Physiologic Effects of Stress Dose Corticosteroids in the Management of Inhospital Cardiac Arrest - CORTICA
Phase: PHASE1
Conditions: Inhospital Cardiac Arrest
Sponsor: University of Athens

 
OFFICIAL STUDY TITLE: PHYSIOLOGIC EFFECTS OF STRESS 
DOSE 
CORTICOSTEROIDS 
IN 
THE 
MANAGEMENT 
OF 
INHOSPITAL CARDIAC ARREST – CORTICA  
 
 
PROTOCOL SUBMITTED FOR IRB APPROVAL: Evaggelismos 
General 
Hospital, 
Athens, 
Greece, 
[Protocol 
ID: 
CORTICA 
15519/23/5/16]; Date: MAY 23, 2016. 
 
ClinicalTrials.gov Identifier: NCT02790788 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PHYSIOLOGIC EFFECTS OF STRESS DOSE CORTICOSTEROIDS IN THE 
MANAGEMENT OF INHOSPITAL CARDIAC ARREST - CORTICA 
 
Main Investigators: Evaggelismos Hospital: Spyros D.Mentzelopoulos, Sotirios 
Malachias, Eleni Ischaki, Charikleia Vrettou, Spyros G. Zakynthinos; Larissa 
University Hospital: Dimosthenis Makris, Epaminondas Zakynthinos. 
 
INTRODUCTION AND RATIONALE OF THE STUDY 
Despite recent improvements in the quality of care, in-hospital cardiac arrest is still 
associated with a high probability of poor outcome. [1, 2]. Patients resuscitated from 
vasopressor-requiring cardiac arrest frequently exhibit early postresuscitation 
hemodynamic instability that is poorly responsive to hemodynamic support with high 
vasopressor doses and intravenous fluids titrated to cardiac filling pressures of at least 
12 mmHg [3, 4]. Furthermore, preceding studies indicate that postresuscitation disease 
is a "sepsis-like" syndrome characterized by plasma cytokine elevation, endotoxemia, 
coagulopathy and adrenal insufficiency contributing to postresuscitation shock [5-14]. 
Steroids are currently being used for improving hemodynamics in septic patients [15]; 
however, their effect on postresuscitation hemodynamics has not been thoroughly 
elucidated yet. 
 
 
OBJECTIVES 
To determine whether stress-dose steroid supplementation during and after 
cardiopulmonary resuscitation (CPR) improves the hemodynamic parameters (arterial 
blood pressure, cardiac output, cerebral blood flow) in patients with in-hospital cardiac 
arrest. Furthermore to study the effects of steroid administration on the inflammatory 
response and organ failures, and to determine potential, corticosteroid- associated 
complications such as hyperglycemia, infections, bleeding peptic ulcers and paresis. In 
summary, we aim to directly assess the physiological effects and safety of steroids 
during and after CPR. The possible clinical usefulness of steroids during and after CPR 
- in the context of early postresuscitation hemodynamic support - currently corresponds 
to an important knowledge gap, as recently acknowledged by Guidelines Evidence 
Reviewers. [16, 17]. 
 
 
METHODS 
Setting: Intensive/coronary care units, (ICUs/CCUs) of the Evaggelismos Hospital, 
Athens, Greece (1,200 beds), and of the Larissa University Hospital, Larissa, Greece 
(700 beds). 
 
Clarification: Every effort will be made to admit patients to an Intensive Care Area as 
soon as possible, with an estimated time limit of 24 hours. In cases of inability of 
ICU/CCU admission within 24 hours of resuscitation, every effort will be made to 
optimize the patient’s treatment conditions. Until ICU/CCU admission, patients will be 
monitored by ICU doctors for adequate respiratory and hemodynamic support, as well 
as adequate treatment of any life-threatening pathology. Hemodynamic / respiratory 
monitoring will include continuous electrocardiogram (ECG - lead II), noninvasive 
blood pressure every 5 min, pulse oximetry, and arterial blood gas analysis at 20 min, 
and at 4, 12, and 24 hours (and every 12 hours thereafter) 

following the Return of Spontaneous Circulation (ROSC). Therapeutic orders and/or 
recommendations will ultimately be provided by a senior Intensivist. 
 
PATIENTS 
Eligibility criteria: Patients who have experienced an in-hospital, vasopressor- 
requiring cardiac arrest, according to the Guidelines for Resuscitation from 2015. [16, 
17]. Patients should have ROSC for at least 20 minutes. 
Exclusion criteria: Age <18 years; and/or "end-stage" disease [survival expectancy <6 
weeks - mainly cancer patients with bone and / or cerebral metastases, or metastatic / 
primary disease causing failure of vital organs, including the respiratory system, 
Sequential Organ Dysfunction Assessment score ≥15 prior to cardiac arrest and 
immunocompromised patients with new, sepsis-induced complications]; and/or an 
existing DNAR (Do not-Attempt-Resuscitation) order; and/or Coordinator Intensivist’s 
estimated inability to admit the patient to an Intensive Care Area within 48 hours of 
ROSC; and/or any deviation from the hospital’s standard resuscitation procedure; 
and/or uncontrollable hemorrhage (e.g., aortic aneurysm rupture); and/or cardiac arrest 
before hospital admission; and/or any prior treatment with intravenous corticosteroids; 
and/or any "positive" history of allergic reaction, or active peptic ulcer; and/or presence 
of evidence compatible with transmural myocardial infarction; and/or any prior 
inclusion in or exclusion from the present study. Finally, ROSC at any time prior to 
epinephrine administration, corresponding to "premature randomization" [18], will 
result in the patient’s exclusion due to the "absence of cardiac arrest requiring 
vasopressors [4] ". 
 
ETHICS AND INFORMED CONSENT 
 
The study will be conducted in concordance with the European Union Clinical Trials 
Regulation No 536/2014 and the Helsinki Declaration [19, 20]. Due to the emergency 
situation, consent will not be requested for steroids supplementation during CPR [3, 4]. 
The patients' families and patients who regain consciousness and communication ability 
during follow-up will be informed about the study as soon as possible, and any objection 
will result in exclusion of the patient data from any subsequent analyses. Informed, 
written next-of-kin consent and non-written patient consent (whenever feasible) will be 
requested as soon as possible for stress-dose hydrocortisone in postresuscitation shock 
and continued participation in the study [3, 4]. If consent cannot be obtained before 
patient death, the patient's next of kin will be informed of the study and their permission 
for inclusion of the patient data in the subsequent analyses will be requested – (of course 
in the absence of fulfilment of any exclusion criteria). 
 
The original protocol version has been approved by the Institutional Review Board 
(IRB) of Evaggelismos General Hospital on June 14 2016 (Approval No. 126/16-6- 
2016), and by the IRB of the Larissa University Hospital on October 10, 2016 (Approval 
No. 46113/11-10-2016 - IRB Discussion No. 13/10-10-2016 Θ.6). Subsequent protocol 
amendments have been approved by the Evaggelismos IRB on January 24, 2017 
(Approval No. 8/26-1-2017), and this has been communicated to the IRB of the Larissa 
University Hospital. The aforementioned amendments were ratified through Approval 
No. 1769/17-5-2017 of the IRB of the Larissa University Hospital. 

STUDY DESIGN 
We propose a prospective, randomized, double-blind, placebo-controlled, parallel- 
group clinical trial. 
Randomization: Research Randomizer version 4 (https://www.randomizer.org/) will be 
used by the study statistician for group allocation. For each study center, random 
numbers (range, 1-100) will be generated in sets of 4. Each random number of each set 
will be unique and correspond to 1 of the consecutively enrolled patients. In each set, 
an odd or even first number (for example) will result in assignment of the corresponding 
patient to the Control or Steroids group, respectively. In each study center, the group 
allocation rule will be known solely by the pharmacists who will prepare the study 
drugs. 
 
CPR AND POSTRESUSCITATION INTERVENTIONS 
We will enroll adult in-patients with cardiac arrest due to ventricular 
fibrillation/pulseless tachycardia not responsive to three direct current countershocks, 
or asystole, or pulseless electrical activity. Study treatments will be administered during 
the first CPR cycle postenrollment. Patients will be randomized to receive either 
methylprednisolone 40 mg (Steroids group) or normal saline placebo (Control group) 
on the first, postenrollment CPR cycle. Otherwise, advanced life support will be 
conducted according to the 2015 Guidelines for Resuscitation. After resuscitation, 
patients will be treated with either stress-dose hydrocortisone of 240 mg daily for 7 
days maximum (Steroids group), or saline placebo (Control group). More specifically, 
at 4 hours after ROSC, patients will receive 100 mL/day (average pump infusion rate 
~ 4.2 mL/h) of normal saline that will either contain the stress-dose of hydrocortisone 
(Steroids group) or solely saline placebo (Control group) for a maximum of 9 days. On 
days 8 and 9 the hydrocortisone dose of the Steroids group will be tapered to 120 mg 
and 60 mg, respectively, and finally discontinued on day 10 postrandomization. On 
ICU/CCU admission, patients will receive a central venous line, and an arterial line 
either standard or as part of pulsatility index continuous cardiac output monitoring. 
Patients with a standard arterial line may also receive a pulmonary artery catheter, 
depending on the materials’ availability and attending physicians’ judgment. 
 
DOCUMENTATION AND PATIENT FOLLOW-UP 
 
CPR attempts will be documented according to the Utstein style [4, 21]. Hemodynamics 
and gas-exchange, electrolytes, glucose, core body temperature, lactate, and 
administered fluids and vasopressor/inotropic support will be determined/recorded 
during CPR, and at ~20 min and ~4 hours as well as at 24, 48, and 72 hours after ROSC; 
ROSC will be defined as sustained presence of a palpable arterial pulse for at least 20 
min. Postresuscitation cardiac output will be monitored for at least 72 hours post-
ROSC, and postresuscitation cardiac function will be assessed by ultrasonography 
within the first hour after ICU admission and at 72 hours post-ROSC. Central-venous 
blood gas analysis will also be performed at the aforementioned time points and blood 
samples will be taken for the determination of cytokines at approximately 20 min and 
at 4, 24, 48, and 72 hours post-ROSC. Follow- up during the first 10 days 
postrandomization will include 1) Determination/recording of hemodynamics and 
hemodynamic support, gas-exchange, fluid balance (of the preceding 24 hours), and 
arterial blood lactate and central venous oxygen saturation at 9 a.m.; 2) Daily 
determinations of serum pro-inflammatory cytokines (first 72 hours and day 7), and 
3) Daily recording (within 8-9 a.m.) of laboratory data, and prescribed medication. The 
results of 4 daily determinations (1 every 6 hours) of blood glucose will also be recorded 
to subsequently analyze the incidence of hyperglycemia (i.e., blood glucose exceeding 
200 mg/dL) [3, 4]. Follow-up to day 60 post-ROSC will include organ failure-free days, 
and ventilator-free days. Morbidity/complications throughout ICU/CCU and hospital 

stay, and times to ICU/CCU and hospital discharge will also be recorded. 
 
OUTCOME MEASURES 
 
Primary: 1] Hemodynamic parameters including arterial blood pressure and central 
venous oxygen saturation at 20 minutes after resuscitation and at 4, 24, 48 and 72 hours 
after ROSC. 
Secondary: 1] Cardiac output at 4, 24, 48 and 72 hours after ROSC. 2] Left and right 
end-diastolic areas of the right and left ventricle, left ventricular ejection fraction, and 
eccentricity index within the first 12 hours, and at 72 hours after ROSC. 3] In a total of 
50 patients: Blood Flow Index (BFI) of the frontal cortex and the vastus lateralis by 
Near-Infrared Spectroscopy (NIRS) and intravenous Indocyanine Green (ICG) dye at 4 
and 72 hours after resuscitation [22]. 4] Body temperature in the first 48 hours after 
resuscitation. 5] Levels of TNFα, IL-1β, IL-6, IL-8, IL-10, at 4, 24, 48, and 72 hours 
after randomization. 6] Number of organ failure-free days within days 1 to 60 after 
randomization. 7] Survival to hospital discharge with good neurological outcome 
defined as Cerebral Performance Category Score 1 or 2 [4]. 8] Potentially 
corticosteroid-associated complications such as hyperglycemia, infections, bleeding 
peptic ulcers, and paresis throughout hospital stay. 
 
STATISTICAL ANALYSIS 
Data will be reported as mean ± standard deviation, or median (interquartile range), or 
number (percentage), unless otherwise specified. Distribution normality will be tested 
by Kolmogorov-Smirnov test. Dichotomous and categorical variables will be compared 
by two-sided chi-square or Fisher's exact test. Continuous variables will be compared 
by two-tailed, independent samples t test or the Mann-Whitney exact U  test. P-values 
of multiple t-test comparisons will be subjected to the Bonferroni correction. We will 
use mixed-model analysis to compare repeatedly measured variables between the two 
groups. Survival data will be analyzed by a previously employed methodology of 
multivariable Cox regression. [4]. Based on previously published data on the mean 
arterial pressure at 24 hours postresuscitation [3, 4], to detect an effect size d of 0.761 
with an α error probability of 0.015 and a power of 0.80, we need to enroll a total of 78 
patients (39 in each group). A target enrollment of 100 patients with ROSC for at least 
20 min will likely adequately compensate for possible dropouts or missing data (or for 
a possible effect of protocol breaches – please see below).   
 
NOTE 
This study will not cause any financial burden to the hospital; determination of 
secondary outcomes (especially #3 and #5) will be based on the adequacy of external 
funding. 

REFERENCES 
 
1. Girotra S, Nallamothu BK, Spertus JA, et al. Trends in survival after in- hospital 
cardiac arrest N Engl J Med 2012; 367:1912-1920. 
2. Al-Alwan A, Ehlenbach WJ, Menon PR, Young MP, Stapleton RD. 
Cardiopulmonary resuscitation among mechanically ventilated patients. 
Intensive Care Med 2014; 40:556–563. 
3. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al. Vasopressin, 
epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 
2009; 169:15-24. 
4. Mentzelopoulos SD, Malachias S, Chamos C, et al. Vasopressin, steroids, and 
epinephrine and neurologically favorable survival after in-hospital cardiac 
arrest: a randomized clinical trial. JAMA 2013; 310:270-279. 
5. Adrie C, Adib-Conquy M, Laurent I, et al. Successful cardiopulmonary 
resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 
2002;106:562-568. 
6. Adrie C, Laurent I, Monvhi M, Cariou A, Dhainou JF, Spaulding C. 
Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin 
Crit Care. 2004;10:208-212. 
7. Pene F, Hyvernat H, Mallet V, et al. Prognostic value of relative adrenal 
insufficiency after out-of-hospital cardiac arrest. Intensive Care Med. 
2005;31:627-633. 
8. Kim JJ, Lim YS, Shin JH, et al. Relative adrenal insufficiency after cardiac 
arrest: impact on postresuscitation disease outcome. Am J Emerg Med. 
2006;24:684-688. 
9. Hékimian G, Baugnon T, Thuong M, et al. Cortisol levels and adrenal reserve 
after successful cardiac arrest resuscitation. Shock. 2004;22:116-119. 
10. Tsai MS, Huang CH, Chang WT, Chen WJ, Hsu CY, Hsieh CC, et al. The effect 
of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: a 
pilot study. Am J Emerg Med. 2007;25:318-325. 
11. Schultz CH, Rivers EP, Feldkamp CS, et al. A characterization of hypothalamic-
pituitary-adrenal axis function during and after human cardiac arrest. Crit Care 
Med. 1993;21:1339-1347. 
12. Vaahersalo J, Skrifvars MB, Pulkki K, et al; FINNRESUSCI Laboratory  Study 
Group. Admission interleukin-6 is associated with post resuscitation organ 
dysfunction and predicts long-term neurological outcome after out-of- hospital 
ventricular fibrillation. Resuscitation. 2014;85:1573-1579. 
13. Bro-Jeppesen J, Kjaergaard J, Stammet P, et al; TTM-trial investigators. 
Predictive value of interleukin-6 in post-cardiac arrest patients treated with 
targeted temperature management at 33°C or 36°C. Resuscitation. 2016;98:1- 
8. 
14. Peberdy MA, Andersen LW, Abbate A, et al; National Post Arrest Research 
Consortium (NPARC) Investigators. Inflammatory markers following 
resuscitation from out-of-hospital cardiac arrest-A prospective multicenter 
observational 
study. 
Resuscitation. 
2016. 
doi: 
10.1016/j.resuscitation.2016.01.006. [Epub ahead of print]. 
15. Dellinger RP, Levy MM, Rhodes A, et al, Surviving Sepsis Campaign 
Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis 
Campaign: international guidelines for management of severe sepsis and  septic 
shock, 2012. Intensive Care Med 2013;39:165-228. 

16. Perkins GD, Handley AJ, Koster RW, et al European Resuscitation Council 
Guidelines for Resuscitation 2015 Section 2. Adult basic life support and 
automated external defibrillation Resuscitation 2015; 95:81–99. 
17. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced 
Cardiovascular Life Support: 2015 American Heart Association Guidelines 
Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular 
Care. Circulation. 2015;132(18 Suppl 2):S444-64. 
18. Fergusson D, Aaron SD, Guyatt G, Hébert P. Post-randomisation exclusions: 
the intention to treat principle and excluding patients from analysis. BMJ. 2002; 
325(7365):652-654. 
19. World Medical Association. World Medical Association Declaration of 
Helsinki: ethical principles for medical research involving human subjects. 
JAMA. 2013;310:2191-2194. 
20. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT 
AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal 
products for human use, and repealing Directive 2001/20/EC. Official Journal 
of the European Union 2014; L158/1-L158/76. 
21. Cummins RO, Chamberlain D, Hazinski MF, et al; American Heart 
Association. Recommended guidelines for reviewing, reporting, and conducting 
research on in-hospital resuscitation: the in-hospital "Utstein style." Circulation 
1997;95:2213-2239. 
22. Boushel, R., Langberg, H., Olesen, J., Nowak, M., Simonsen, L., Bulow, J. & 
Kjaer, M. (2000). Regional blood flow during exercise in humans measured by 
near – infrared spectroscopy and indocyanine green. J Appl Physiol 2000; 89: 
1868-1878. 

 
CORTICA CHECKLIST FOR MINIMUM RECORDING REQUIREMENTS 
 
 
 
During resuscitation 
⃝ Study Box Number 
⃝ Initial rhythm 
⃝ Τime of resuscitation team call 
⃝ Time to ALS initiation (min) 
⃝ Time of first shock 
⃝ Time of second shock 
⃝ Intubation time (before or during resuscitation)* 
⃝ Central venous catheter placement (before or during resuscitation)* 
⃝ Time of study drug administration* 
⃝ Total epinephrine dose 
⃝  Arterial blood gas 
⃝  Venous blood gas 
⃝ Arterial pressure (Systolic and Diaastolic) 
⃝ Vasopressors 
⃝  Inotropes 
(calculate total dose if possible) 
⃝ Other drugs [& corrections of electrolyte disturbances / acid-base status] 
⃝ Total fluids / red blood cell or plasma transfusion 
⃝ Temporary pacing 
⃝ Total number of shocks 
⃝ Reversible cause 
⃝ Total number of CPR cycles 
⃝ ALS duration (min) 
⃝ Resuscitation Outcome-Complications 
⃝ Any comments [always valuable!!!] 
 
 
 
 
*Time or Number of CPR cycle 

 
15-20 min and 4 hours after ROSC 
⃝ Arterial pressure (Systolic / Diastolic) 
⃝ Heart rate 
⃝ Twelve-lead ECG abnormalities 
⃝ Patient responsiveness to voice 
⃝ Arterial blood gas 
⃝ Hemodynamic support (norepinephrine, epinephrine, etc. in μg/kg/min) 
⃝ Total fluids since CPR initiation until 15-20 min after resuscitation 
⃝ Temperature 
⃝ Blood sample 
⃝ Any comments [always valuable!!!] 
 
 
 
 
Patient history: Each investigator is responsible for collecting the patient’s medical 
history. In this source document, the investigator has to indicate the age, sex, body 
weight and height, past medical history, past medication, cause of current hospital 
admission, days in hospital before cardiac arrest, cause of cardiac arrest and any other 
clinically relevant comment regarding the peri-arrest period. This checklist must be e- 
mailed to the study coordinator. 

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 
 
Pharmacy Trial Instructions 
 
 
IT IS THE RESPONSIBILITY OF ALL USERS OF THIS SOP TO ENSURE THAT 
THE CORRECT VERSION IS BEING USED 
 
 
 
 
 
Approved by: 
Name/Position: 
Signature: 
Date: 
Name/Position: 
Signature: 
Date: 
 
 
 
Version History Log 
 
This area should detail the version history for this document. It should detail the key 
elements of the changes to the versions. 
 
Version 
Date Implemented 
Details of significant changes 
1.0 
 
 
 
 
 
 
 
1 
1.0 
Template Reference: 
Version Number: 
Author: 
Implementation date of current version: 
This Template will normally be reviewed every 2 years unless changes to the 
legislation require otherwise 

 
 
IT IS THE RESPONSIBILITY OF ALL USERS OF THIS SOP TO ENSURE THAT 
THE CORRECT VERSION IS BEING USED AND THAT THEY HAVE SIGNED THE 
SIGNATURE LOG IN SECTION 4.2 
 
Staff must ensure that they are adequately trained in this procedure and must make 
sure that all copies of superseded versions are promptly withdrawn from use unless 
notified otherwise. 
 
If you are reading this in printed form check that the version number and date below 
is the most recent one. 
Pharmacy Trial Instructions 
 
 
 
Study Short Title 
CORTICA 
Study Long Title 
PHYSIOLOGIC EFFECTS OF STRESS 
DOSE CORTICOSTEROIDS IN THE 
MANAGEMENT 
OF 
INHOSPITAL 
CARDIAC ARREST (CORTICA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study SOP Reference: 
Short study title/Cortica 
Version Number: 
Enter number 
Author: 
Enter Author 
Implementation date of current version: 
Enter date 
 
Approved by: 
Name/Position: 
Signature: 
Date: 
Research Pharmacist / Directorate Pharmacist 
Enter Date 
Name/Position: 
Signature: 
Date: 
Pharmacy Trial Manager/Senior Pharmacy 
Technician 
Enter Date 
 
This SOP will normally be reviewed every 2 years unless changes to the legislation 
require otherwise 

Evaggelismos General Hospital CORTICA Srudy 
 
Version History Log 
 
This area should detail the version history for this document. It should detail the key 
elements of the changes to the versions. 
 
Version 
Date Implemented 
Details of significant changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 

Contents 
 
Page no 
1. Introduction, Background and Purpose 
5 
2. Who should use this SOP 
5 
3. When this SOP should be used 
5 
4. Procedures 
5 
4.1 Contact details 
5 
4.2 Staff Signature Log 
6 
4.3 CORTICA Trial Summary 
8 
4.4 Patient Log 
9 
4.5 Prescription Checking Procedure 
10 
4.5.1 Prescription Checking 
10 
4.5.2 Study Drug Checking 
10 
4.5.3 Drug Accountability Checking 
11 
4.6 Dispensing Procedure 
11 
4.6.1 Study Drugs Involved 
11 
4.6.2 Pharmacy Signature Log 
11 
4.6.3 Patient log 
12 
4.6.4 Prescription 
12 
4.6.5 Drugs to Dispense 
13 
4.6.6 Expiry Dates 
13 
4.6.7 Labelling 
13 
4.6.8 Accountability Records 
13-15 
4.7 Ordering of Trial Supplies 
15 
4.8 Randomization 
15 
5 Appendix A Staff Signature Log 
16-17 
5 Appendix B Patient Log 
18-19 

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 
1. Introduction, Background and Purpose 
It is a requirement that all Pharmacy study files contain a comprehensive standard 
operating procedure (SOP) to cover all aspects of running the study within 
Pharmacy. 
 
 
2. Who Should Use This SOP 
This SOP applies to all members of Pharmacy staff involved in undertaking 
activities relating to this clinical trial. 
 
 
3. When this SOP Should be Used 
This Standard Operating Procedure (SOP) specifically relates to Cortica study and 
should be followed when undertaking trial activities. 
 
 
4. Procedure(s) 
This document should be retained within the Pharmacy clinical trial file. The 
Version History Log must be updated whenever a new version is implemented. 
 
4.1 Contact Details 
[The contact details of the following individuals should be obtained and included in 
this section. Add rows as appropriate] 
 
Name, address, email and telephone number 
CI/PI 
Study Pharmacist 
 
 
 
 
 
 
 
 
 
 
 
 
5 

4.2 Staff Signature Log 
 
Name 
Job Title 
Signature 
Date 

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 

 
4.3 CORTICA Study Summary 
 
 
Background: Patients resuscitated from vasopressor-requiring cardiac arrest frequently 
exhibit severe, postresuscitation hemodynamic instability, partly attributable to an 
impaired adrenal release of hydrocortisone. Also, postresuscitation disease is a "sepsis-
like" syndrome characterized by plasma cytokine elevation, endotoxemia, 
coagulopathy, and adrenal insufficiency/impaired hydrocortisone release contributing 
to postresuscitation shock. Preceding study results testing combined interventions (i.e. 
vasopressin and stress dose steroids in addition to epinephrine) are consistent with 
significant physiological benefits of steroid supplementation during and after 
cardiopulmonary resuscitation (CPR). We propose to test this hypothesis in a 
randomized, double-blind, parallel-group, prospective study.  
Setting and Participants: Two Greek, tertiary care centers (approximately 2000 beds). 
One hundred patients with vasopressor-requiring cardiac arrest.  
Methods–Intervention: 
Patients 
will 
be 
randomized 
to 
receive 
either 
methylprednisolone 40 mg (Steroids group) or saline placebo (Control group) on the 
first, postenrollment CPR cycle. Otherwise, advanced life support will be conducted 
according to the 2015 guidelines for resuscitation. Shock after resuscitation will be 
treated with either stress- dose hydrocortisone (240 mg daily for 7 days maximum and 
gradual taper; Steroids group) or saline placebo (Control group).  
Methods - Endpoints: Primary outcomes will be arterial blood pressure, cardiac 
output, and central venous oxygen saturation at 20 min, and at 4, 24, 48 and 72 hours 
after ROSC. Secondary outcomes will include left and right ventricular diastolic area 
and ejection fraction, blood flow index of the brain, and postresuscitation inflammatory 
response within the first 72 hours after ROSC; organ dysfunction/failure within days 1-
60 postenrollment; survival to hospital discharge with/without favorable neurological 
recovery; and steroid-related complications throughout in-hospital follow-up. 
Expected Results: Steroid- associated benefit with respect to the primary outcomes, 
consistent with results on secondary outcomes. 
 
The medication will be normal hospital stock, but will be refered to as investigational 
medicinal product (IMP) for the purpose of the study. CORTICA is a blinded 
randomized trial. 

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 
 
4.4 Patient Log 
 
Patient ID 
Number 
Patient Name 
Hospital number 
Date of Birth 
(DD/MM/YY) 
Date of 
randomization 
/start of treatment 
Treatment arm 
(if applicable) 
Comments (e.g. discontinuation 
withdrawal of patient) 
(DD/MM/YY) 
In the event that this table is completed during the course of the trial – please use a continuation page from Appendix B. 
 
 
 
 
 
 
 
 
 
9 

 
 
 
 
 
4.5 Prescription Checking Procedure 
All clinical trial prescriptions must be checked by a Pharmacist after being dispensed. The signature of a Pharmacist on a prescription for 
this trial confirms that the following checking procedures have been undertaken by that Pharmacist. 
 
 
4.5 ,1 Prescription checking 
 
A Pharmacist should: 
 
 
Read through the checking procedure and sign the staff signature log to confirm this has been done 
 
Check the study details referring to the trial summary 
 
Check the prescription as follows: 
o correct prescription is in use refer to current version in file 
o patient addressograph is attached to the prescription (or patient details (Name, DOB, Hospital Number) are completed on the 
prescription) 
o patient details have been completed on the patient log 
o study prescription is completed in full and signed by the person who dispensed 
o allergies box has been completed on the prescription 
o prescribers signature against the delegation log 
4.5.2 Study drug checking 
 
A Pharmacist should: 
 
 
Check the study drugs as follows: 
o Appropriate according to the randomization of the patient. 
o drug, strength, dose level and route 
o Treatment number, pack number or container numbers are correct against the prescription. 
o correct number of containers/packs dispensed 
o quantity and expiry date/retest date of the IMP is sufficient for the duration of treatment. 

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 
IMP has been labelled correctly 
 
o storage conditions of the drugs dispensed are correct 
 
4.5.3 Drug Accountability checking 
 
A Pharmacist should: 
 
 
Check the Drug Accountability records have been completed accurately (and add signature or initials to confirm this) as follows: 
o Master accountability record 
o Subject specific accountability record 
o Prescription Pharmacy use only section 
 
4.6 Dispensing Procedure 
 
4.6.1 Study drugs involved 
Methylprednisolone Sodium or Hydrogen Succinate 40 mg Single Dose Vial. 
Reconstituted with 1.2 mL bacteriostatic water for injection with benzyl alcohol. 
This solution may then be added to indicated amounts of isotonic normal saline solution. 
 
Hydrocortisone Sodium or Hydrogen Succinate 250 mg 
Single Dose Vial Reconstituted with 2 mL bacteriostatic 
water for injection 
This solution may then be added to indicated amounts of isotonic normal saline solution. 
 
Pharmacy signature log 
All Pharmacy staff involved in dispensing for a clinical trial must sign the Pharmacy Signature log within this document. 
 
 
 
 
 
11 

 
 
 
4.6.2 Patient log 
Patient information needs to be completed on the patient log specific to this trial . 
 
4.6.3 Prescription 
 
A prescription will need to be prepared by Pharmacy to include the following relevant details for the study: 
 
 
Study title
 
Patients addressograph
 
Patients study/trial number
 
Drug allergies box
 
Details of study drug being prescribed
 
Principal Investigator signature (or other investigator named on the delegation log)
 
Investigator name (PRINT)
 
Date of signature
 
Pharmacy use only section to include; 
 
 
Box to complete Drug batch number and expiry date and any other pharmacy relevant information e.g. randomization if 
appropriate
 
Signature of dispenser and date
 
Signature of checker and date
 
Signature of person collecting prescription and date and time.
 
The signature of the Dispenser on the prescription confirms that the above points have been checked and are complete on the 
prescription. 
 
The dispensing Technician and checking Pharmacist must check that the Prescriber is authorized to prescribe medication as part of the 
trial by checking the delegation log held in section 7.3 of the Pharmacy Trial File. 

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 
 
4.6.4 Drugs to dispense 
 
 Methylprednisolone Sodium or Hydrogen Succinate 40 mg in isotonic saline solution-prefilled syringes [total solution volume 
= 5 mL].
 5 mL isotonic saline solution-prefilled syringes [Saline placebo – Control Group].
 Hydrocortisone Sodium or Hydrogen Succinate 240 mg in 100 mL isotonic saline solution piggy bags.
 Hydrocortisone Sodium or Hydrogen Succinate 120 mg in 100 mL isotonic saline solution piggy bags.
 Hydrocortisone Sodium or Hydrogen Succinate 60 mg in 100 mL isotonic saline solution piggy bags.
 100 mL isotonic saline solution piggy bags.
 
4.6.5 Expiry dates 
 
The batch number and expiry date of the drugs dispensed should be checked and recorded by the dispensing pharmacist on the Drug 
Accountability Log. 
 
4.6.6 Labelling 
 
The dispensing label to be added during dispensing must include the patient’s name and trial number, date of dispensing and the 
signatures of the persons who dispensed and checked the drugs. 
 
4.6.7 Accountability Records 
Master Accountability log 
The log heading should contain the following; 
 Trial name
 Drug name and strength
 Site name and number
 Investigator name
The main body of the log should contain the following column’s; 
 
 
 
 
13 

 
 
 Date
 Action (Drug receipt or dispense or return)
 Drug strength
 Quantity
 Batch number
 Expiry date
 Dispensed items
 Dispensed by/received by
 Checked by (initials)
 Quantity discarded (initials and date) STUDY DRUG SOLUTIONS MUST BE STORED AT 2-8 DEGREES CELCIUS AND 
USED WITHIN 24 HOURS OF PREPARATION TO PREVENT POSSIBLE EFFECTS OF HYDROLYTIC DEGRADATION - 
SOLUTIONS NOT USED WITHIN 24 HOURS MUST BE DISCARDED
 Checked by
 
Subject Specific accountability log 
 
The log heading should contain the following; 
 Trial name
 Patient trial/study number
 Patient name/initials
 Site name/number
 Principal Investigator name
The main body of the log should contain the following columns; 
 Date
 Action (drug receipt or dispense)
 Dose
 Drug strength
 Quantity
 Batch number
 Expiry date

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 Dispensed items, patients name, trial number
 Dispensed/receipted by
 Checked by (initials)?
 Quantity discarded (initials and date)
 Checked by ?
 
4.7 Ordering of Trial Supplies 
The normal hospital stock will be used for the study purpose. 
 
4.8 Randomization Procedure 
Research randomizer-generated random numbers will be allocated in sets of four. Each random number of each set will be unique and 
correspond to 1 of the consecutively enrolled patients. In each set an odd or even first number (example) will result in assignment of the 
corresponding patient to the No Steroids or Steroids group respectively. The group allocation rule will be known solely by the study 
Pharmacists who will prepare and dispense study drugs. 
Methylprednisolone 40 mg in 5 mL isotonic saline or isotonic saline-preloaded 5-ml syringes will be placed in boxes bearing patient codes. 
At the time of enrollment, a box will be opened, and the drug will be administered according to protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 

 
 
 
 
5. Appendix A – Staff Signature Log 
The following Pharmacy staff sign to confirm that they have read the current version of this study specific dispensing and checking 
procedure (Pharmacists are only required to read the study summary and checking procedure). 
 
Name 
Job Title 
Signature 
Date 

Evaggelismos General Hospital CORTICA Srudy 
 
 
 
 
Duplicate page as necessary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 


Appendix B – Patient Log continuation page 
Duplicate page as necessary 
 
 
 
 
 
 
 
Patient ID 
Number 
Patient Name 
Hospital 
Date of Birth 
(DD/MM/YY) 
Date of 
randomization 
/start of treatment 
(DD/MM/YY) 
Treatment arm 
Comments (e.g. discontinuation or 
withdrawal of patient) 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 

 
STUDY 
CORTICA 
TEST MATERIAL 
Methylprednisolone 40 mg (in 5 mL Normal Saline/) 
Normal Saline (5 mL) 
Hydrocortisone (60-240 mg) in 100 mL Normal Saline 
100 mL Normal Saline 
 
Date 
Temperature oC 
Initials of the person 
collecting data 
Comments 
MIN 
MAX 
 
 
Investigator’s Signature  
 
Page……… 

 
STUDY 
CORTICA 
TEST MATERIAL 
Methylprednisolone 40 mg (in 5 mL Normal Saline/) 
Normal Saline (5 mL) 
Hydrocortisone (60-240 mg) in 100 mL Normal Saline 
100 mL Normal Saline 
 
Date 
Temperature oC 
Initials of the person 
collecting data 
Comments 
MIN 
MAX 
 
 
Investigator’s Signature  
 
Page……… 

 
STUDY 
CORTICA 
TEST MATERIAL 
Methylprednisolone 40 mg (in 5 mL Normal Saline/) 
Normal Saline (5 mL) 
Hydrocortisone (60-240 mg) in 100 mL Normal Saline 
100 mL Normal Saline 
 
Date 
Temperature oC 
Initials of the person 
collecting data 
Comments 
MIN 
MAX 
 
 
Investigator’s Signature  
 
Page……… 

 
STUDY 
CORTICA 
TEST MATERIAL 
Methylprednisolone 40 mg (in 5 mL Normal Saline/) 
Normal Saline (5 mL) 
Hydrocortisone (60-240 mg) in 100 mL Normal Saline 
100 mL Normal Saline 
 
Date 
Temperature oC 
Initials of the person 
collecting data 
Comments 
MIN 
MAX 
 
 
Investigator’s Signature  
 
Page……… 

 
STUDY 
CORTICA 
TEST MATERIAL 
Methylprednisolone 40 mg (in 5 mL Normal Saline/) 
Normal Saline (5 mL) 
Hydrocortisone (60-240 mg) in 100 mL Normal Saline 
100 mL Normal Saline 
 
Date 
Temperature oC 
Initials of the person 
collecting data 
Comments 
MIN 
MAX 
 
 
Investigator’s Signature  
 
Page……… 

 
STUDY 
CORTICA 
TEST MATERIAL 
Methylprednisolone 40 mg (in 5 mL Normal Saline/) 
Normal Saline (5 mL) 
Hydrocortisone (60-240 mg) in 100 mL Normal Saline 
100 mL Normal Saline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s Signature  
 
Page……… 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
Standard Operating Procedure for the Recording, Management 
and Reporting of Adverse Events by Investigators 
IT IS THE RESPONSIBILITY OF ALL USERS OF THIS SOP TO ENSURE THAT 
THE CORRECT VERSION IS BEING USED 
Template Reference: 
Version Number: 
Author: 
Implementation date of current 
version: 
1.0 
Approved by: 
Name/Position: 
Signature: 
Date: 
Name/Position: 
Signature: 
Date: 
This Template will normally be reviewed every year unless changes to the 
legislation require otherwise 
1 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
Version History Log 
Version 
Date Implemented 
Details of significant changes 
1.0 
2 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
ACRONYMS 
AE 
Adverse Event 
AR 
Adverse Reaction 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
GCP 
Good Clinical Practice 
PI 
Principal Investigator 
IMP 
Investigational Medicinal Product 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SEC 
Scientific and Research Ethics Committee 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
3 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
Contents 
1.PURPOSE 
2. BACKGROUND 
2.1. DEFINITIONS 
2.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN 
THE CLINICAL TRIAL. 
2.3 SEVERE ADVERSE EVENT OR REACTION 
2.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR 
3. SCOPE OF THIS SOP 
4. RESPONSIBLE PERSONNEL 
5. PROCEDURE 
5.1 Duration of AE Recording 
5.2 Which AE to record and which Forms to use 
5.3 Which AE to report to the SEC 
5.4 Evaluation of AE/Rs during the trial 
5.5. Evaluation of causality 
5.6. Evaluation of expectedness 
5.7 How to manage reports 
6. REFERENCES 
4 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
1. PURPOSE 
This Standard Operating Procedure (SOP) describes the procedure to be 
used by the investigator for the recording, management and reporting of 
Adverse Events (AEs), Adverse Reactions (ARs), Serious Adverse Events 
(SAEs), Suspected Serious Adverse Reactions (SSARs) and Suspected 
Unexpected Serious Adverse Reactions (SUSARs) which occur in subjects 
participating in the non-commercial, academic, investigator-initiated, 
prospective, parallel-group, randomized, double-blind CORTICA study. 
2. BACKGROUND 
This SOP is written in accordance with Good Clinical Practice (GCP) 
requirements as previously outlined in Directives 2001/20/EC and 
2005/28/EC, and currently supported by the CLINICAL TRIALS 
REGULATION (EU) No 536/2014. 
2.1. DEFINITIONS 
The following definitions have been adapted: 
Adverse Event 
Any untoward medical occurrence in a patient or clinical trial subject 
administered an Investigational Medicinal Product (IMP) and which does 
not necessarily have a causal relationship with this treatment. 
Therefore, an AE can be any unfavorable or unintended change in the 
structure (signs), function (symptoms) or chemistry (laboratory data) in 
a subject to whom an IMP has been administered, including occurrences 
which are not necessarily caused by or related to that product. 
Adverse Reaction 
All untoward and unintended responses to an IMP related to any dose 
administered. 
This definition also covers medication errors and uses outside what is 
foreseen in the protocol, including misuse and abuse of the product. 
The definition implies a reasonable possibility of a causal relationship 
between the event and the IMP. This means that there are facts (evidence) 
or arguments to suggest a causal relationship. 
Serious Adverse Event and Serious Adverse Reaction 
Any adverse event or reaction in a trial subject that: 
(a) results in death; or 
(b) is life threatening; places the subject, in the view of the investigator, 
at immediate risk of death from the experience as it occurred (this does 
not include an adverse experience that, had it occurred in a more severe 
form, might have caused death); or 
(c) requires hospitalization or prolongation of existing hospitalization; 
(d) results in persistent or significant disability or incapacity 
or 
(e) consists of a congenital anomaly or birth defect 
Note: in offspring of subjects taking the IMP regardless of time of 
diagnosis. 
Important Safety Issues 
5 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
Important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may 
require intervention (medical or surgical) to prevent one of the other 
outcomes listed in the definition above should also be considered serious. 
Such events might include: 
1. Overdoses (accidental or intentional) 
2. Pregnancy (of subject) 
3. An alarming adverse experience 
4. Specific Adverse events and/or laboratory abnormalities which are 
listed in the trial protocol as critical to safety evaluations and requiring 
reporting. 
Suspected Serious Adverse Reaction 
An adverse reaction that is classed in nature as serious and which is 
consistent with the information about the medicinal product listed in the 
relevant reference documentation in the case of a licensed product being 
used within its licensed dosage and indication or in the Investigator’s 
Brochure (IB) in the case of a licensed product being used outside its 
licensed dosage and indication. 
Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with 
the applicable product information. 
Suspected Unexpected Serious Adverse Reaction 
An adverse reaction that is classified in nature as both serious and 
unexpected. 
2.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN THE 
CLINICA TRIAL. 
Events which may materially alter the current benefit-risk assessment of 
an investigational Medicinal Product (IMP) or which could be sufficient to 
consider changes in the IMP administration or in the overall conduct of 
the trial may fall into the category of ‘Other Safety Issues’ and be 
considered as serious events which will require reporting to the sponsor 
in a letter headed Safety Report: 
a. An increase in the rate of occurrence or a qualitative change of an 
expected serious adverse reaction, which is judged to be clinically 
important, 
b. Post-study Suspected Unexpected Serious Adverse Reactions 
(SUSARs) that occur after the patient has completed a clinical trial and are 
reported by the investigator to the Sponsor, 
c. New events related to the conduct of the trial or the development of the 
IMPs and likely to affect the safety of the subjects, such as: 
1) A Serious Adverse Event (SAE) which could be associated with the trial 
procedures and which could modify the conduct of the trial, 
2) A significant hazard to the subject population such as lack of efficacy of 
an IMP used for the treatment of a life-threatening disease, 
3) A major safety finding from a newly completed animal study 
d. Recommendations of the Data Monitoring Committee (DMC), if any, 
where relevant to the safety of the subjects. 
6 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
An "Other Safety Issue" can also fall into the category of Urgent Safety 
Measures. Please refer to the Standard Operating Procedure for the 
Recording and Reporting of Deviations, Violations, Potential Serious 
Breaches, Serious Breaches and Urgent Safety Measures. 
2.3 SEVERE ADVERSE EVENT OR REACTION 
The term “severe” is often used to describe the intensity of an event or 
reaction (e.g. mild, moderate or severe) and should not be confused or 
interchanged with the term “serious”. 
2.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR 
This section describes the key pharmacovigilance responsibilities of the 
investigator, further delegation of these responsibilities to other team 
members must be documented on the trial delegation log. 
1. The principal investigator (PI) must further ensure that the team are all 
familiar with the appropriate use of the IMP(s), as described in the 
protocol. 
2. Adverse Event (AE) Recording: All AEs must be recorded in the medical 
records (if source data) and/or the patient case report form (CRF), 
Serious Adverse Event (SAE) forms and AE logs as described in the 
protocol. 
3. AE Assessment: The PI / investigator(s) must assess each event for 
seriousness, expectedness and causality using the appropriate 
documentation (protocol and safety reference document). 
4. Trend/signal analysis: The PI must ensure the AE log is reviewed 
regularly. This can be performed by the PI alone or reviewed collectively 
at trial meetings. These reviews need to be documented. 
5. SAE Reports: The PI must ensure that initial and follow-up SAE reports 
are sent to the Scientific and Ethics Committee (SEC), according to the 
protocol. 
6. Confidentiality: The PI must always maintain subject confidentiality. 
7. Urgent Safety Measure: The PI / investigator(s) may take appropriate 
urgent safety measures to protect clinical trial subjects from any 
immediate hazard to their health and safety. This may be taken 
immediately. However, following the measure the PI / investigator must 
follow the SOP on “Deviations, serious breaches and urgent safety 
measures” . 
3. SCOPE OF THIS SOP 
This SOP covers the procedures for the recording, management and 
reporting of all AEs, ARs, SAEs, SSARs and SUSARs that occur in subjects 
participating in the CORTICA Study. This document further details 
overdose reports, safety alerts, safety reference document updates, and 
highlights the key pharmacovigilance responsibilities of the PI. All 
pertinent documentation must always be readily accessible by the 
DMC. 
7 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
4. RESPONSIBLE PERSONNEL 
The PI and the individual investigators within a trial team are responsible 
for keeping records of all adverse events that occur in trial subjects as per 
protocol. 
5. PROCEDURE 
Please ensure that you are using the most recent SOP version. 
5.1 Duration of AE Recording 
The protocol must clearly define the duration of AE recording. 
5.2 Which AE to record and which Forms to use? 
The table below provides guidelines for where to record AE information: 
The PI may further delegate who within the trial team is responsible for 
reporting to the Sponsor. This delegation must be performed on whether 
trial members are qualified to perform the delegated task. This must be 
authorized in the delegation log. 
Type of Adverse Events 
Format of Recording Information 
All Adverse events 
Medical Records 
All AEs and SAEs (as per protocol) 
AE section of CRF 
All SAEs (as per protocol) 
AE log 
All SAEs (as per protocol) 
SAE report form 
5.3 Which AE to report to the SEC? 
All AEs/ARs that fulfill the criteria for the definition of serious, whether 
expected or not, need to be reported to the SEC. 
5.4 Evaluation of AEs/ARs during the trial 
The following documents need to be referred to when assessing any AE in 
the trial: 
 Protocol 
 Trial specific Procedure for unblinding (if applicable) 
Each AE must be evaluated for seriousness, causality, severity and 
expectedness. The PI must assess the AE as serious as per the definition 
of an SAE in section 2. 
5.5. Evaluation of causality 
The PI’s / investigator's causality assessment is vital information since 
the PI / investigator(s) is / are best placed to review how the subject has 
changed since baseline (before treatment is administered). Every effort 
must be made by the PI to obtain all the required information to 
determine whether the AE is related to the trial intervention. 
The PI is asked to consider the following before reaching a decision: 
 Medical History 
 Lack of efficacy/worsening of existing condition 
 Study treatment(s) 
 Other treatments-concomitant or previous 
8 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 Withdrawal of study treatment-especially following study 
discontinuation/end of study 
 Erroneous treatment with study medication (or concomitant) 
 Protocol related process 
 The PI’s / investigator’s evaluation of severity 
5.6. Evaluation of expectedness 
The PI must evaluate whether the event is expected or unexpected 
against the protocol and the safety reference documents for the trial. An 
event can be considered as “unexpected” if it adds significant information 
on the specificity or severity of an expected event. 
5.7 How to manage reports 
The blind for the PI / investigator and if applicable, for those persons 
responsible for data-analysis and interpretation of results will be 
maintained until the trial data is locked. 
However, a patient’s allocation may need to be unblinded under the 
following conditions: 
1. Emergency unblinding: Patient experiencing an AE and requiring 
treatment which cannot be given without knowledge of the trial arm the 
patient was randomized to. 
2. SUSAR Unblinding: The SEC requires unblinding for the submission of a 
SUSAR report. 
Further information is provided in the Standard Operating Procedure for 
the Preparation of a Study Specific Randomization, Blinding and Code 
Break Standard Operating Procedure”. 
9 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
6. REFERENCES 
1. DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL of 4 April 2001 on the approximation of the laws, regulations 
and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use. Official Journal of the European 
Communities. 2002; L121/34-L121/43. 
2. COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down 
principles and detailed guidelines for good clinical practice as regards 
investigational medicinal products for human use, as well as the 
requirements for authorisation of the manufacturing or importation of 
such products (Text with EEA relevance). Official Journal of the European 
Union. 2005; L91/13-L91/19. 
3. INFORMATION FROM EUROPEAN UNION INSTITUTIONS, BODIES, AND 
AGENCIES. EUROPEAN COMMISSION. Communication from the 
Commission — Detailed guidance on the collection, verification and 
presentation of adverse event/reaction reports arising from clinical trials 
on medicinal products for human use (‘CT-3’) Official Journal of the 
European Union 2011; C172/1–C172/13. 
4. World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Subjects. World Medical Association. 
JAMA. 2013; 310:2191-2194. 
5. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND 
OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products 
for human use, and repealing Directive 2001/20/EC. Official Journal of 
the European Union 2014; L158/1-L158/76. 
10 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
Adverse Events Recording and Reporting Log 
All events should continue to be recorded in source data and CRF as per protocol. This log must 1) be kept on site; 2) be readily 
accessible by the DMC; and 3) be sent to SEC upon request 
The PI CANNOT DOWNGRADE THE ASSESSMENT. 
Patient 
trial no 
Adverse 
Event 
term 
IMP Name 
Is 
Event 
Serious 
Y/N 
Serious 
‘Type’1 
Start date - 
stop date 
Causal 
relationship2 
Severity 
Grade* 
Expected 
(Y/N) 
Outcome³ 
Date 
site 
aware 
of SAE 
Date SAE 
1st 
reported 
to the SEC 
 
 
 
 
 
 
 
 
 
 
KEY: 
1 
 1=resulted in Death, 2=life Threatening, 3=required inpatient or prolonged existing 
hospitalization, 4=resulted in persistent or significant disability/incapacity, 5=resulted in 
congenital anomaly/birth defect, 6= Important Medical Event. 
2 
a= definitely, b=probably, c=possibly, d=unlikely, e= not related, f=not assessable 
* 
as per approved protocol or as per trial CRF definition 
³ 
1= Resolved, 2 = Resolved with sequelae, 3 = Unresolved, 4= Worsening, 5 = Fatal, 6= not 
assessable 
11 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
Serious Adverse Event 
Reporting Form 
Protocol No: 
Name of PI: 
Name of Site: 
Initial Report 
Follow-up Report 
12 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
FOR THE ATTENTION OF: 
DMC / SEC / Pharmacovigilance Manager / Regulatory Advisor 
Please complete 
Name of Person sending report: 
Job title of Person sending report: 
Email of Person sending report: 
Contact Phone number of Person sending report: 
THIS IS AN URGENT REPORT THAT REQUIRES IMMEDIATE ATTENTION 

13 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
1. 
SAE Onset Date:  
(dd/mm/yyyy) 
2. 
SAE Stop Date:  
(dd/mm/yyyy) 
3. 
Location of serious adverse event:   
 
4. 
Was this an unexpected adverse event? 
Yes 
No 
5. 
Brief description of participant(s) with no personal identifiers: 
Sex:  F 
M 
Age:   
 
6. 
Brief description of the nature of the serious adverse event (attach description if more 
space needed):   
 
 
7. 
Category of the serious adverse event: 
death – date   /  /  (dd/mmm/yyyy) 
congenital anomaly / birth defect 
life-threatening  
 
required intervention to prevent 
hospitalization-initial or prolonged 
permanent impairment 
disability / incapacity 
other:  
 
8. 
Intervention type: 
Medication or Nutritional Supplement: specify  
       
Device: Specify:   
 
Surgery: Specify:   
                      
Behavioral: Specify:   
  
9. 
Relationship of event to intervention: 
Unrelated (clearly not related to the intervention) 
Possible (may be related to intervention) 
Definite (clearly related to intervention) 
14 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
10. Was study intervention discontinued due to event? 
Yes 
No 
11. What medications or other steps were taken to treat the serious adverse event? 
12. List any relevant tests, laboratory data, history, including preexisting medical 
conditions 
13. 
Type of report: 
Initial 
Follow-up 
Final 
14. Full list of medications the patients was receiving at the time of the SAE 
-------------------------- 
-------------------------- 
-------------------------- 
--------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
-------------------------- 
Signature of PI / investigator:  
Date:   
 
15 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
 
 
Standard Operating Procedure 
for the Recording and Reporting of 
Deviations, Violations, Potential Serious breaches, Serious breaches and 
Urgent Safety Measures 
 
 
Template Reference: 
Version Number: 
Author: 
Implementation date of current 
version: 
1.0 
Approved by: 
Name/Position: 
Signature: 
Date: 
Name/Position: 
Signature: 
Date: 
This Template will normally be reviewed every year unless changes to the 
legislation require otherwise 
 
 
 
 
 
 
ACRONYMS: 
GCP 
Good Clinical Practice 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
DMC 
Data Monitoring Committee 
SOP 
Standard Operating Procedure 
ISF 
Investigator Site File 
PI 
Principal Investigator 
CI 
Chief Investigator (Study Chair) 
CRF 
Case Report Form 
SEC 
Scientific and Research Ethics Committee 
USM 
Urgent safety measures 
TMF 
Trial Master File 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
Standard Operating Procedure for the Recording and Reporting of (protocol 
and /or GCP) Deviations, Violations, Potential Serious breaches, Serious 
Breaches and Urgent Safety Measures 
 
1. PURPOSE 
 
This Standard Operating Procedure (SOP) specifies the overall process and 
procedure for investigators to follow for the CORTICA study in the event of a 
protocol and/or Good Clinical Practice (GCP) deviation. Criteria to follow are 
outlined to assess the impact of the deviation in light of the definition of a potential 
serious breach and / or an urgent safety measure. 
 
This SOP describes the procedure for the principal investigator (PI) / investigator 
to record the event and notify the Scientific and Research Ethics Committee (SEC). 
 
2. RESEARCH POLICY 
All CORTICA SOPs will be reviewed and approved by the SEC of Evaggelismos 
Hospital, Athens, Greece; This SEC is directly linked to the National Research Ethics 
Committee. 
 
3. BACKGROUND 
 
In concordance with the currently applicable European Union Clinical Trials 
Regulation 536/2014, the Investigator/Institution should only conduct the trial in 
accordance with the approved protocol unless an urgent safety measure must be 
taken. 
 
The PI / investigator, or a person designated by the PI (in the trial delegation log), 
should document and explain any deviation from the approved protocol. 
 
Definitions used throughout this document 
 
3.1 Protocol Deviation: A deviation is usually an un-intended departure from the 
expected conduct of the trial (protocol, SOPs), e.g. a protocol visits date deviation (a 
common deviation in clinical trials). These events will be identified by the trial team 
during trial conduct and must be continually monitored by the chief investigator 
(CI)/PI and site team. 
 
It is recognized that minor deviations from approved clinical trial protocols and 
GCP occur commonly in Clinical Trials of Investigational Medicinal Products 
(CTIMPs). Not every deviation from the protocol will result in a serious breach. 
Many of these instances are technical deviations that do not result in harm to the 
trial subjects or significantly affect the scientific value of the reported results of the 
trial. These cases should be documented in the case report form (CRF) and 
appropriate corrective and preventative action taken to ensure they do not recur. 
Please use the CRF and the PI’s Log of (Protocol and/or GCP) Deviations / 
Violations / Potential Serious breaches / Serious breaches / Urgent Safety 
Measures. 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
3.2 Violations: A violation can occur when there is a consistent variation 
in practice from trial protocol, SOPs. A violation can be classified as major 
if there is a significant occurrence which affects participant safety 
or integrity of the research. You are required to report to the PI any 
violation that may impact on the subjects’ safety or affects the integrity of the 
study data. 
 
Examples of this include but are not limited to; 
 
o Failure to obtain informed consent (i.e. no documentation in source data or an 
Informed Consent form). 
o Enrolment of subjects that do not meet the inclusion/exclusion criteria. 
o Undertaking a trial procedure not approved by the SEC (unless for immediate safety 
reasons). 
o Failure to report a Serious Adverse Event/Reaction. 
o Investigational Medicinal Product (IMP) dispensing/dosing error. 
 
Minor Violation - a violation that does not impact on subjects’ safety or 
compromise the integrity of study data. Examples of this maybe; 
 
Missing original signed consent form (but clearly legible photocopy present) 
 
3.3 Serious Breaches of the protocol and/or GCP 
 
Please consider whether the violation that has occurred on site meets the following 
definitions. These cases must be reported to the SEC as soon as the PI / investigator 
has become aware of the event. 
 
(1) The PI of CORTICA shall notify the SEC in writing of any serious breach of - 
(a) the conditions and principles of GCP in connection with CORTICA; or 
(b) the protocol relating to CORTICA, as amended from time to time. 
 
A “serious breach” is a breach which is likely to affect to a significant degree – 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial. 
 
 
 
3.4 Urgent Safety Measures (Implementing a Protocol Deviation under an 
emergency) 
 
The PI / investigator may implement a deviation from, or a change of the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior approval from 
the SEC. This is defined as an Urgent Safety Measure: 
The PI / investigator may take appropriate urgent safety measure(s) to protect 
clinical trial subjects from any immediate hazard to their health and safety. The 
measures should be taken immediately. However, to meet the legal timelines, the 
PI / investigator must inform the SEC in writing immediately and within 24 
hours. 
See section 6.13 below for the REPORTING procedures. 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
4. SCOPE OF THIS SOP 
 
This SOP details the process (for PI / investigators) to follow for the recording and 
reporting of CORTICA protocol deviations and violations. It describes what 
consideration must be considered to assess whether the deviations and violations 
also meet the definition of a potential serious breach or urgent safety measure 
and the reporting requirements. 
 
 
5. RESPONSIBLE PERSONNEL 
 
The site PI has the responsibility to record and report any violations to the SEC 
within the agreed timeframes and in accordance with this SOP if these are deemed a 
potential serious breach/urgent safety measure. Deviations need only be 
documented on site, in the case report form (CRF) and on the PI’s Log of (Protocol 
and/or 
GCP) 
Deviations/Violations/Potential 
Serious 
breaches/Serious 
breaches/Urgent Safety Measures and file noted where required. Any corrective 
and preventative action should also be documented and retained in the site file. 
 
The SEC must consider the following actions: 
Receipt and Assessment (i.e. assessment of deviations/violations, 
isolated/systematic incident, patient(s) harmed or put at risk/data credibility etc.) 
 Investigation 
 Corrective and Preventative Action (CAPA) 
 Reporting to the National Research Ethics Committee 
 Trial suspension or Trial termination 
 Compliance with a 7-day reporting timescale 
 
If the PI is unsure whether a deviation or violation is a potential serious 
breach, then please notify the Data Monitoring Committee (DMC) and the SEC 
as soon as possible and provide as much information as possible. 
 
The DMC and SEC should assess the impact of the breach on the scientific value of 
the trial; this can be carried out in conjunction with the PI/ chief investigator (CI). If 
a potential serious breach is identified by a member of the DMC, the DMC should 
further discuss with the CI/PI in order to clarify the situation and recommend 
appropriate corrective and preventative action. Furthermore, The DMC must report 
the serious breach to the SEC. 
 
The regulatory timeline will only commence once the DMC has been notified of an 
event and has assessed the event as being a serious breach. 
 
6. PROCEDURE 
 
6.1 Identification of deviations, violations and potential serious breaches 
 
The judgment on whether a breach is likely to have a significant impact on the 
scientific value of the trial depends on a variety of factors e.g. the design of the trial, 
the type and extent of the data affected by the breach, the overall contribution of 
the data to key analysis parameters, the impact of excluding the data from the 
analysis etc. 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
In addition, it is important that the PI notifies the SEC of what corrective and 
preventative action has been taken (CAPA) to devise a formal plan of corrective 
and preventative action. 
 
6.1.1 Deviations 
 
Recording: In the CRF and the deviations and violations log and file noted if 
necessary. 
 
Reporting: Where a deviation is reoccurring and may result in identification of a 
serious breach, this should be notified to the PI / CI and the DMC. 
 
Escalation: Corrective and preventative actions should be implemented for 
deviations. It is recommended that reoccurring deviations be discussed at trial 
meetings, trigger protocol amendments, and if required, detailed in the clinical 
study report. 
 
6.1.2 Violations 
 
Recording: In the CRF and the deviations and violations log and file noted if 
necessary. 
 
Reporting: Violations of GCP, protocol and regulations must be notified to the PI / 
and the DMC within 2 calendar days of becoming aware of that violation. 
 
Escalation: Corrective and preventative actions (including protocol amendments as 
appropriate) should be implemented for violations. If the violation is determined to 
be a potential serious breach, then this would be reported to the SEC within 
regulatory timelines. 
It is recommended that reoccurring violations be discussed at trial meetings and 
detailed in the clinical study report. Violations may result in trial suspension by 
Oversight Authorities. 
 
A violation may constitute the DMC / SEC to undertake a triggered monitoring visit. 
All major violations must be resolved to conclusion. Depending on the nature of 
the violation it may constitute a Serious Breach of GCP and further follow up and 
reporting may be required by the DMC in line with current regulations. 
 
6.2 Procedure for notifying Oversight Authorities of a serious breach 
 
6.2.1. Site team to complete the “Notification of Serious Breaches of GCP or Trial 
Protocol form (see Appendix 1) all available details pertaining to the breach should 
be documented on the form. 
 
6.2.2. Completed Notification of Serious Breaches of GCP form to be sent to the DMC 
and the SEC. 
 
6.2.3. SEC to assess and collate information relating to the potential serious breach 
and report to the National Research Ethics Committee within 7 calendar days. 
 
6.2.4. Violation / serious breach to be noted on the Log of (Protocol and/ or GCP) 
Deviations/Violations/Potential Serious breaches/Serious breaches/Urgent Safety 
Measures 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
In addition, the PI must log the Potential serious breach in the PI’s Log of (Protocol 
and/ 
or 
GCP) 
Deviations/Violations/Potential 
Serious 
breaches/Serious 
breaches/Urgent Safety Measures. 
 
6.3 Assessment by the DMC / SEC 
 
DMC / SEC to discuss potential serious breach internally through: 
 
Discussion 
with 
appropriate 
team 
members 
(e.g. 
regulatory 
advisor, 
pharmacovigilance coordinator) 
 
Assess which relevant GCP, regulatory or protocol section the breach was identified 
in. 
 
Evaluate whether the breach fulfils the regulatory definition of a serious breach. 
The SEC may seek clarification from the National Research Ethics Committee on a 
potential serious breach. All supporting documentation pertaining to the breach 
must be compiled and submitted to the National Research Ethics Committee within 
7 days of assessing the event as a serious breach. 
 
If the PI obtains clear and unequivocal evidence that a serious breach has occurred 
the default position should be for the SEC to notify the National Research Ethics 
Committee first, within 7 days, investigate and act simultaneously or after 
notification. In this case, the SEC should not wait to obtain all the details of the 
breach prior to notification. 
 
6.4 Corrective and Preventative Actions (CAPA): 
 
The DMC, SEC, and the CI/PI must agree on the appropriate corrective and 
preventative action to be taken and this should be documented and detailed within 
the body of the notification report. 
 
6.5 Notification to the National Research Ethics Committee: 
 
The completed form should be sent within 7 days of the SEC having assessed an 
event as a serious breach. It is not necessary to wait until all the information is 
obtained, updates to the report are acceptable. In such cases, plans should be 
indicated with projected timelines for completion on follow up reports. 
 
 
6.6 Follow up reports: 
 
Follow up reports should be made in writing; the serious breaches form can also be 
used for this, provided that the "follow-up" nature of the report is clearly identified. 
 
6.7 Escalation and dissemination process: 
Internally: 
The institutional manager(s) of the PI / investigator from the site where the breach 
took place must be notified of the “notification of serious breach” having been sent 
to the National Research Ethics Committee and be informed of what CAPA is in 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
place. The manager(s) may have to inform their quality assurance and senior 
management if necessary. 
 
Externally: 
 
This will be dependent on the nature of the breach and may include other sites and 
pharmacies affected, other SECs / National Research Ethics Committees etc. 
 
The breach should be circulated to relevant staff for inclusion of relevant 
information into the study report or publication. 
 
6.8 Urgent Safety Measure and pertinent notification by a site 
 
Where unexpected events require an urgent modification of a clinical trial, the PI 
may take urgent safety measures without awaiting prior authorization. If such 
measures justify a temporary halt of the trial, the PI should apply for a substantial 
modification before restarting the trial. 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
REFERENCES 
 
1. DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL of 4 April 2001 on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use. Official Journal of the European 
Communities. 2002; L121/34-L121/43. 
2. COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down 
principles and detailed guidelines for good clinical practice as regards 
investigational medicinal products for human use, as well as the 
requirements for authorization of the manufacturing or importation of such 
products (Text with EEA relevance). Official Journal of the European Union. 
2005; L91/13-L91/19. 
3. INFORMATION FROM EUROPEAN UNION INSTITUTIONS, BODIES, AND 
AGENCIES. EUROPEAN COMMISSION. Communication from the Commission 
— Detailed guidance on the collection, verification and presentation of 
adverse event/reaction reports arising from clinical trials on medicinal 
products for human use (‘CT-3’) Official Journal of the European Union 2011; 
C172/1–C172/13. 
4. World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Subjects. World Medical Association. 
JAMA. 2013; 310:2191-2194. 
5. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for 
human use, and repealing Directive 2001/20/EC. Official Journal of the 
European Union 2014; L158/1-L158/76. 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
8. APPENDICES 
 
Appendix 1 Notification of a Serious Breach form 
Appendix 2 Notification Examples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
 
Appendix 1: Notification of a Serious Breach form 
Notification of Serious Breach of Good Clinical Practice or Trial Protocol 
 
 
Your Name: 
Your Organization: 
Your Contact Details: 
Date Breach Identified by PI: 
Date Breach Notified to National 
Research Ethics Committee: 
Details of Individual committing 
breach: 
CORTICA; ClinicalTrials.gov 
Identifier: NCT02790788 
Report: 
Tick 
appropriately 
Initial 
Report 
Follow-up 
Report 
Please give details of the breach 
Potential impact to patient safety and/or data credibility: 
Patient safety 
Patient confidentiality 
Approval Issues 
Scientific value / data credibility 
NA/None 
Other Non-compliances (specify) 
IMP 
Background: 
(continue on additional sheets if required) 
Other relevant information: 
(i.e. study status, site(s), SEC, PI details etc.) 
(continue on additional sheets if required) 
Please give details of the action taken: 
This should include: Any investigations by your institution, the results and outcomes 
of the investigations (if known or details of when they will be available/submitted), 
how it will be reported in the final report/publication, the corrective & preventative 
action implemented to ensure the breach does not occur again. 
(continue on additional sheets if required) 
Actual impact to patient safety and/or data credibility: 
Patient safety 
Patient confidentiality 
Approval Issues 
Scientific value / data credibility 
NA/None 
Other Non-compliances (specify) 
IMP 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
SIGNATURE PAGE 
 
Author and Job Title: 
Signature: 
Date: 
Authorized by: 
Name and Job Title 
Signature: 
Date: 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
Appendix 2: Notification Examples [Please pay special attention to the last 2 
Examples] 
 
Notifier 
Breach 
Is it considered a Serious 
Breach? 
PI 
Dosing error. SEC informed. The 
PI stated that there were no 
serious consequences to subjects 
or data. 
No. As no significant impact on 
the integrity of trial 
subjects or on scientific validity of 
the trial. 
PI 
Patient Information Leaflet and 
Informed Consent updated. At one 
trial site this was not relayed to 
the patients until approximately 
2-3 weeks after approval. More 
information on the potential 
consequences of the delay should 
have been provided. 
Possibly not. If this was not a 
systematic or 
persistent problem and if no 
harm to trial subjects 
resulted from the delay. 
Yes, if there was a significant 
impact on the integrity of trial 
subjects (e.g. there was key safety 
information not relayed to 
subjects in a timely manner etc.). 
PI 
Visit date deviation. 
A common deviation in clinical 
trials. 
No. Minor protocol deviation, 
which does not meet the criteria 
for notification. 
PI 
Investigator failed to report a 
single SAE as defined in the 
protocol (re-training provided). 
No, if it did not result in this or 
other trial subjects 
being put at risk, and if it was not 
a systematic or persistent 
problem. 
In some circumstances, failure to 
report a Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) could have a significant 
impact on trial subjects. 
Sufficient information and 
context should be 
provided for the impact to be 
assessed adequately. 
DMC / SEC 
Investigator failed to stop trial 
medication, in response to a 
peptic ulcer bleed. This occurred 
with 3 patients over a one-year 
period, despite identification by 
the DMC of the first case. Patients 
were put at increased risk of 
death. 
Yes 
PI 
At 24 hours after resuscitation, 
attending physician prescribed 
open label stress-dose 
hydrocortisone for a 22-year 
old patient with severe 
hemodynamic instability 
(norepinephrine requirement 
Yes, but there is no way to 
prevent such attending 
physician decisions, because 
they have a strong ethical basis. 
We cannot prevent any 
Emergency / Urgent Safety 
Measure aimed at managing a 

1st Department Of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
0.5 μg/kg/min to maintain a 
mean arterial pressure of 70 
mmHg) – the CORTICA-related 
treatment was immediately 
discontinued, and patient 
follow-up was continued 
according to protocol. The 
patient’s data will be analyzed 
according to the original 
patient group allocation 
(intention to treat principle). 
life-threatening condition. 
Nevertheless, all such cases will 
be reported to the DMC and SEC 
on a monthly basis. Any 
potential impact on the study 
results will be discussed at 
regular trial team meetings and 
with the DMC and or SEC 
whenever deemed necessary. 
PI 
At 24 hours after resuscitation, 
the patient is still in the 
hospital’s ward where he/she 
experienced the cardiac arrest. 
Despite duty intensivists’ 
efforts for Intensive Care Unit 
(ICU) bed availability, there 
seems to be no prospect of 
imminent ICU admission, ie, 
within the subsequent 12-24 
hours. The patient’s vital signs 
are being monitored 
[continuous electrocardiogram, 
and pulse oximetry, and 
noninvasive blood pressure 
once every 5 min], a central 
venous catheter has been 
placed, and mechanical 
ventilatory settings have been 
adjusted by the duty intensivist. 
Yes, but on the other hand, 
every effort is being made to 
achieve an acceptable quality 
of monitored care. If admission 
to the ICU of another hospital 
becomes possible, then the 
patient data will be recorded 
until the time point of patient 
transfer to the other hospital. 
Otherwise, efforts aimed at 
admitting the patient to our ICU 
will continue until this is 
achieved. 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
 
 
 
 
 
 
 
 
Standard Operating Procedure for the 
Randomization, Blinding, and Study Code Breaking 
 
 
Template Reference: 
Version Number: 
Author: 
Implementation date of current 
version: 
1.0 
Approved by: 
Name/Position: 
Signature: 
Date: 
Name/Position: 
Signature: 
Date: 
This Template will normally be reviewed every year unless changes to the 
legislation require otherwise 
 
 
ACRONYMS: 
PI 
Principal Investigator 
DMC 
Data Monitoring Committee 
GCP 
Good Clinical Practice 
SEC 
Scientific and Research Ethics Committee 
SOP 
Standard Operating Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOP for Study Specific Randomization, Blinding and Code Break 
Page 1 of 4 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
 
 
Standard Operating Procedure for the 
Randomization, Blinding, and Study Code Breaking 
 
1. PURPOSE 
This Standard Operating Procedure (SOP) describes the procedure that the Princippal 
Investigator (PI) of the CORTICA study must follow for the trial Specific Randomization, 
Blinding, and Code Break Procedures 
 
 
2. BACKGROUND 
Clinical trials are often blinded to hide the treatment group assignment from participants 
and investigators (in double-blinded studies) to prevent the unintentional biases of either 
parties affecting subject data. 
 
In order to protect the wellbeing and safety of the trial subject as required in the principles 
of Good Clinical Practice (GCP), the coding system for the Investigational Medical 
Product(s) in blinded trials should include a mechanism that permits rapid identification of 
the product(s) in case of a medical emergency, but one that does not permit undetectable 
breaks of the blinding in order to protect the integrity and validity of the data. To ensure 
this, code break procedures must be clearly established. 
 
At the start of any clinical trial the PI should have a written procedure on the randomization, 
blinding and process for rapidly identifying a blinded Investigational Medicinal Product, as 
well as the details of authorized personnel who will have access to unblinded data. 
 
Definitions 
Allocation concealment: Is where the person randomizing the patient does not know 
what the next treatment allocation will be. 
 
Blinding: A procedure in which one or more parties to the trial are kept unaware of the 
treatment assignment(s). 
 
Block Randomization: Is the arranging of treatment allocations in groups (blocks) that 
are similar to one another. 
 
Code Break: is also known as breaking the blind. It is the mechanism that permits the 
rapid identification of the trial treatment in case of a medical emergency but does not 
permit undetectable breaks of the blinding. 
 
Double-blinding: Where the subject(s), investigators, monitor and in some cases, data 
analyst(s) are unaware of the treatment assignment(s). 
 
Randomization: The process of assigning trial subjects to treatment or control groups 
using an element of chance to determine the assignments to reduce bias. 
 
 
SOP for Study Specific Randomization, Blinding and Code Break 
Page 2 of 4 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
 
Randomization Code: A unique number or code that is linked via a randomization list  
to treatment. 
 
Simple Randomization: is a subset of individuals (a sample) chosen from a larger set (a 
population). Each individual is chosen randomly with equal chance of receiving each 
treatment. 
 
Unblinding: Is the disclosure of the identity of blinded treatment. 
 
3. SCOPE OF THIS SOP 
Randomization, blinding and code break procedures (if applicable). 
 
 
4. RESPONSIBLE PERSONNEL 
Any researcher or member of a study team should follow this SOP. The Principal 
Investigator (PI) of the trial must review, correct as necessary, sign and date the SOP. 
 
The PI is responsible for training all staff personnel in the trial team to ensure their SOP 
on randomization, blinding and code breaking is well understood and complied with. 
 
5. PROCEDURE 
 
5.1 Randomization Procedure 
Research randomizer-generated random numbers will be allocated in sets of four. Each 
random number of each set will be unique and correspond to 1 of the consecutively 
enrolled patients. In each set an odd or even first number (example) will result in 
assignment of the corresponding patient to the No Steroids or Steroids group respectively. 
The group allocation rule will be known solely by the study Pharmacists who will 
prepare and dispense study drugs. 
 
Methylprednisolone 40 mg in 5 mL isotonic saline or isotonic saline-preloaded 5-ml 
syringes will be placed in boxes bearing patient codes. At the time of enrolment, a box will 
be opened, and the drug will be administered according to protocol. 
 
5.2 Blinding 
 Please refer to the Pharmacy Randomization SOP. 
 
5.3 
Code Breaking 
Pertains to: 
 
 Circumstances where unblinding of individual can be broken such as in a medical 
emergency where knowledge of the blinded treatment is necessary, for the treatment of 
an adverse event, in the event of a SUSAR (Suspected Unexpected Serious 
 
 
 
SOP for Study Specific Randomization, Blinding and Code Break 
Page 3 of 4 

1st Department of Intensive Care Medicine 
Evaggelismos General Hospital 
CORTICA Study 
 
 
 
Adverse Reaction) needing expedited reporting, or if requested by the Data Monitoring 
Committee (DMC). 
 For the case of an emergency, the Pharmacy Team provides 24-hour cover to access 
the code break. 
 A pertinent to the code break file note should contain: The date & time, reason for 
unblinding, name & signature of the person requesting the code break, name & signature 
of the person breaking the code. 
 The PI must inform the DMC and other investigators in writing following a code break, 
with the reasons for unblinding. 
 Circumstances where patients will be able to remain on the trial following unblinding 
include all code breaks on grounds of managing a life-threatening condition. Otherwise, 
a code break will be considered as a protocol violation – please refer to the pertinent 
SOP. Protocol violations will be treated case wise, and in conjunction with the DMC and 
the Scientific and Research Ethics Committee (SEC). 
 Details of unblinding after study completion should be provided to the DMC and the 
study analysts. 
 Participants or their next-of-kin should be informed of their blinded treatment allocation, 
if applicable. 
 
6. REFERENCE 
1.  REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF  THE 
COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and 
repealing Directive 2001/20/EC. Official Journal of the European Union 2014; L158/1-
L158/76. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOP for Study Specific Randomization, Blinding and Code Break 
Page 4 of 4 

THE CEREBRAL PERFORMANCE CATEGORY (CPC) SCORE CHECK LIST 
⃝ CPC score=5; Criteria of Brain Death fulfilled? 
⃝ CPC Score=4; Vegetative State – [absence of any interaction with the environment]? 
⃝ CPC Score=3; Patient dependent on others for daily nutrition and hygiene? 
⃝ CPC Score=3; Severe disturbance of memory or dementia diagnosed by a psychiatrist? 
⃝ CPC Score=3; Patient paralyzed? 
⃝ CPC Score=3; Any Sequential Organ Dysfunction Assessment (SOFA) subscore(s) of ≥1 
causing or contributing to dependency on others? 
 
 
 
Respiratory system, PaO2/FiO2 (mmHg) 
< 400 
1 
SOFA score 
< 300 
2 
< 200 
3 
< 100 
4 
Nervous system, Glasgow coma scale 
13–14 
1 
SOFA score 
10–12 
2 
6–9 
3 
< 6 
4 
Cardiovascular system, Mean arterial pressure OR vasopressors required SOFA score 
MAP < 70 mm/Hg 
1 
dop ≤ 5 µg/kg/min or dob (any dose) 
2 
dop > 5 µg/kg/min OR epi ≤ ;0.1 µg/kg/min OR nor ≤ 0.1 µg/kg/min 
3 
dop > 15 µg/kg/min OR epi > 0.1 µg/kg/min OR nor > 0.1 µg/kg/min 
4 
Drug abbreviations: dop for dopamine, dob for dobutamine, epi for epinephrine and nor for 
norepinephrine. 
 
 
 
 
 
 
 
 
 
 
 
 
Kidneys, Creatinine (mg/dl) [μmol/L] (or urine 
output) 
1.2–1.9 [110-170] 
1 
2.0–3.4 [171-299] 
2 
3.5–4.9 [300-440] (or < 500 ml/d) 
3 
> 5.0 [> 440] (or < 200 ml/d) 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOFA score 
Liver, Bilirubin (mg/dl) [μmol/L] 
1.2–1.9 [> 20-32] 
1 
SOFA score 
2.0–5.9 [33-101] 
2 
6.0–11.9 [102-204] 
3 
> 12.0 [> 204] 
CoagulationPlatelets×103/µl 
< 150 
4 
1 
SOFA score 
< 100 
2 
< 50 
3 
< 20 
4 

 
 
 
 
 
 
 
 
 
 
 
 
 
⃝ CPC Score=2; Can the patient perform independent activities of daily life? – Specify 
/ provide examples 
⃝ CPC Score=2; Does the patient have hemiplegia, seizures, ataxia, dysarthria, dysphasia, 
or permanent memory or mental changes? – Specify – Is diagnosis confirmed by a 
neurologist and/or psychiatrist? 
⃝ CPC Score=2; Any (SOFA) subscore(s) of ≥1? - please see also above 
 
⃝ CPC Score=1; Is the patient conscious and alert? – Does he or she seem able to work 
and lead a normal life? 

 
The Glasgow Pittsburgh Cerebral Performance Category (CPC) scale; 
Please check ALL boxes as appropriate. 
CPC level 
Item 
Yes 
No 
1 
Good cerebral performance (i.e., patient is conscious, alert and 
able to work and lead a normal life) 
2 
Moderate cerebral disability (i.e., patient is conscious and has 
sufficient cerebral function for independent activities of daily life; 
hemiplegia, seizures, ataxia, dysarthria, dysphasia, or permanent 
memory or mental changes, and/or noncerebral organ system 
dysfunction causing moderate disability may be present) 
3 
Severe cerebral disability (i.e., patient is conscious and 
ambulatory but dependent on others, because of severe memory 
disturbance or dementia, or patient is paralyzed and can 
communicate only with his/her eyes, as in the locked-in 
syndrome; severe disability from noncerebral organ system 
dysfunction can coexist) 
4 
Coma/vegetative state (i.e., patient is unconscious and unable of 
any verbal and/or psychological interaction with the 
environment); 
5 
Death (i.e. certified brain death) 

1st Department of Critical Care Medicine & 
Pulmonary Services 
GP Livanos and M Simou Laboratories 
Medical School of Athens University 
Evangelismos Hospital 
STANDARD OPERATING PROCEDURE 
 
Written By 
Name 
Vassiliki Karavana 
Function 
Lab Manager 
Date 
Signature 
 
 
 
 
Verification 
Name 
Prof. 
S. Zakynthinos 
Function 
Head of the Dept 
Date 
Signature 
 
 
 
Plasma Isolation from Human Peripheral Blood 
 
PURPOSE 
 
To isolate plasma from whole blood using centrifugation 
 
PERSONNEL 
 
All staff trained in molecular biology methods 
 
Equipment and Accessories 
 
Laminar flow hood 
Centrifuge (eppedorf 5804R ) 
Pipettes 10-1000 μl (Gilson) 
1.5 ml sterile eppedorf tubes endotoxin free 
Disposable sterilize tips 
Racks 
Disposable gloves 
Small ice bucket 
 
METHOD 
 
Invert gently the vacutainer tubes once to mix 
Place the tubes into a centrifuge and spin at 2,000 xg for 10 minutes at 40C 
(program N) 
 
 
1 

Remove the tubes from the centrifuge 
Open the tubes and aliquot in 1.5 ml eppendorf using pipette. Be careful not to 
withdraw any of the white interfacial layer 
Label the tubes and store at -800C. 
Discard the pellet 
Wipe relevant lab surfaces and lab equipment with a solution of 10% bleach 
(90% water) 
 
DOCUMENTATION 
 
Fill in the patient form 
Patient name -Protocol code 
Date and time of blood collection 
Number and volume of aliquots prepared into -80ºC 
 
RISK ASSESMENT 
 
All handlings of blood samples should be done in a biohazard safety cabinet 
Gloves, lab coat and eye protection must always be worn. 
Put all blood-related items, gloves used in working with blood into a biohazard waste 
container located under the hood. 
Dispose tips in a biohazard container. 
Taking off gloves, wash hands vigorously with water and disinfecting soap 
For additional safety information, refer to the risk assessment, hazard data sheets and 
the Departmental policy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 

1st Department of Critical Care Medicine & 
Pulmonary Services 
GP Livanos and M Simou Laboratories 
Medical School of Athens University 
Evangelismos Hospital 
 
STANDARD OPERATING PROCEDURE 
 
Written By 
Name 
Spyros D. 
Mentzelopoulos 
Function 
Principal 
Investigator 
Date 
Signature 
 
 
 
 
Verification 
Name 
Spyros G. 
Zakynthinos 
Function 
Head of the Dept 
And Study Chair 
Date 
Signature 
 
 
 
Near Infrared Spectroscopy (NIRS) assessment of Cerebral Autoregulation and 
of Cerebral (Frontal Cortex) Blood Flow 
 
PURPOSE 
 
To assess Cerebral Autoregulation and Cerebral Blood Flow 
 
PERSONNEL 
 
Spyros D. Mentzelopoulos; Sotirios Malachias; Spyros Zakynthinos; Zafeiris 
Louvaris. 
 
Equipment and Accessories 
 
NIRS monitor; NIRO-200, HAMAMATSU, Photonics KK- Japan, 
Two sets of NIRS Transmitter and Receiver Probes and 2 black-colored, elastic cases, 
each one specifically designed to accommodate a Transmitter and a Receiver Probe. 
Sterile Gauzes and disinfectant solution appropriate for skin cleansing and prepping 
3M™ Tegaderm™ Transparent Film Dressing with Border [size: 10.0 cm x 15.5 cm] 
Medical Adhesive Tape, 
Ruler for the measurement of distances in cm, 
Disposable gloves, 
Laptop Personal Computer (PC) with NIRO200ICG software [HAMAMATSU, 
Photonics KK- Japan] installed, 
METHOD 
 
1 

1. Carefully clean/prep the skin of the forehead and the skin area overlying the 
right vastus lateralis within 5 to 15 cm of the patella. 
2. Place a set of NIRS Transmitter and Receiver probes at either side of the 
midline of the forehead; approximate distance from eyebrows, 15-20 mm. 
Interoptode distance should be 40 mm and the imaginary line connecting the 
centers of the optodes should be perpendicular to (and bisected by) the midline 
of the forehead. 
3. Place a set of NIRS Transmitter and Receiver over the skin overlying the 
vastus lateralis at 10 cm proximally to the upper rim of the patella. Interoptode 
distance should be 40 mm and the midpoint of the imaginary line connecting 
the centers of the optodes should be 10 cm proximal to the upper rim of the 
patella. 
4. Cover the elastic optode cases with gauzes and firmly secure them using 
tegaderm dressing and adhesive tape. 
5. Connect the frontal set of optodes to Channel 1 of the NIRS monitor and the 
vastus lateralis set of optodes to Channel 2 of the NIRS monitor. 
6. Initiate monitor display of NIRS variables and open the "N200ICG.exe" in the 
laptop PC. 
7. Record variables for 10 min (sampling rate, 6 Hz); also record baseline mean 
arterial pressure/heart rate data and vasopressor and/or sedative/anesthetic 
drug infusion rates [acceptable mean arterial pressure values: 70-110 mmHg]. 
8. Press "Event" at the NIRS monitor and infuse 5mg (1 mL solution) of 
indocyanine green (ICG); concurrently record mean arterial pressure/heart rate 
data and vasopressor and/or sedative/anesthetic drug infusion rates [acceptable 
mean arterial pressure values: 70-110 mmHg]. 
9. Continue recording of NIRS variables for another 35-40 min. 
10. Press "Event" at the NIRS monitor and adjust vasoactive drugs to 
increase or decrease mean arterial pressure by at least 15-20% [acceptable 
mean arterial pressure values: 70-110 mmHg]. 
11. Record mean arterial pressure/heart rate data for 10-15 min, i.e. until the new, 
"desired" mean arterial pressure level is reached and maintained for at least 3 
min. 
12. Press "Event" at the NIRS monitor and infuse 5mg (1 mL solution) of 
indocyanine green (ICG); concurrently record mean arterial pressure/heart rate 
data and vasopressor and/or sedative/anesthetic drug infusion rates [acceptable 
mean arterial pressure values: 70-110 mmHg]. 
13. Record NIRS variables for another 20-25 min. 
14. Store data as both "OD2" and "txt" files and switch off PC/NIRS monitor; 
remove optodes; and conclude cerebral autoregulation protocol. 
15. Autoregulation will be assessed by using tissue oxygenation index values and 
concurrently recorded MAP values in a regression analysis, and will be 
considered as adequate if the pertinent Pearson correlation coefficient is lower 
than 0.3.1 
16. Cerebral blood flow and vastus lateralis blood flow will be determined by 
determination of the respective blood flow indexes after a bolus injection of 5 
mg of ICG (2-4). 
 
 
DOCUMENTATION 
Hard copy-recorded data. 
Fill in electronic patient form. 
 
2 

Patient name - Protocol code. 
 
RISK ASSESMENT 
 
Any adverse reaction to ICG to be recorded / reported as study protocol-related serious 
adverse event. Any other complication during the aforementioned NIRS determination 
of the cerebral autoregulation/blood flow will be accordingly evaluated 
/ reported. 
 
 
REFERENCES 
 
1. Ono M, Brady K, Easley RB, et al. Duration and magnitude of blood pressure 
below cerebral autoregulation threshold during cardiopulmonary bypass is 
associated with major morbidity and operative mortality. J Thorac Cardiovasc 
Surg. 2014; 147(1):483–489. 
2. Boushel R, Langberg H, Olesen J, et al. Regional blood flow during exercise in 
humans measured by near-infrared spectroscopy and indocyanine green. J Appl 
Physiol 2000;89: 1868-1878. 
3. Guenette JA, Henderson WR, Dominelli PB, et al. Blood flow index using near-
infrared spectroscopy and indocyanine green as a minimally invasive tool to 
assess respiratory muscle blood flow in humans. Am J Physiol Regul Integr 
Comp Physiol 2011;300: 984-92, 2011. 
4. Habazettl H, Athanasopoulos D, Kuebler WM, et al. Near-infrared spectroscopy 
and indocyanine green derived blood flow index for noninvasive measurement 
of muscle perfusion during exercise. J App Physiol 2010;108: 962-967. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 

1st Department of Critical Care Medicine & 
Pulmonary Services 
GP Livanos and M Simou Laboratories 
Medical School of Athens University 
Evangelismos Hospital 
 
STANDARD OPERATING PROCEDURE 
 
Written By 
Name 
Spyros D. 
Mentzelopoulos 
Function 
Principal 
Investigator 
Date 
Signature 
 
 
 
 
Verification 
Name 
Spyros G. 
Zakynthinos 
Function 
Head of the Dept 
And Study Chair 
Date 
Signature 
 
 
 
Echocardiographic Assessment of right ventricular (RV) and left ventricular 
(LV) performance after the return of spontaneous circulation (ROSC) 
 
PURPOSE 
 
To assess RV and LV function within 72 hours of ROSC 
 
PERSONNEL 
 
Aikaterini Megalou; Fotini Lagiou; Panagiotis Politis. 
 
Equipment and Accessories 
Vivid 3 Expert machine (General Electric Healthcare, Aurora, OH, USA) 
Vivid 7 Expert machine (General Electric Healthcare, Aurora, OH, USA) 
3-MHz transducer 
 
 
 
 
 
 
METHOD 
 
 
 
 
1 

1. Within 12 hours of randomization: Obtain four-chamber views of the heart in 
order to determine the RV end-diastolic area (RVEDA), and the LV end- 
diastolic area (LVEDA). 
2. Within 12 hours of randomization: Determine the left ventricular ejection 
fraction by the "area-length" method.1 
3. Within 12 hours of randomization: Obtain parasternal short-axis views of the 
heart to determine the Eccentricity Index, i.e. the ratio of the LV anteroposterior 
to the LV septolateral diameter, measured at end systole and end diastole. 
4. Repeat the aforementioned measurements at 72 hours after randomization. 
 
 
DOCUMENTATION 
Hard copy-recorded data. 
Add the data to the dedicated boxes of the electronic patient case report form. 
Patient name - Protocol code. 
 
RISK ASSESMENT 
 
No adverse event is expected due to the transthoracic echocardiographic examination 
of the heart. 
 
 
REFERENCES 
 
1. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber 
quantification: a report from the American Society of Echocardiography’s 
Guidelines and Standards Committee and the Chamber Quantification Writing 
Group, developed in conjunction with the European Association of 
Echocardiograph. J Am Soc Echocardiogr. 2005;18:1440–63. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 

1 
 
STUDY INFORMATION SHEET 
 
PATIENT INITIALS: 
PATIENT CODE NUMBER: 
 
MAIN INVESTIGATORS, Evangelismos Hospital: Spyros Mentzelopoulos, Ch 
Vrettou, Sotirios Malachias, Helen Ischaki, Spyros Zakynthinos. University Hospital 
of Larissa: Demosthenes Makris, Epaminondas Zakynthinos. 
 
STUDY TITLE: PHYSIOLOGIC EFFECTS OF STRESS DOSE 
CORTICOSTEROIDS IN THE MANAGEMENT OF INHOSPITAL CARDIAC 
ARREST (CORTICA) 
 
INTRODUCTION 
 
    We request your consent for your family member’s participation in this scientific 
study. The has been approved by our Institutional Review Board (IRB – Scientific 
Committee). To decide whether you agree (or disagree) with your relative’s 
participation in this study you should fully understand the pertinent risks and benefits. 
You are asked to read this text and discuss anything you do not understand with the 
study investigators, or other medical personnel of the Department of Intensive Care 
Medicine, or any other competent doctor who enjoys your confidence. If you 
understand the study, you will be asked to sign and date the consent form. If you 
choose your relative’s participation in the study, you will be given a copy of the 
signed consent form. 
 
CONSENTING FOR YOUR RELATIVE’S PARTICIPATION CONSTITUTES 
A FREE AND RESPONSIBLE CHOICE OF YOURS. 
 
    Your relative may participate or discontinue his/her participation in the study at any 
time, according to your decision, without in any way losing the advantages of 
scientifically sound medical care based international guidelines and available medical 
literature evidence. 
 
    If desired, the principal investigators of the study or your relative’s attending 
physician will contact your relative’s family physician to inform him/her about the 
study. 
 
PURPOSE OF THE STUDY 
    Despite recent improvements in the quality of care, the probability of poor outcome 
after in-hospital cardiac arrest (death or survival to hospital discharge with severe 
brain damage) remains high (about 80%) (1). The probability of por outcome is even 
higher (90-95%) among postresuscitation patients who require mechanical ventilation 
(2), and among those treated with vasopressors (e.g. epinephrine and / or vasopressin) 
during cardiopulmonary resuscitation (CPR) (3, 4). Therefore, there remains an urgent 
need for substantial improvements in the medical management of patients resuscitated 
from cardiac arrest (5-7). 
    In previous single center (3) and a recent, three-center prospective, randomized, 
double-blind study (4), the combination of VSE (Vasopressin-Steroids-Epinephrine) 
proved superior to Epinephrine alone with respect to the survival to hospital discharge 

2 
 
(3), and discharge with good neurological outcome (4). Although the VSE 
combination VSE did not enable determination of the relative contribution of 
vasopressin and steroids on the observed positive results (4), the results of a 
subsequent (post hoc) statistical analysis and sensitivity analysis (4) were consistent 
with the hypothesis that the administration of stress-dose steroids may be associated 
with reduced risk of poor outcome (death or survival to hospital discharge with severe 
neurological disabilities) (2, 4, 8). Furthermore, administering at least one dose of 
hydrocortisone in patients with postresuscitation shock was associated with a 
decreased likelihood of poor outcome during in-hospital follow-up compared to 
control group patients who did not receive steroids (4). 
    The objective of this research is to study the effect of low-dose (stress-dose) 
corticosteroids on the hemodynamic status after the restoration of spontaneous 
circulation and of the postresuscitation systemic inflammatory response. More 
specifically, we will study the addition of 40 mg of methylprednisolone to standard 
treatment during CPR, and the use of stress-dose hydrocortisone in the treatment of 
postresuscitation shock. 
 
INVESTIGATIONAL INTERVENTIONS 
 
    Your family member has suffered a cardiac arrest from which he/she has been 
resuscitated after having received standard treatment or the above-described study 
intervention. You are being informed about the current study at this particular time 
point and after the (possible) administration of 40 mg of methylprednisolone during 
CPR, because of the previously extremely emergent situation of your relative’s 
medical status (i.e., cardiac arrest). This is thoroughly consistent with the Declaration 
of Helsinki [2013 World Medical Association Declaration of Helsinki] and the current 
European Clinical Trials Regulation No 536/2014, and this specific Informed Consent 
Procedure has already been adopted.by prior trials (3, 4, 9-11).   
  
    This study includes adult patients with cardiac arrest who did not respond to three 
consecutive countershocks (according to indications), or asystole or pulseless 
electrical activity. Patients are being randomized to receive either 40 mg 
methylprednisolone (steroid group) or normal saline placebo (control group) during 
the first CPR cycle after study (cycle time duration: about 3 minutes). For the first 30 
minutes of CPR the vasopressor regimen will include epinephrine (1 mg); vasopressin 
(currently unavailable) may be added if (and when) it becomes available (3, 4, 12, 
13). 
    Postresuscitation shock is treated either with hydrocortisone [240 mg daily up to 7 
days followed by gradual taper over the next 2 days, and then, discontinuation (3, 4, 
14-16)], or placebo (control group). Specifically, at 4 hours after the return of 
spontaneous circulation (ROSC), patients with hemodynamic instability receive 100 
mL / day (average pump infusion rate ~ 4.2 mL / hour) of a normal saline solution 
either containing (steroid group) or not containing (control group) the aforementioned 
stress-dose of hydrocortisone (3, 4, 14-16). On days 8 and 9, the dose of 
hydrocortisone (steroid group) is decreased to 120 mg and 60 mg, respectively, and 
finally stopped on day 10 after randomization. 
    If ROSC is not achieved after 10 CPR cycles, corresponding to at least 5 doses of 
vasopressors, the CPR is continued (at the discretion of the leader of the resuscitation 
team) with 1 mg of epinephrine per 1-2 CPR cycles or approximately 1 mg of 
epinephrine every three to five minutes. 

3 
 
    The only modification compared to conventional CPR protocols (13) pertains to the 
use of methylprednisolone in the treatment of the cardiac arrest-associated adrenal 
insufficiency. In cases of postresuscitation shock, patients who received 
methylprednisolone according to the study’s randomization rule receive stress doses 
of hydrocortisone exactly as described in the IRB-approved study protocol. Please 
note that the aforementioned investigational interventions will be mandatorily 
canceled whenever an attending physician decides to prescribe stress-dose 
hydrocortisone for postresuscitation shock (3, 4, 14-16). 
 
WE REQUEST YOUR CONSENT FOR THE FOLLOWING CASES: 
 
1) USE OF STRESS-DOSE HYDROCORTISONE FOR CARDIAC ARREST-
ASSOCIATED CIRCULATORY SHOCK REQUIRING THE USE OF 
VASOPRESSORS AND FLUIDS TO MAINTAIN THE PERFUSION OF THE 
PATIENT’S VITAL ORGANS  (3, 4, 14-16) AND 
2) BLOOD SAMPLING [OVER THE FIRST 3 DAYS, AND DAY 7] FOR THE 
EVALUATION OF SYSTEMIC INFLAMMATORY RESPONSE THAT IS 
USUALLY OBSERVED AFTER SUCCESSFUL CPR. 
3] ASSESSMENT OF CEREBRAL BLOOD FLOW (BLOOD FLOW INDEX - 
BFI) WITH THE METHOD OF NEAR INFRARED SPECTROSCOPY (NIRS) 
IN CONJUNCTION WITH THE DYE INDOCYANINE GREEN (ICG) AT 4 
HOURS (WITH ALLOWANCE UP TO 12 HOURS) AND AT 72 HOURS 
AFTER ROSC [17]. THIS CONCERNS ONLY PATIENTS WITH NO 
HISTORY OF ANY ALLERGIC REACTION. 
4] ULTRASOUND MONITORING OF THE HEART. 
 
POTENTIAL RISKS FROM STUDY INTERVENTIONS AND THEIR 
PREVENTION  
Potential Hazards: These pertain to corticosteroid side effects, such as susceptibility to 
infections, digestive tract hemorrhage, healing disorders, hyperglycemia, muscle 
weakness and myopathy, and transient disorders of orientation, thinking, and 
behavior. The probability of any allergic reaction associated with a study intervention 
is considered as close to zero for patients without a history of allergy. Prevention-
Control: According to data from extensive analyses of prior studies (18-20), we do not 
expect an increased incidence of adverse events associated with the protocol; the 
administered dose of hydrocortisone is low, and the treatment is of limited duration 
(particularly in patients with increased healing requirements), while patients will be 
receiving appropriate antibiotic therapy, ulcer prophylaxis, and insulin. Patients will 
undergo continuous hemodynamic monitoring and will have (at minimum) daily 
determination of their hematocrit and hemoglobin concentration. The low dose of 
hydrocortisone is exclusively targeted at the very likely postresuscitation adrenal 
insufficiency and the associated severe hemodynamic instability (3, 4, 14-21). 
Patients with a diagnosis of transmural myocardial infarction or with a peptic ulcer 
will not be included in the study. The protocol will also be suspended in cases of 
poorly regulated blood glucose, or whenever attending physicians opine that an awake 
patient has developed steroid treatment-associated confusion / delirium. 
  
EXPECTED BENEFITS 
For the patient involved: rapid clinical improvement after resuscitation (3, 4). 
For Resuscitation Science: filling of important knowledge gaps and improvement of 

4 
 
clinical practice. 
 
INTERRUPTION OF PARTICIPATION IN THE STUDY 
Doctors (attending or principal investigator and attending physician) have the right 
(and obligation) to terminate your relative’s participation in this study without your 
consent, in case of any unexpected and potentially harmful (to your relative) event. 
 
The participation of your relative in this study is completely voluntary and you may 
discontinue it at any time. You will be timely informed about the time of study 
termination. You will be timely informed about the clinical course of your relative 
throughout the study’s follow-up period. 
 
COMPENSATION IN CASE OF INJURY RELATED WITH 
INVESTIGATIONAL INTERVENTIONS 
In case of a study protocol-related complication, the responsible researchers will 
inform you about the complication, the potential for complication reversal, and about 
your relative’s compensation. 
 
USE OF MEDICAL INFORMATION, PRIVACY AND AUTHORIZATION 
All data collected will be safe-guarded for the protection of medical confidentiality. 
Your relative will be referred to only by initials and a code number. The study 
information may be used in study reports or scientific presentations. 
Additional scientific information of the study (eg, values of variables resulting from 
measurements of the protocol) will not be recorded in the patient's file. This 
information will be entered electronically by researchers and will be protected by a 
password and antiviral computer programs. If desired, the researchers will provide 
you with a pertinent study information note. 
 
By signing the consent form you permit the aforementioned persons to take the above 
actions. There will be no publication or communication of the data that reveal your 
relative’s identity. The withdrawal of your relative from the study does not 
automatically cancel the use of his-her personal information. If you wish to cancel the 
use of your relative’s data you should provide a written request to the responsible 
investigators, who will then be obliged to respond (to your request). 
 
YOU UNDERSTAND THAT YOU HAVE THE RIGHT OF ACCESS TO THE 
MEDICAL RESEARCH RECORDS OF YOUR RELATIVE IN ACCORDANCE 
WITH THE LAW. 
 
 
 
 
 
 
 
 
 
 
 
 

5 
 
REFERENCES 
1.   Girotra S, Nallamothu BK, Spertus JA, et al. Trends in survival after in- hospital 
cardiac arrest N Engl J Med 2012; 367:1912-1920. 
2. Al-Alwan A, Ehlenbach WJ, Menon PR, Young MP, Stapleton RD. 
Cardiopulmonary resuscitation among mechanically ventilated patients. Intensive 
Care Med 2014; 40:556–563. 
3. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al. Vasopressin, epinephrine, 
and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009; 169:15-24. 
4. Mentzelopoulos SD, Malachias S, Chamos C, et al. Vasopressin, steroids, and 
epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a 
randomized clinical trial. JAMA 2013; 310:270-279. 
5. Neumar RW, Nolan JP, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, 
pathophysiology, treatment, and prognostication. A consensus statement from the 
International Liaison Committee on Resuscitation, (American Heart Association, 
Australian and New Zealand Council on Resuscitation, European Resuscitation 
Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, 
Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the 
American Heart Association Emergency Cardiovascular Care Committee; the Council 
on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, 
Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke 
Council. Circulation 2008; 118: 2452-2483. 
6. Chalkias A, Xanthos T. Pathophysiology and pathogenesis of post- resuscitation 
myocardial stunning. Heart Fail Rev. 2012; 17:117-128. 
7. Chalkias A, Xanthos T. Post-cardiac arrest brain injury: pathophysiology and 
treatment. J Neurol Sci. 2012; 315:1-8. 
8. [No authors listed] A randomized clinical trial of calcium entry blocker 
administration to comatose survivors of cardiac arrest. Design, methods, and patient 
characteristics. The Brain Resuscitation Clinical Trial II Study Group. Control Clin 
Trials. 1991;12:525-545. 
9. Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin and 
epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004; 
350: 105-113. 
10. Stiell IG, Hébert PC, Wells GA, et al. Vasopressin versus epinephrine for 
inhospital cardiac arrest: a randomized controlled trial. Lancet 2001;358:105-109. 

6 
 
11. Gueugniaud PY, David JS, Chanzy E, et al. Vasopressin and epinephrine vs. 
epinephrine alone in cardiopulmonary resuscitation. N Engl J Med 2008; 359(1):21-
30.  
12. Layek A, Maitra S, Pal S, Bhattacharjee S, Baidya DK. Efficacy of vasopressin 
during cardio-pulmonary resuscitation in adult patients: A meta- analysis. 
Resuscitation. 
2014 
pii: 
S0300-9572(14)00447-X. 
doi: 
10.1016/j.resuscitation.2014.03.303.  
13. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced 
Cardiovascular Life Support: 2015 American Heart Association Guidelines Update 
for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 
2015;132(18 Suppl 2):S444-64. 
14. Keh D, Boehnke T, Weber-Cartens S, et al. Immunologic and Hemodynamic 
Effects of “Low-Dose”Hydrocortisone in Septic Shock A Double-Blind, Randomized, 
Placebo-controlled, Crossover Study Am J Respir Crit Care Med 2003;167: 512-520. 
15. Adrie C, Adib-Conquy M, Laurent I, et al. Successful cardiopulmonary 
resuscitation after cardiac arrest as a "sepsis-like" syndrome. Circulation 
2002;106:562-568.   
16. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of 
hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 
2002;288:862-871. 
17. Boushel, R., Langberg, H., Olesen, J., Nowak, M., Simonsen, L., Bulow, J. & 
Kjaer, M. Regional blood flow during exercise in humans measured by near – infrared 
spectroscopy and indocyanine green. J Appl Physiol 2000;89:1868-1878. 
18. Moran JL, Graham PL, Rockliff S, Bersten AD. Updating the evidence for the 
role of corticosteroids in severe sepsis and septic shock: a Bayesian meta- analytic 
perspective. Crit Care. 2010;14:R134. 
19. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of 
severe sepsis and septic shock in adults: a systematic review. JAMA 2009 
10;301:2362-2375. 
20. Minneci PC, Deans KJ, Eichacker PQ, Natanson C. The effects of steroids during 
sepsis depend on dose and severity of illness: an updated meta-analysis. Clin 
Microbiol Infect 2009;15:308-318. 
21. Yang S, Zhang L. Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol. 
2004;2:1-12.