup analyses ............................................................................... 23

9.6 Interim analysis ............................................................................ 23

9.7 Protocol Changes ....................................................................................... 24

10 Ethical, Administrative, Regulatory aspects ....................................................... 24

10.1 Information to patients .............................................................................. 24

10.2 Approval ................................................................................................... 24

10.3 Monitoring .................................................................................................. 25

10.4 Insurance ................................................................................................ 25

11 Publication policy .............................................................................................. 25

12 References ........................................................................................................ 27

Annex 1................................................................................................................ 29

Annex 2 ............................................................................................................ 31

Annex 3 ............................................................................................................ 32


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2. SUMMARY

EudraCT No 2011-002876-18

Project title CYCLosporinE A in reperfused acute myocardial infarction (CYCLE-Trial)

Sponsors

Istituto di Ricerche Farmacologiche Mario Negri, Milano (+390239014454) Fondazione per il Tuo cuore – Centro Studi ANMCO, Firenze (+39055510205)

Principal Investigators Chair+co-chair of Steering Co (see front page)

Rationale and Objective

Infarct size is a major determinant of prognosis after AMI. As recently reported, cyclosporine A (CsA) administered immediately prior to PCI can significantly reduce infarct size in STEMI patients.

The primary objective of the present study is to determine whether CsA improves outcomes after successful primary PCI, by improving myocardial reperfusion in patients with STEMI.

Trial design and population; statistical aspects

Study Population Inclusion criteria: All (male and female) patients, aged over 18, presenting with a large STEMI within 6 hours of onset (defined as angina pectoris or equivalent symptoms of more than 20 minutes duration within the last 6 hours and ST elevation in ≥ 3 leads in anterior MI and/or a deviation in ≥ 4 leads in inferior MI, with a TIMI-flow 0 or 1 in the culprit artery, committed to treatment with PCI) are eligible for the study. Patients will only be included if they are able to understand the nature, scope, and possible consequences of study participation, and written informed consent will be sought. Exclusion criteria: Left bundle branch block; TIMI-flow >1 in the identified culprit artery; current (≤ 10 days) treatment with CsA or contraindication regarding treatment with CsA; coronary anatomy not suitable for PCI; thrombolytic therapy within 24 h. before randomization; previous myocardial infarction; 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.


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Trial design and population; statistical aspects

Trial design: randomized, open-label, controlled, multicenter. Central randomization stratified by center, performed in the catheterization laboratory by telephone will allow comparison of 2 groups of patients: one receiving right before PCI an intravenous bolus of 2.5 mg/kg of CsA on the top of recommended standard care, the other receiving recommended standard care. Study Endpoints Primary endpoint: Improvement of myocardial reperfusion, measured with ST-segment resolution >=70% 1 hour after PCI. Secondary endpoints: High sesnsitive troponin T (hsTnT) at day 4 after PCI. All-cause mortality, HF or shock within 6 months of randomization; re-hospitalization for CV reasons within 6 months of randomization. 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.

Data safety and monitoring board

An independent DSMB will follow-up the study safety and will receive the results of the interim analyses.

Time scale

Randomization: Start: September 1, 2011 End: April 30, 2014 Study duration The expected duration of the study for each subject is 6 months, for a total study duration of 38 months.


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3. BACKGROUND AND RATIONALE 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 hypotheses and targets (1-4). 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 (4-9), was reported to limit ischemia−reperfusion injury in 50

patients with anterior MI who underwent primary PCI (10). In these patients, the

attenuation of LV dilation and improvement of LV ejection fraction by CsA at 6

months were correlated with infarct size reduction (11). Since infarct size and left

ventricular function are the main determinants of long-term morbitidy 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.

Patients with STEMI, candidates for primary PCI, appear to be the best candidates to

be included in the trial as those who could get the highest benefit from an

intervention aimed at reducing reperfusion injury.

On the other side, the safety of an intravenous administration of CsA should be

carefully assessed, in view of the fact that, though very rare, allergic reactions

(anaphylactoid reactions) have been reported likely attributable to the excipient (12,

13). Even rarer, but to be specifically monitored, are the other two events, acute renal

failure and hypertensive crisis, which appear to be dose and treatment duration

dependent (14). In the present trial, patients will receive only one dose of CsA.

Therefore, adverse effects such as acute renal failure or hypertensive crisis, related

to repeated administrations, are unlikely. In fact, in the previous study comparing the

efficacy of a single i.v. dose of CsA in 30 patients with AMI versus placebo there was

no clinical or biological adverse events after administration of 2.5 mg/kg of CsA (10).


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4. STUDY DESIGN

CYCLE is a multicenter, controlled, randomized open label study, with blind

assessment of end-point measures. All patients meeting inclusion/exclusion criteria

and receiving the treatments recommended in each center will be randomized into

two groups, one of which will receive CsA on the top of the standard treatments.

Figure 1. Study design

5. OBJECTIVE AND TRIAL ENDPOINTS 5.1 The purpose of the study is to test the hypothesis that the administration of

a single in dose of 2.5mg/kg of CsA right before primary PCI could

improve the outcome of AMI patients, by improving myocardial

reperfusion.


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5.2 The primary end-point is the improvement of myocardial reperfusion,

measured with ST-segment resolution, defined as >=70%, 60 minutes after

PCI (first evidence of antegrade blood flow).

5.3 Secondary end-points include:

5.3.1 Troponin T (assayed in the core laboratory as high sensitive TnT)

at day 4 after PCI; this will be the most relevant among secondary

endpoints given its value as readout of cardiac protection.

5.3.2 Clinical events within 6 months of randomization: all-cause

mortality, HF or shock; rehospitalization for CV reasons.

5.3.3 Infarct size: Troponin (T or I, assayed locally) curve;

5.3.4 LV remodeling and function at 6 months, as assessed by

echocardiography;

5.3.5 No reflow, as assessed by myocardial blush.

6. STUDY POPULATION 6.1 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 the 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

6.2 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


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• 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

6.3 Participation in other research Patients included in the study will not be authorized to participate in another

interventional research during their inclusion period to avoid interference of

another investigational product.

7. OPERATIONAL ASPECTS 7.1 Randomization

Central randomization will be performed in a 1:1 ratio.

The following information will be required:

• Center code,

• patient initials,

• date of birth,

• sex,

• hours from onset of symptoms of MI,

• number of leads with ST elevation,

• Infarct location,

• TIMI flow before PCI.

The system will ask to confirm all inclusion and exclusion criteria. A patient will

be considered randomized when the randomization system will assign the

patients identification number according to a pre-established randomization

list.

Randomization will be stratified by Center; block size will be 4.


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7.2 Study treatments

7.2.1 Delivery It is the Investigator’s/institution’s responsibility to establish a system for

handling trial treatments, so as to ensure that deliveries of such products from

the National Coordinating Center are correctly handled in compliance with

GCP criteria (i.e. received by a responsible person such as the pharmacist),

recorded, handled and stored safely and properly, dispensed only to trial

subjects in accordance with the protocol, unused products are returned to the

National Coordinating Center. At the end of the trial, it must be possible to

reconcile delivery records with records of used and returned stocks. Any

discrepancies must be accounted for. Certificates of delivery and return must

be signed, preferably by the Investigator or the center pharmacist.

7.2.2 Pharmaceutical preparation 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.

The National Coordinating Centre will also be in charge of packaging and

delivering the study drug to the Investigator or the pharmacy of every

participating center of the country.

7.2.3 Dose regimen of the study treatment 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.


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7.3 Study discontinuation

Since the study treatment will be administered as single i.v. bolus over about

30 sec, it is unlikely that drug discontinuation will occur.

A patient will be considered discontinued from the study only if he or she

withdraws the consent to be followed by the participating centre, he or she is

lost to follow-up after exhausting all means of contact.

In both cases, the status of the patient at the last visit or contact will be used

for the final analysis. Vital status through public records can be assessed by

the local clinical Investigator in case of failure of all other ways of contact.

7.4 Concomitant treatments Associated treatments (anti-platelet agents, abciximab, anticoagulants, ACE-i,

β-blockers, statins, etc…) will reflect the practices of the study sites expected

to comply with the European Society of Cardiology guidelines for the treatment

of STEMI patients corresponding to the eligibility profile of the present study

(par. 6). Only intracoronary administration of nitrates is allowed. Intracoronary

administration of other treatments (adenosine, verapamil, sodium

nitroprusside, …) should be avoided (if done, it should be reported in the

CRF).

7.5 Coronary angiography / angioplasty Coronary angiography is performed using a standard catheterization

technique. Coronary angiography allows to identify the culprit coronary artery

and to check that reperfusion has not occurred before PCI (TIMI 0-1 flow

grade at admission) (4). TIMI flow grades, assessing coronary flow at the

epicardial coronary artery level, are assessed according to the following

classification: grade 0: no perfusion, grade 1: penetration without perfusion,

grade 2: partial perfusion, grade 3: complete perfusion. TIMI flow is graded on

the angiograms performed immediately before and after PCI by two

experienced Investigators who are blinded to all data apart from the coronary

angiograms.

Coronary angioplasty with or without stenting will be performed according to

the usual procedures utilized by the cardiologist in charge. Thrombo-


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aspiration, proximal or distal protection devices for prevention of coronary

thrombus embolization may be used. Time of PCI start and PCI end will be

considered as the time of first insertion of whatever device in the culprit

coronary artery, and the time of removal of guiding catheter after completion of

PCI, respectively.

8. DATA COLLECTION AND FOLLOW-UP SCHEDULE 8.1 Follow-up visits and study plan

The study involves a single-dose treatment given during the hospitalization for

the index event. Follow-up coincides with routine post-PCI/MI visits. A follow-

up clinical visit is mandatory at 4 weeks and at 6 months, consisting of a

cardiovascular examination, measurement of vital signs (heart rate and blood

pressure), 12-lead electrocardiogram, assessment of serious adverse events,

and routine blood chemistry tests when needed (final visit). In case a clinical

visit is not feasible, the Clinical Research Assistant will call by phone the

patient to check for her/his vital status and whether any Serious Adverse

Event have occurred.


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Study plan

Hospitalisation 4 weeks 6 months

Clinical visit Clinical visit

Written informed consent √

Study treatment administration √

Coronary-angiography / angioplasty / LV angiography

√

Clinical examination √ √

Endpoints

Qualifying ECG (before PCI) and primary EP-ECG (1 hour after PCI)

√

Cardiac enzymes (troponin T or I) √ 1

Serum creatinine, Sodium, Potassium √ 2 √

Glycemia, total Bilirubin, ALT, AST,

hemoglobin, white-cell count √ 3 √

Centralised blood samples √ 4 √

Blood pressure √ 5 √ √

Heart rate √ 6 √ √

Echocardiogram √ 7 √

Serious Adverse Event records √ √ √

1 at admission before study treatment and at 4, 12, 24 hours and 4 days after

randomization, to be assayed locally, with centralized quality control; data

normalized as fold-increase above the upper limit of normality (ULN) for each

troponin assay, defined as the 99th percentile of a reference population (15). 2 at admission, at 24 hours and 4 days after randomization; 3 at admission and at 24 hours after randomization; 4 at randomization, the following morning and 4 days after randomization, to be

analyzed in core laboratories; 5 at admission before study treatment administration and 3 hours after

randomization (regular monitoring otherwise in the ICU); 6 at admission and 3 hours after randomization; 7 at 4 days.


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8.2. Data collection

8.2.1 Clinical record forms (CRF) Investigators must enter the information required by the protocol into the web-

based CRFs. The CRFs will be available to the study data management center

in real time.

8.2.2 Endpoints Documentation supporting the clinical endpoints will be forwarded to the data

management center for adjudication by the Event Validation Committee, while

all ECG tracings (possibly in digital format) will be evaluated for ST-resolution

by the ECG Core Laboratory. The required documentation is outlined in the

Event Validation Committee Manual (see a drafted version in Annex 1).

8.2.3 Safety Patients will be monitored as usual at the acute phase of an AMI:

hospitalization, clinical and biological monitoring in an ICU with repeated

measures of the vital constants and biological parameters.

The very rare, but specific severe adverse events possibly attributable to the

study drug or to its solvent (i.e. allergic/anaphylactoid reaction) will be

specifically monitored during the hospital phase and sent to the Coordinating

Center within 24 hours. The presence of adverse events will also be carefully

checked for at the scheduled follow-up visits.

8.3 Database management and quality control Database management and quality control for this study are under the

responsibility of the National Coordinating Center, which complies with all the

technical obligation of a certified CRO with respect to data handling till data base

locking.

8.4 Study committees

Besides the Steering Committee which acts as the Sponsor of CYCLE, and has

the full responsibility for the planning, conduction, analysis, publication of the study

protocol and results, the following Committees are established.


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8.4.1 ECG Core Lab

The primary end-point of ST resolution will be assessed by the ECG Core Lab.

The core lab will receive from each Center an ECG tracing at randomization

and another after 60 minutes after the antegrade flow was observed, for each

patient enrolled to CYCLE.

8.4.2 Event Validation Committee

The Event Validation Committee members will be independent and will not

have direct contact with patients randomized into this study. The main roles

and responsibilities of the Event Validation Committee are:

- To agree on definitions of the clinical endpoints and on standard

procedures for assessing these endpoints;

- To validate blindly the events recorded and reported by the Investigators

as end-points of the study.

The decisions of the ECG Core Lab and the Event Validation Committee will

be used for health authority submissions and publications.

An Event Validation Committee manual will be pre-defined, by the members of

the Committee (see preliminary definitions in Annex 1).

8.4.3 Data and Safety Monitoring Board (DSMB)

The roles and responsibilities of the Data and Safety Monitoring Board will be

defined by the same DSMB with special focus on intensive monitoring of the

safety aspects in the whole study population. No specific interim analysis is

foreseen for efficacy.

8.5 Collection of biological samples Infarct size evaluated by the area under the curve of the release of biomarker of

necrosis (troponin T or I as locally assayed). Additional aliquots from 4 serial

samples (see figure 1 at page 12) will be assayed for a natriuretic peptide and

other biomarkers in a central core laboratory (see Annex 2).


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8.6 Instrumental examinations

Echocardiographic and angiographic (TIMI myocardial perfusion grade) exams will

be read locally first and then there will be a central quality control on randomly

selected recordings (see Annex 2).

9. STATISTICAL PLAN

9.1 Study Population and Randomization

The treatments are assigned to the patients using a centrally generated randomisation plan, balanced in every centre by a stratified randomization scheme. Patients will be assigned to the treatment with CsA (group A) and to control (group B) in a 1:1 ratio.

9.2 Endpoints

Primary endpoint The primary efficacy endpoint will be the improvement of myocardial reperfusion

measured by ST-segmental resolution, defined as >=70%, one hour after PCI.

Secondary endpoints

The following secondary efficacy endpoints will be analysed:

- Centrally assayed hsTnT at day 4 after PCI;

- all-cause mortality, HF or shock within 6 months of randomization;

- combined endpoint of all-cause mortality, HF or shock within 6 months of

randomization;

- rehospitalization for CV reasons at 6 months.

9.3 Statistical Analyses

The main analysis will be performed according to an intention-to-treat (ITT)

approach, therefore all patients randomised in the study will be included in the

analysis.

Background and relevant baseline information will be summarized for the ITT

population by treatment and overall, and presented using descriptive statistics

(mean, standard deviation, median and range for continuous variables and

proportions for nominal variables).


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Primary efficacy endpoint

The study objective is to show that CsA efficacy is superior to control on the

primary endpoint of the study as defined above.

The occurrence of a complete ST-segmental resolution could be defined as a 0/1

random variable. In a homogeneous target population we assume that, the sum of

those variables in a simple random sample with size n could be modelled as a

binomial random variable, with a distribution characterized by parameter p. With

the indices A an B the defined study groups are labeled as follows:

Null Hypothesis: pA = pB.

Alternative Hypothesis: pA ≠ pB

The statistical test for the primary endpoint will be performed using approximately

normal distributed differences (16). Results will be expressed as proportions and

presented in terms of relative risks (RR) at their 95% confidence intervals. CsA will

be considered superior to control if the lower limit of the two-sided 95% confidence

interval of the relative risk of CsA vs control exceeds 1. A p value <0.05 will be

considered statistically significant.

Relative risk regression will be used instead of a standard logistic model since the

incidence of the outcome of interest is common (improvement of myocardial

reperfusion measured by ST-segmental resolution = 55%). A generalized linear

model will be applied using a log-linear function and a Poisson distribution with

robust sandwich variance estimates (17).

Secondary efficacy endpoints The biochemical marker hsTnT will be summarized descriptively at baseline and at

4 days. Treatment effect on hsTnT at 4 days will be evaluated by analysis of

covariance with treatment as fixed factor and hsTnT baseline measurement as

covariate. Other covariates, imbalanced for the randomized treatment will be

added to the model.

Cox proportional hazards model will be adopted to test for treatment effect (CsA vs

control) on the following secondary endpoints:

• All-cause mortality

• Time to first HF


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• Time to first shock

• time to first occurrence of all-cause death, HF, shock

• time to first occurrence of CV rehospitalizations. The significance level for the analysis of the secondary endpoints is set at the

two-sided 5% level.

9.4 Sample size calculations

The incidence of complete ST-resolution (i.e. >=70%, 60 minutes after PCI) in the

control group is estimated to be 55% (18). It has been 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 troponin T: 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%.

Although in the literature there is a reported average of 10% patients with

revascularization failure (< TIMI 3 after PCI) of the culprit artery, these patients will

be kept in the final ITT analysis.

Sample size calculation was performed using the software nQuery Advisor 6.01.

9.5 Subgroup analysis

The effects of CsA on the primary endpoint will be evaluated in the following

predefined subgroups of patients:

• Age (<=75 vs>75);

• Site of AMI (anterior vs other);

• Diabetes (yes vs no).

• Pre-PCI time (0-3 versus 3-6 hours)

• Post-PCI TIMI (< 3 vs = 3)

• Time from symptom onset (<=2 vs>2 hours)

• Number of leads showing ST elevation at enrollment.


25

9.6 Interim analysis

There is no formal interim analysis for efficacy planned for this study. Safety

aspects will be monitored throghout the whole duration of the trial. No formal

boundaries will be proposed, but clear, consistent, and persistent evidence of net

harm that overwhelms any benefit will be made apparent to the DSMB.

9.7 Protocol Changes

If changes in the protocol are needed, the Steering Committee will propose a

protocol amendment. Based upon their periodic review of study data, the DSMB

will have the authority to recommend amendments to the protocol. Prior to

implementation, all amendments will be reviewed and approved by the local health

authorities and Institutional Review Board/Independent Ethics Committee

(IRB/IEC) as required.

10. ETHICAL, ADMINISTRATIVE, REGULATORY ASPECTS

10.1 Information to patients The information to the patients (see Annex 3) will be provided by taking into

account the conditions of urgency/emergency which characterize the clinical

status. All the efforts will be made without unduly urging the patient to have a

written informed consent before the PCI. Otherwise the patient will be briefed and

requested to sign as soon as the clinical conditions will allow.

10.2 Approval Before implementing this study, the protocol, the proposed informed consent form

and other information to subjects, must be reviewed by a properly constituted

IRB/IEC. A signed and dated statement that the protocol and informed consent

have been approved by the IRB/IEC must be given to the Coordinating Center

before study initiation. The name and occupation of the chairman and the

members of the IRB/IEC must be supplied to the Coordinating Center. Any

amendment to the protocol, other than administrative ones, must be approved by

this committee.


26

10.3 Monitoring

Essential documents, as listed below, must be retained by the Investigator for as

long as needed to comply with national and international regulations (generally 2

years after discontinuing clinical development or after the last marketing approval).

The Coordinating Centers will notify the Investigator(s)/Institution(s) when the

study-related records are no longer required. The Investigator agrees to adhere to

the document retention procedures by signing the protocol. Essential documents

include:

1. IRB approvals for the study protocol and all amendments

2. Source documents (specifically ECG) and laboratory records

3. CRF copies

4. Patients' informed consent forms

5. Any other pertinent study document.

10.4 Insurance The sponsor will make a clinical trial insurance, safeguarding participating patients

against any harm they may encounter as a consequence of their participation in

this trial and which is in accordance with the local laws and requirements. The

insurance contract has been shaped in order to comply with a progressive accrual

of patients enrolled, so that after enrollment of the first 250 patients, the insurance

will be extended to the remaining 194 patients, up to the target number of 444

patients.

11. PUBLICATION POLICY

The main results of the study will be published under the responsibility of the

Steering Committee with a complete listing of all Investigators who contributed to the

implementation of the protocol. Ad hoc agreements for the publication of other

papers will be taken with all participating sites.


27

12. STUDY AGENDA

Duration Date

Protocol / documents writing and Regulatory formalities

12 months 1/09/2010 (end)

Recruitment period Start 18 months

1/09/2011

End 30/04/2014

End of follow-up 6 months 31/10/2014

Data analysis 2 months 31/12/2014


28

12. REFERENCES

1. Kloner RA, Jennings RB. Consequences of brief ischemia: stunning,

preconditioning, and their clinical implications: part 1. Circulation.

2001;104:2981-2989.

2. Kloner RA, Jennings RB. Consequences of brief ischemia: stunning,

preconditioning, and their clinical implications: part 2. Circulation.

2001;104:3158-67.

3. Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy

DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R; Working Group of

Cellular Biology of Heart of European Society of Cardiology. Postconditioning

and protection from reperfusion injury: where do we stand? Position paper

from the Working Group of Cellular Biology of the Heart of the European

Society of Cardiology. Cardiovasc Res. 2010 Aug 1;87(3):406-23.

4. Granfeldt A, Lefer DJ, Vinten-Johansen J. Protective ischaemia in patients:

preconditioning and postconditioning. Cardiovasc Res. 2009 Jul 15;83(2):234-

46.

5. Crompton M, Costi A. A heart mitochondrial Ca induced pore of possible

relevance to reperfusion injury. BiochemJ 1990;266:33-9.

6. Bernardi P, Petronelli V. The permeability transition pore as a mitochondrial

calcium release channel: a critical appraisal. J BioenergBiomembr

1996;28:129-136.

7. Javadov S, Karmazyn M. Mitochondrial permeability transition pore opening

as an endpoint to initiate cell death and as a putative target for

cardioprotection. Cell PhysiolBiochem 2007; 20:1-22.

8. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial

permeability transition pore opening: a new paradigm for myocardial

preconditioning? Cardiovasc Res 2002;55:534-43.

9. DiLisa F, Menabo R, Canton M, Barile M, Bernardi P. Opening of

themitochondrial permeability transition pore causes depletion of

mitochondrialand cytosolic NAD(+) and is a causative event in the deathof

myocytes in postischemic reperfusion of the heart. J BiolChem2001;276:2571-

5.


29

10. Piot C, Croisille C, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R,

Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C,

Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP,

Derumeaux G, Ovize M. Effect of Cyclosporine on Reperfusion Injury in Acute

Myocardial Infarction. N Engl J Med 2008;359:473-81.

11. Mewton N, Croisille P, Gahide G, Rioufol G, Bonnefoy E, Sanchez I, Cung TT,

Sportouch C, Angoulvant D, Finet G, André-Fouët X, Derumeaux G, Piot C,

Vernhet H, Revel D, Ovize M. Effect of cyclosporine on left ventricular

remodeling after reperfused myocardial infarction. J Am CollCardiol. 2010 Mar

23;55(12):1200-5.

12. Volcheck GW, Van Dellen RG. Anaphylaxis to intravenous cyclosporine and

tolerance to oral cyclosporine: case report and review. Ann Allergy Asthma

Immunol. 1998 Feb;80(2):159-63.

13. Liau-Chu M, Theis JG, Koren G. Mechanism of anaphylactoid reactions:

improper preparation of high-dose intravenous cyclosporine leads to bolus

infusion of Cremophor EL and cyclosporine. Ann Pharmacother. 1997

Nov;31(11):1287-91.

14. Sandimmune. Novartis Pharmaceuticals Corporation East Hanover, New

Jersey 07936, rev. Oct 2009.

15. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S,

Biedert S, Schaub N, Buerge C, Potocki M, Noveanu M, Breidthardt T,

Twerenbold R, Winkler K, Bingisser R, Mueller C. Early diagnosis of

myocardial infarction with sensitive cardiac troponin assays. N Engl J Med

2009; 361: 858-867.

16. Fleiss JL: Statistical Methods for Rates and Proportions. Wiley 1981: 38 – 42.

17. Zou G. A modified poisson regression approach to prospective studies with

binary data. Am J Epidemiol 2004 Apr 1;159:702-6

18. Buller CE, Fu Y, Mahaffey KW, Todaro TG, Adams P, Westerhout CM, White

HD, van 't Hof AW, Van de Werf FJ, Wagner GS, Granger CB, Armstrong PW.

ST-segment recovery and outcome after primary percutaneous coronary

intervention for ST-elevation myocardial infarction: insights from the

Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.

Circulation. 2008 Sep 23;118(13):1335-46.


30

ANNEXES

ANNEX 1 Event Validation Committee The validation of the clinical events included in the primary and secondary endpoints

will be ensured by an ad-hoc Event Validation Committee of at least three expert

cardiologist / physicians blinded to the patients’ treatment assignment. This

committee will receive documentation of the events by the Coordinating Center and

will meet on a regular basis. During its first meeting the Event Validation Committee

will elect a Chair, will discuss the definitions of events proposed below and approve

its charter.

Cardiovascular death

Cardiovascular death is defined as death of a patient with history of MI in the

absence of evidence of other causes (i.e. cancer, accident).

Heart failure

Congestive heart failure, at the time of hospital admission (or re-admission), is

defined on the basis of the physician’s decision to treat CHF with an intravenous

diuretic or inotropic agent, or vasodilator and at least 1 of the following: presence of

pulmonary edema or pulmonary vascular congestion on chest radiograph believed to

be of cardiac cause; rales reaching greater than a third up the lung fields believed to

be due to CHF; or dyspnea, with documented PO2 less than 80 mm Hg on room air

or oxygen saturation less than 90% on room air, without significant lung disease. Re-

hospitalization for CHF to an acute care facility primarily for the treatment of CHF has

to include intravenous treatment of CHF with a diuretic or inotropic agent, or

vasodilator.

Cardiogenic shock

It is defined as the presence of systolic blood pressure < 90 mmHg with HR >90

bpm, unresponsive to fluid replacement and associated with signs of peripheral and

end-organ hypoperfusion (cold extremities, cyanosis, oliguria and mental confusion).


31

Myocardial infarction

Fatal myocardial infarction will be taken to be present if the Investigator had identified

this complication on a standard form or if a death certificate or hospital records

showed a fatal myocardial infarction. Non-fatal reinfarction is defined as the presence

of rise and/or fall of cardiac biomarkers (CK-MB or troponin) with at least one value

above 99th percentile of the upper reference limit (URL) together with evidence of

ischemia with a least one of the following: symptoms of ischemia; ECG changes

indicative of new ischemia (new ST-T changes or new left bundle branch block),

development of pathological Q waves in the ECG.

Unstable angina

Unstable angina is defined as the presence of acute chest pain associated with ST

depression or new onset of negative T waves and no elevation of troponins.

Stroke

The diagnosis of non-fatal stroke will require unequivocal signs or symptoms of

remaining neurological deficit, with sudden onset and a duration of more than 24 h.

Diagnosis of fatal stroke (almost impossible in the absence of autopsy) will also use

these criteria. Alternatively, we will use the diagnosis documented in hospital records

or on death certificates.


32

ANNEX 2

Definitions Electrocardiogram (ECG) For all patients at least two 12 lead ECG will be obtained: Qualifying ECG (before

PCI) and primary endpoint ECG (60 minutes after PCI, i.e. 60 minutes after the last

coronary injection of contrast into the treated vessel).

Cardiac markers

For each patient, 4 12 ml blood samples for cardiac enzymes (high sensitive

Troponin T to be assayed in a core laboratory) and for other biomarkers will be drawn

at admission and at serial times (see Fig 1, page 12). These 4 samples are

independent of those collected for local laboratory assays according to each center’s

predefined protocols.

Echocardiography Conventional echocardiography (assessment of global LV function) will be performed

as a routine exam in all patients at day 4 and at 6 months after AMI.

Patients will be scanned in the left supine position. Images will be obtained in

parasternal and apical views. Three cardiac cycles of the apical 4-, 3-, and 2-

chamber views will be captured in conventional 2D. Echo data will be stored digitally

in DICOM format for subsequent offline analysis, such as central quality control on

randomly selected recordings.

Left ventricular volumes and ejection fraction will be calculated by the biplane

Simpson’s rule.

BIO-BANK A central biobank will be set up at Mario Negri, Milano, where all samples collected

from Clinical Centers will be stored at -70°C until analyzed for markers of

cardiovascular injury.

Other clinical and biological investigations - CK, Hemoglobin, creatinine, bilirubin, white blood cell count will be measured at

hospital admission (i.e. before angioplasty), according to each center routine.


33

Annex 3 INFORMAZIONE PER IL PAZIENTE

STUDIO CYCLE

Ciclosporina A nell’infarto miocardico acuto riperfuso

Gent.le Signora/e,

Come Lei già sospetta o sa, i sintomi che l’hanno condotta a questo ricovero sono

dovuti a una “sindrome coronarica acuta”, che richiede un intervento quanto più

tempestivo possibile per far sì che le sue arterie coronarie che si sono occluse

vengano riaperte rapidamente. Le procedure e le terapie per la cura delle sindromi

coronariche acute sono ormai ben note e standardizzate; Lei sarà sottoposto, allo

scopo di riaprire le sue arterie, ad angioplastica coronarica con applicazione di stent

che è una procedura che ha portato ad un notevole miglioramento della prognosi (sia

per la sopravvivenza che per le complicazioni) dei pazienti.

La riapertura molto rapida delle arterie coronarie (che è senza alcun dubbio

“salvavita”) potrebbe però essere accompagnata da un danno cardiaco circostante,

dovuto alo “stress” della successione rapida degli eventi di occlusione-riperfusione. A

questo proposito la somministrazione di un'unica dose di ciclosporina – un farmaco

ormai considerato da più di 30 anni imprescindibile nella terapia dei trapianti –

sembrerebbe essere in grado, e sufficiente, per proteggere il tessuto cardiaco dalle

conseguenze di questo “stress”.

I dati finora disponibili, in pazienti nelle sue condizioni sembrano molto promettenti al

punto da aver suggerito ad un gruppo di clinici - ricercatori di diversi paesi europei di

formulare un protocollo di studio per valutare definitivamente l’efficacia di questo

farmaco in questo tipo di situazione clinica. Questa ipotesi deve essere valutata

rigorosamente, con la metodologia oggi riconosciuta come la più affidabile in campo

medico e perciò obbligatoria, attraverso uno studio clinico al quale Le chiediamo di

partecipare.

Se Lei deciderà di partecipare a questa sperimentazione Lei potrà ricevere, in

maniera del tutto casuale, nel corso della procedura di angioplastica, la ciclosporina


34

oppure un placebo (sostanza non attiva) così che possa essere possibile valutare in

maniera appropriata la efficacia di questo farmaco.

Ci preme informarla che:

a) tutti i/le pazienti riceveranno il meglio delle terapie e dell’assistenza oggi

disponibili;

b) i/le pazienti saranno randomizzati (=assegnati non dal medico, ma secondo una

metodologia statistica che assicura il bilanciamento dei pazienti nei due gruppi) a

ricevere la ciclosporina o un suo placebo (=una preparazione farmaceutica identica,

ma che non contiene una sostanza attiva).

Ci preme inoltre sottolineare che:

l’iniziativa è stata assunta direttamente dai clinici, poichè lo sviluppo di questa nuova

indicazione del farmaco non rientra tra gli interessi delle industrie che ne sono titolari;

Il promotore è l’Istituto di Ricerche Farmacologiche Mario Negri, che ha stipulato

un’assicurazione per tutto quanto Le potesse capitare per il fatto di partecipare a

questa ricerca, così come richiesto dall’attuale normativa vigente.

La Sua partecipazione allo studio è volontaria e Lei può pertanto rifiutarsi di

partecipare o può sospendere la Sua partecipazione in qualsiasi momento e senza

dare giustificazioni.

Naturalmente se Lei rifiuta di partecipare allo studio non avrà nessuna conseguenza

in termini di assistenza medica e qualità delle cure.

Avendo avuto l’approvazione del Comitato Etico responsabile per la ricerca in questo

Ospedale, riteniamo nostro dovere informarLa di questa nuova opportunità di terapia

che si aggiunge a quelle previste per la Sua angioplastica coronarica con

applicazione di stent.

Per tutto quanto abbiamo potuto verificare c’è solo un rischio che potrebbe essere

associato a questa unica somministrazione del farmaco: una reazione allergica, (che

si ipotizza possa manifestarsi in casi veramente rari) media e clinicamente ben

controllabile.

Nell'ambito dello studio è sembrato inoltre importante valutare gli effetti del farmaco

in studio su alcune sostanze presenti nel sangue che possono influenzare la gravità

dei Suoi sintomi.


35

A questo scopo Le verrà richiesto di sottoporsi a 4 prelievi di circa 20 ml di sangue

durante il Suo ricovero in ospedale e a un prelievo nel corso della visita 1 mese dopo

la Sua dimissione dall’ospedale, per un totale di 5 prelievi.

Tali campioni verranno identificati attraverso un codice anonimo in modo che Lei non

possa essere identificato e verranno inviati ad un laboratorio centrale situato presso

l’Istituto di Ricerche Farmacologiche Mario Negri che eseguirà le analisi in modo

cieco. I campioni verranno conservati in congelatori alla temperatura di -70°C sotto

costante controllo termico, in attesa di essere analizzati. Il laboratorio centrale potrà

conservare i campioni per un periodo di 15 anni dalla conclusione dello studio.

A fine studio potrà conoscere i risultati raggiunti. I principali risultati dello studio

verranno pubblicati in riviste scientifiche internazionali. Se Lei desiderasse potrà

ricevere sia gli estremi di tali pubblicazioni sia un riassunto dei principali risultati dello

studio.

Per le domande sullo studio, può contattare:

Dr. _____________________________ Ospedale __________________________

Telefono: ________________________


36

MODULO DI CONSENSO INFORMATO PER LA PARTECIPAZIONE ALLO STUDIO

STUDIO CYCLE

C Ciclosporina A nell’infarto miocardico acuto riperfuso

Io sottoscritto _______________________ ho ricevuto le informazioni relative al

progetto, ho letto quanto scritto nell’informativa e ho avuto il tempo sufficiente per

prendere in considerazione la mia partecipazione. Accetto pertanto di prendere parte

allo studio CYCLE. Autorizzo lo staff di questa struttura a visionare le mie cartelle

cliniche ed a compararne i dati con quelli raccolti sulla scheda raccolta dati del

progetto.

Ho compreso che la partecipazione è facoltativa, e che posso ritirare il mio

consenso in qualsiasi momento, senza la necessità di fornire una ragione e senza

che questo abbia conseguenze sulla qualità delle mie cure e sul rapporto con i

miei medici.

Sono consapevole che i dati raccolti potranno essere utilizzati solo per scopi

scientifici.

Dichiaro inoltre che mi è stata data l’opportunità di rivolgere domande richieste di

chiarimenti e di aver ricevuto riposte chiare e esaustive.

Confermo che mi è stata consegnata copia sia del documento informativo che di

consenso.

Acconsento/non acconsento inoltre ad informare il mio medico curante della mia

partecipazione al presente progetto.

Esprimo il consenso, anche ai sensi della legge in materia di tutela dei dati

personali (D. Lgsl. 196 del 30.06.2003), affinché i dati delle mie cartelle cliniche

relative allo studio vengano resi disponibili dal medico dell’ospedale responsabile

dello studio al monitor dello studio, alle Autorità Sanitarie e ai Comitati Etici nel

totale rispetto dei miei diritti così come precisatimi nella parte informativa di

questo documento.

Acconsento in particolare che il trattamento dei miei dati personali, compresi

quelli inerenti allo stato di salute, venga effettuato per gli scopi specifici della


37

ricerca nei limiti e con le modalità indicatemi nel presente documento di

informazione e consenso.

_______________________________ _________________ Nome e Cognome del paziente Firma Paziente

________________________________ __________________ Nome e Cognome del legale rappresentante Firma legale del paziente ( se previsto)

_________________________________ __________________ Nome e Cognome del medico Firma Medico che raccoglie il consenso

Luogo della ricerca __________________________________________________

Data ___/___/_____


38

LETTERA INFORMATIVA PER IL MEDICO CURANTE

STUDIO CYCLE

C Ciclosporina A nell’infarto miocardico acuto riperfuso

Caro Collega,

con la presente desidero informarTi che il Tuo paziente, Sig./Sig.ra

___________________________________________________________________,

che come sai è stato sottoposto a angioplastica primaria presso il nostro Centro in

[data] per infarto miocardico acuto, ha acconsentito a partecipare a uno studio clinico

randomizzato di confronto fra ciclosporina A e controllo nel ridurre il danno da

ischemia e riperfusione, susseguente ad una angioplastica andata a buon esito. Il

Centro clinico guida è quello di Forlì (Dott Filippo Ottani), i promotori sono l’Istituto

Mario Negri di Milano e la Fondazione per il Tuo cuore.

La ciclosporina A non ha indicazione per l’infarto miocardico acuto, mentre è

largamente usata come immunomodulatore nei trapianti d’organo, dal 1983, anno

della sua introduzione sul mercato. A parte un bolo endovenoso di ciclosporina A, a

un dosaggio terapeutico usato in regimi di trattamenti ripetuti, pazienti inclusi nello

studio verranno trattati in accordo con la pratica clinica corrente senza introduzione di

nessuna procedura diagnostica o di monitoraggio che non siano quelle utilizzate

nella pratica clinica. I farmaci saranno utilizzati in accordo con le indicazioni per le

quali sono commercializzati. I rischi associati alla somministrazione endovena di

ciclosporina A sono bassi, di fatto sono state riportati casi molto rari di reazione

anafilattoide subito dopo inieizione endovena di ciclosporina A, attribuite al solvente,

il Cremofor. Crisi ipertensive o insufficienza renale acuta sono effetti dose dipendenti,

riportati solo in corso di somministrazioni ripetute del farmaco. Inoltre, in uno studio

precedentemente pubblicato (Ovize NEJM), la dose endovena di 2.5 mg/kg

somministrata a 30 pazienti non ha prodotto alcuna reazione indesiderata. La stessa

dose verrà impiegata nello studio CYCLE.


39

Il/La Sig./Sig.ra _____________________________________________________

è stato assegnato al trattamento con _____________________________________

Il nostro Centro, nella persona del Dr. Roberto Latini, referente dello studio, è a Tua

disposizione per qualunque chiarimento. Grazie per la collaborazione, cordiali saluti.

Dr. _______________________ Ospedale _________________________________

Indirizzo ________________________ Telefono ____________________________


40

DA STAMPARE SU CARTA INTESTATA DEL CENTRO Studio CYCLE Ciclosporina A nell’infarto miocardico acuto riperfuso Versione 2.0 del 20/06/2011 INFORMATIVA E MANIFESTAZIONE DEL CONSENSO AL TRATTAMENTO DEI DATI PERSONALI (*) All. 1, Linee guida per i trattamenti di dati personali nell’ambito delle sperimentazioni cliniche di medicinali, Deliberazione n. 52 del 24 luglio 2008. Titolo del protocollo: CYCLE Efficacia della ciclosporina A nell’infarto miocardico acuto riperfuso Titolari del trattamento dei dati e relative finalità Il Centro di Sperimentazione (Indicare il nome del Centro) e l’Istituto di Ricerche Farmacologiche Mario Negri, con sede in via La Masa 19, Milano, promotore dello studio che Le è stato descritto, sono titolari del trattamento dei Suoi dati, nelle persone dei loro legali rappresentanti pro tempore. I titolari, ciascuno per gli ambiti di propria competenza e in accordo alle responsabilità previste dalle norme della Buona Pratica Clinica (D.L. 211/2003), tratteranno i Suoi dati personali e in particolare quelli sulla salute, soltanto nella misura in cui sono indispensabili in relazione all'obiettivo dello studio e a fini di farmacovigilanza. A tal fine i dati indicati saranno raccolti dal Centro di Sperimentazione e trasmessi all’Istituto di Ricerche Farmacologiche Mario Negri. Il trattamento dei Suoi dati personali e clinici è indispensabile allo svolgimento dello studio: il rifiuto di conferirli non Le consentirà di parteciparvi. Natura dei dati I Suoi dati personali saranno costituiti dai dati anagrafici e dai dati sensibili, cioè, dati clinici idonei a rivelare il suo stato di salute. Il medico che La seguirà nello studio La identificherà con un codice: i dati raccolti nel corso dello studio che La riguardano, saranno trasmessi, registrati, elaborati e conservati unitamente a tale codice. Soltanto il medico e i soggetti da lui autorizzati potranno collegare questo codice al Suo nominativo. Modalità del trattamento I Suoi dati personali, saranno trattati secondo principi di correttezza, liceità e trasparenza con modalità, anche automatizzate, strettamente connesse alle finalità dello studio. I dati personali non saranno resi accessibili e disponibili a terzi, fatta eccezione per la comunicazione alle Autorità sanitarie, richiesta ai sensi di legge; dette Autorità potranno, altresì, richiedere di verificare la Sua cartella clinica, con lo scopo di valutare la correttezza dei dati raccolti e con modalità tali da garantire la riservatezza e la confidenzialità dei dati. L’eventuale diffusione dei dati, per il tramite di pubblicazioni scientifiche e/o di presentazione in congressi, convegni e seminari, avverrà esclusivamente a seguito di un’elaborazione meramente statistica degli stessi e, quindi, in forma assolutamente anonima. Diritti dell’interessato ai sensi del D. Lgs. 30 giugno 2003 n. 196 Nella Sua qualità di interessato al trattamento dei dati personali Lei potrà in


41

qualunque momento esercitare i diritti a Lei attribuiti dall’art. 7 del Codice in materia di protezione dei dati personali. Più precisamente, Lei potrà: • accedere ai suoi dati personali, integrarli, aggiornarli; • opporsi, per motivi legittimi, al loro trattamento. Potrà esercitare tali diritti rivolgendosi direttamente al Dr.(indicare il nome di una persona fisica o di un ufficio responsabile e un recapito) o, per il suo tramite, al promotore dello studio. Potrà interrompere in ogni momento e senza fornire alcuna giustificazione la Sua partecipazione allo studio. Non saranno inoltre raccolti ulteriori dati che La riguardano, ferma restando l'utilizzazione di quelli eventualmente già raccolti per determinare, senza alterarli, i risultati della ricerca.


42

Consenso Sottoscrivendo tale modulo acconsento al trattamento dei miei dati personali per

gli scopi della ricerca nei limiti e con le modalità indicate nell'informativa fornitami

con il presente documento.

________________________________________________________________

Partecipante allo studio (nome in stampatello)

________________________________________________________________

(firma)

________________________

(data)

(*) Da sottoporre agli interessati unitamente al modulo di consenso informato che

descrive le caratteristiche scientifiche dello studio, anche mediante integrazione

dello stesso.

cycle protocollo emendato3 versione finale 08012014 · director: prof. silvio garattini via la...

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