Low-dose Dobutamine Infusion and Single-dose Tocilizumab in Acute Myocardial Infarction Patients With High Risk of Cardiogenic Shock Development - a 2x2 Multifactorial, Double-blinded, Randomized, Placebo Controlled Trial
Phase: PHASE2
Conditions: Acute Myocardial Infarction, Cardiogenic Shock
Sponsor: Rigshospitalet, Denmark

Protocol version 2.7.6 
1
TRIAL PROTOCOL 
LOW-DOSE DOBUTAMINE INFUSION AND SINGLE-DOSE TOCILIZUMAB IN ACUTE 
MYOCARDIAL INFARCTION PATIENTS WITH HIGH RISK OF CARDIOGENIC SHOCK 
DEVELOPMENT 
 
– A 2X2 MULTIFACTORIAL, DOUBLE-BLINDED, RANDOMIZED,  
PLACEBO-CONTROLLED TRIAL 
 
Acronym: DOBERMANN  
 
 
 
 
 
 
 
 
Version: 2.7.6 
Date: 9th of July 2021   
 
 
 
 
 
 
 
 
 
Revision 01/08/2022 
Sponsors protocol code no.: RH-CARD-Pharma001  
 
EudraCT: 2021-002028-19 
Health Research Ethics: H-21045751 
 
 
 
 
 
ClinicalTrials: NCT05350592 
 
Department of Cardiology 
Rigshospitalet, University Hospital of Copenhagen 
Blegdamsvej 9, 2100 Copenhagen OE, Denmark 
 
 
 
 
Principal Investigator: 
Helle Søholm, MD, PhD 
Dept. of Cardiology, Rigshospitalet 
helle.soholm@gmail.com,  
tel.: +45 28770229 
Registration ID: 08H8S  
Co-Primary Investigator: 
Martin Frydland, MD, PhD 
Dept. of Cardiology, Rigshospitalet 
martin.steen.frydland.01@regionh.dk, 
tel.: +45 29923273 
Registration ID: 0987M 
 
Sponsor: 
Christian Hassager, professor, MD, DMSc 
Dept. of Cardiology, Rigshospitalet 
christian.hassager@regionh.dk 
tel.: +45 35450572 
Registration ID: 00CFQ 
GCP Monitor Representative: 
Henriette Døssing 
The Danish GCP Units 
Nordre Fasanvej 57 
Skadestuevej 1, parterre 
2000 Frederiksberg 
henriette.doessing@regionh.dk 
tel.: +45 38635623 
 
 
 

Protocol version 2.7.6 
2
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................. 2 
STATEMENT .................................................................................................................................. 4 
AIM ................................................................................................................................................. 4 
BACKGROUND .............................................................................................................................. 6 
METHODS ...................................................................................................................................... 8 
SAMPLE SIZE CALCULATION ..................................................................................................... 10 
RECRUITING ............................................................................................................................... 10 
INCLUSION CRITERIA ......................................................................................................... 12 
EXCLUSION CRITERIA ........................................................................................................ 12 
OUTCOMES ................................................................................................................................. 14 
PRIMARY OUTCOME .............................................................................................................. 14 
SECONDARY OUTCOMES ...................................................................................................... 14 
LONG-TERM OUTCOMES ................................................................................................... 15 
QUALITY OF LIFE, MENTAL HEALTH AND PATIENT-RELATED CLINICAL 
DEMOGRAPHICS ................................................................................................................. 15 
QUALITY OF LIFE AND MENTAL AND COGNITIVE HEALTH ............................................. 15 
The 5-level EuroQol-5 (EQ-5D-5L) ........................................................................................ 16 
CLINICAL CHARACTERISTICS............................................................................................ 17 
SAFETY ........................................................................................................................................ 19 
TREATMENT PROCEDURES AND IMP BLINDING ................................................................. 20 
INVESTIGATIONAL PRODUCT DOSAGE ............................................................................... 22 
TREATMENT DEESCALATION / TERMINATION..................................................................... 22 
ADVERSE EVENT REPORTING .............................................................................................. 23 
Adverse Events (AE) ............................................................................................................. 23 

Protocol version 2.7.6 
3
Serious Adverse Events (SAE) .............................................................................................. 23 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ............................................ 24 
Severity of Adverse Events ................................................................................................... 24 
Relationship of AE to Trial Intervention.................................................................................. 24 
Reference Document ............................................................................................................ 25 
Procedures for Un-Blinding the Treatment Allocation ............................................................ 25 
SAFETY MONITORING ............................................................................................................ 26 
INFORMED CONSENT ............................................................................................................ 26 
ETHICAL CONSIDERATIONS ...................................................................................................... 28 
DATA HANDLING AND RECORD KEEPING ............................................................................... 29 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION .................................................... 29 
QUALITY CONTROL AND ASSURANCE ..................................................................................... 29 
FINANCE ...................................................................................................................................... 31 
TASKS AND RESPONSIBILITIES ................................................................................................ 32 
REFERENCES ............................................................................................................................. 33 
 

Protocol version 2.7.6 
4
LOW-DOSE DOBUTAMINE INFUSION AND SINGLE-DOSE TOCILIZUMAB IN ACUTE 
MYOCARDIAL INFARCTION PATIENTS WITH HIGH RISK OF CARDIOGENIC SHOCK 
DEVELOPMENT 
– A 2X2 MULTIFACTORIAL, DOUBLE-BLINDED, RANDOMIZED, PLACEBO-CONTROLLED TRIAL 
 
DANISH TITLE 
LAV-DOSIS DOBUTAMIN INFUSION OG EN ENKELT DOSIS TOCILIZUMAB TIL PATIENTER 
MED AKUT MYOKARDIEINFARKT OG HØJ RISIKO FOR UDVIKLING AF KARDIOGENT SHOCK 
– ET 2X2 MUTLIFAKTORIELT, DOBBELT-BLINDET, RANDOMISERET, PLACEBO-KONTROLLERET STUDIE. 
 
STATEMENT 
This protocol including amendments, as well as written information and consent forms will 
be submitted to the regional ethics committee for review and approval prior to initiation of 
the trial. The trial will be executed in accordance with this protocol and its amendments, 
compliant to regulatory demands and applicable law. 
 
AIM 
In the present study, we aim to investigate the effects of dobutamine infusion and/or a single 
intravenous (IV) dose of the IL-6 antagonist Tocilizumab administered after percutaneous 
coronary intervention (PCI) to patients with acute myocardial infarction (AMI) presenting < 
24 hours from onset of chest pain and an intermediate to high risk of cardiogenic shock (CS) 
by assessment with the ORBI risk score (≥10 – not in overt shock at hospital admission), 
Table 1. Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NTproBNP) as 
a proxy for development of cardiogenic shock (CS) and hemodynamic instability will be sam-
pled for primary endpoint analysis. Effects on clinical parameters, mortality, morbidity as well 

Protocol version 2.7.6 
5
as specific indicators of inflammation, cardiac function, and infarct size will secondarily be 
assessed noninvasively. 
The rationale behind the current study is that inflammatory and neurohormonal re-
sponses are associated with subclinical hemodynamic instability in patients with AMI with 
high risk of CS have worse outcomes. The potentially unstable condition may be targeted 
pharmacologically as an add-on to existing therapy. This is investigated in patients at ele-
vated risk of CS by sampling biomarkers reflecting the inflammatory and neurohormonal 
responses, as well as determining effects on patient outcomes and infarct size. 
 
TABLE 1. VARIABLES COMPRISING THE ORBI RISK SCORE 
 
First medical contact is defined as time from first ECG confirming the 
AMI-diagnosis to first balloon (PCI).  
Abbreviations: TIA (transient ischemic attack), PCI (percutaneous 
coronary intervention), sBP (systolic blood pressure), PP (pulse 
Variable
Points
Age>70 years old
2
Previous stroke/TIA
2
Presentation as cardiac arrest
3
Anterior myocardial infarction
1
First medical contact-to-PCI>90 min
2
Killip class II on admission
2
Killip class III on admission
6
Heart rate >90/min on admission
3
sBP <125 mmHg and PP <45 mmHg on admission
4
Glycemia >10 mmol/L on admission
3
Culprit lesion of the left main 
5
Post-PCI TIMI flow <3
5

Protocol version 2.7.6 
6
pressure), TIMI (thrombolysis in myocardial infarction), ECG (elec-
trocardiogram), AMI (acute myocardial infarction).  
 
 
BACKGROUND 
Despite an overall reduction in mortality in patients with ST-elevation myocardial infarction 
(STEMI), patients developing CS have a high short-term mortality of up to 50%.1-3 A sys-
temic inflammatory response is often seen in patients with CS thereby complicating the in-
tensive care (ICU) treatment.1 
Approximately 1/3 of STEMI-patients developing CS are not in overt shock at time of 
hospital admission, but will  develop hemodynamical instability within the following hours to 
days.2 3 Patients at risk for CS development may be clinically stable or relative hypotensive 
or tachycardic but with e.g. normal lactate (Society for Cardiovascular Angiography and In-
terventions (SCAI) classification A and B).4 Irrespective of when CS occurs, mortality has 
been shown to remain high.2  
NTproBNP is a biomarker reflecting neurohormonal activation released from the myo-
cardium in response to cardiomyocyte stretch5 and myocardial ischemia.6-8 It is inversely 
correlated with hemodynamic measurements (including cardiac output)9 and associated 
with mortality in patients with STEMI.10 Previous studies suggest that the plasma concen-
tration of biomarkers reflecting neurohormonal activation is higher in patients developing CS 
after hospitalization compared to hemodynamically stable STEMI-patients.11-13  
Dobutamine is a sympathomimetic drug with an agonistic effect primarily on the beta1-
receptor and some beta2- and minimal alpha-receptor activation. In patients with myocardial 
infarction dobutamine induces significant positive inotropic- and dose-dependent 

Protocol version 2.7.6 
7
chronotropic effects and decreases afterload by peripheral vasodilatation. The combination 
of the inotropic effect and the afterload reduction significantly increases cardiac output.14  
In ischemic heart disease (IHD), a range of studies from the pre-primary PCI era to mod-
ern day treatment suggest that modulation of the inflammatory response may prove benefi-
cial – both in the acute and chronic phase.15-20 Interestingly, the humanized anti-interleukin 
(IL) 6 anti-body Tocilizumab targeting the IL-6 receptor (IL6RA) has recently been shown to 
reduce troponin leakage and increase salvage index suggesting reducing final infarct size 
when administered to patients with acute myocardial infarction (MI).21 22 Furthermore, a re-
cently published trial showed reduced troponin / creatin-kinase-MB (CKMB) levels in pa-
tients with out-of-hospital cardiac arrest (OHCA) of cardiac etiology indicating a reduction in 
infarct size and a temporal reduction in NTproBNP in the Tocilizumab group compared to 
the placebo group.23 
A recent study has established and validated a new score for prediction of the develop-
ment of in-hospital CS - the Observatoire Régional Breton sur l’Infarctus (ORBI) risk score 
(Table 1) in two French STEMI-cohorts.24 The risk score showed a high predictive value for 
development of in-hospital CS with an area under the receiver operating characteristics 
(AUCROC) curve of 0.84 (95% confidence interval (CI) = 0.81-0.87) vs. 0.83 (0.80-0.87) in 
the derivation vs. the validation cohort, respectively.24 The ORBI Risk Score was validated 
in a Danish cohort of 2,247 patients with suspected STEMI in two tertiary heart centers and 
found a comparable predictive value with an AUCROC of 0.84 (0.78 – 0.89).2 11 25 
 
 
 

Protocol version 2.7.6 
8
METHODS 
The planned study is an investigator-initiated, randomized, double blinded clinical trial.  
Consecutive patients at Copenhagen University Hospital, Rigshospitalet admitted with AMI 
< 24 hours from chest pain will be screened.  
Patients eligible for trial inclusion will be randomized 2:2 to receive a continuous IV do-
butamine infusion of 5 mcg/kg/minute versus placebo for 24 hours and to receive a single 
IV dose of tocilizumab (1-hour infusion) versus placebo administered after PCI.21 22 
Treatment with the investigational drug will be initiated as soon as possible but no later than 
2 hours after transfer to the coronary care unit (CCU) and after informed consent. All in-
cluded patients will follow usual treatment according to current guidelines.26  
 
The biomarker NTproBNP will be measured in blood samples drawn upon hospital ad-
mission in patients with ORBI risk score ≥10, and after 12, 24, 36 and 48 hours from admis-
sion (Figure 1). After treatment termination, 2D-echocardiography will be performed acutely 
and within 2 days to evaluate left ventricular ejection fraction (LVEF), and cardiac magnetic 
resonance imaging (cMRi) with late gadolinium enhancement technique prior to hospital 
discharge as close to 48 hours post-MI. Echocardiography with sulfurhexafluorid and cMRi 
with late gadolinium will be performed 3 months after discharge to calculate area at risk and 
salvage index after AMI and to compare the two modalities capability to visualize the infarc-
tions damage on the heart.  
Blood samples (40 mL) will be obtained and stored in a biobank for subsequent meas-
urement of biomarkers reflecting inflammation, neurohormonal activation, neuronal injury, 
connective tissue function and other relevant pathophysiological processes. These bi-
omarkers will solely have research interest and no clinical implications. Furthermore, no 
genetic biomarkers and markers associated with malignancy development will be measured. 

Protocol version 2.7.6 
9
Any leftover blood from the research biobank will be transferred to a biobank for future re-
search and stored for up to 10 years solely for research purposes. After this period blood 
samples will be destroyed. 
 
FIGURE 1: Stratification and randomization 
 
Abbreviations: AMI (Acute Myocardial Infarction), PCI (percutaneous coronary intervention), ORBI 
(Observatoire Régional Breton sur l’Infarctus), NTproBNP (N-terminal proB-type natriuretic peptide), 
HeartQoL (European Quality of life survey), EQ-5D-5L (The 5-level EuroQol-5, Health-Related Qual-
ity of Life), HADS (Hospital Anxiety and Depression Scale), MoCA (Montreal Cognitive Assessment).  
 
A research fellow will validate and register data on all screened patients in a REDCap 
database including ORBI risk score, biomarkers, angiographic findings, and PCI (when per-
formed), chest pain after the procedure and ST-segment elevation resolution, age, gender, 
demography, clinical characteristics, and events during index admission will be recorded. 

Protocol version 2.7.6 
10 
Data will be coupled to the national patient registry, which holds information on all Danish 
citizens with regards to ICD-10 codes from all hospital admission and outcome measures, 
and the Danish National Database of Reimbursed Prescriptions.  
 
SAMPLE SIZE CALCULATION 
Based on recent data from our institution (yet unpublished), atrial natriuretic peptide (ANP) 
levels measured 12 hours after admission were assumed be distributed in a log-normal 
fashion with a variation coefficient of 0.59. Assuming a minimal clinically relevant difference 
of 30% between treatment strata, the trial would achieve a power of 0.86 at a significance 
level of 0.05 if 88 patients were included. To correct for dropouts and missing data, we chose 
to include 100 patients in the trial. Assuming that ANP and BNP/NTproBNP have similar 
distributions, we expect a reduction in NTproBNP from 1338 ng/L to 937 ng/L in the inter-
vention group based on previous data.27 
 
RECRUITING 
When the AMI-patient is treated acutely in the catheterization laboratory (cath. lab.) the staff 
will evaluate the ORBI Risk Score in all patients for initial risk stratification. If the patient is 
eligible for inclusion in the study with an ORBI risk score ≥10 and not fulfilling any exclusion 
criteria the treating physician will ask the patient for permission to notify the research fellow 
on call with the purpose of obtaining informed consent for randomization in the study. At the 
CCU written study material is handed to the patient. The patient will be offered to involve an 
impartial witness when receiving information regarding the study, as in the case when 
he/she is unable to read. Verbal information will be given by a delegated sub-investigator 
whom is appropriately qualified, trained and GCP certified. Any delegated tasks related to 

Protocol version 2.7.6 
11 
informed consent and inclusion must be performed under the responsibility and supervision 
of a medical doctor-investigator and appropriately documented. The patient will, to the best 
of the department’s ability, be placed in a quiet, uninterrupted area in order to preserve 
privacy and a freely given consent. The patient will be given a minimum of 30 minutes to 
consider the material, with the opportunity to ask questions before and during this time. The 
time frame for consent has been determined based on the pathophysiology for which inter-
vention is sought in this trial, as a longer delay to treatment implies a risk of patients entering 
the condition of cardiogenic shock before the treatment is initiated. 
All registrations concerning screening and informed consent will be stored in a RedCap da-
tabase.  
 
RANDOMIZATION 
Randomization will be performed utilizing a module integrated with the eCRF in accordance 
with the institution Standard Operating Procedure (SOP-RED.007.01- Randomization i 
REDCap). It follows that the sponsor nominates an entity to perform the technical task of 
setting up and generating an allocation table in accordance with the protocol, as described 
in the referenced SOP section concerning blinded allocation. The investigator or assigned 
co-investigator will enter the eCRF module patient identification data and parameters deter-
mining in- and exclusion and stratification by STEMI/NSTEMI. The computerized module 
will assign the treatment arms corresponding to a label “A” or “B” and “C” or “D”. 

Protocol version 2.7.6 
12 
PARTICIPANTS 
INCLUSION CRITERIA 
- 
Acute myocardial infarction 28  
- 
Revascularization with PCI 
- 
Presentation within 24 hours of chest pain 
- 
ORBI risk score ≥ 1024 
- 
Age ≥ 18 
 
EXCLUSION CRITERIA 
- 
Unwilling to give informed consent to study participation 
- 
Unable to give consent due to language barrier  
- 
Comatose after cardiac arrest 
- 
Cardiogenic shock with systolic blood pressure < 100 mmHg for more than 30 minutes 
or need for vasopressor to maintain blood pressure and arterial lactate > 2,5 (2,0) mmol/L 
developed before leaving the cath. lab. 
- 
Other major clinical non-coronary condition (stroke, sepsis etc.), which can explain a high 
ORBI risk score 
- 
Referral for acute coronary artery bypass grafting (CABG) (< 24 hours) after the CAG, 
whereas subacute (>24 hours will be included)  
- 
Contraindications against dobutamine infusion (sustained ventricular tachycardia prior to 
admission or noted in the cath.lab., known pheochromocytoma, idiopathic hypertrophic 
subaortic stenosis) 
- 
Tocilizumab allergy 
- 
Pregnant- or breastfeeding women 

Protocol version 2.7.6 
13 
- 
Known liver disease/dysfunction 
- 
Ongoing uncontrollable infection 
- 
Immune deficiency/treatment with immunosuppressants 
- 
Known, uncontrolled gastrointestinal (GI) disease predisposing to GI perforation 
 
In patients with coronary biomarkers without dynamic elevation (‘rise-and-fall’) reflecting 
other condition than AMI, treatment with the assigned study drug(s) will be completed and 
the patient will be included in sensitivity analyses but will not have cMRi performed. Inclusion 
in other studies/trials will not automatically lead to exclusion.  
 
 

Protocol version 2.7.6 
14 
OUTCOMES 
PRIMARY OUTCOME 
The primary outcome peak proBNP will be log-transformed and analyzed using baseline 
correction (measurement before infusion) with the analyses of covariance (ANCOVA) mod-
els with adjustment for ORBI risk score, and the effect of the other intervention. Analyses 
for the two interventions (dobutamine and Tocilizumab) will be performed separately. For 
the analysis, we will include the dobutamine-Tocilizumab interaction in order to analyze co-
linearity in possible treatment effects. Logarithmic transformation will be applied to approxi-
mate normal distribution as appropriate. These models will also be applied for the secondary 
endpoints of biomarkers and imaging parameters.  
 
SECONDARY OUTCOMES 
- 
Development of in-hospital CS and/or in-hospital cardiac arrest  
- 
Infarct size and salvage index measured by cMRi  
- 
Long-term all-cause mortality 
- 
Biomarkers reflecting neurohormonal activation, endothelial function/damage, inflamma-
tion (pro- and anti-inflammatory processes – including IL-6 and C-reactive peptide 
(CRP)), connective tissue damage, organ dysfunction, and other relevant processes 
- 
PCI operator’s post-procedure clinical assessment of the patient (survives to discharge 
‘yes/no’) 
- 
Development of non-cardiac arrest arrythmia (sustained ventricular tachycardia, atrial 
fibrillation with a frequency above 120 for more than 30 minutes) during index admission 
(safety) 

Protocol version 2.7.6 
15 
- 
2D echocardiographic measurements of hemodynamics (VTI) and left ventricular func-
tion including strain measurements according to protocol 
- 
Re-admission (all cause and cardiovascular) during the first year after index hospitaliza-
tion  
- 
Re-admission with heart failure and re-infarction 
- 
SOFA score29 30 (PaO2, FiO2, on medical ventilation, Platelets, GCS, Bilirubin, mean 
arterial pressure OR administration of vasoactive agents required, Creatinine, Is this a 
COVID-19 patient?) 
- 
Quality of Life and mental and cognitive health at baseline and after three months  
 
LONG-TERM OUTCOMES 
If a significant reduction in the primary endpoints is observed, we will continue inclusion to 
assess mortality in more centers aiming at a national level. 
 
QUALITY OF LIFE, MENTAL HEALTH AND PATIENT-RELATED CLINICAL DE-
MOGRAPHICS 
 
QUALITY OF LIFE AND MENTAL AND COGNITIVE HEALTH 
 
European Quality of life survey (HeartQoL) 
To measure disease-specific health-related quality of life the HeartQoL is chosen. The de-
velopment of the instrument was supported by the European Society of Cardiology and the 
European Association of Preventive Cardiology.31 The 14 items patient reported outcome 
has been cross-culturally translated into Danish and showed acceptable psychometric 

Protocol version 2.7.6 
16 
properties in cardiac patients following heart valve surgery, ischemic heart disease and re-
cipients of implantable cardioverter defibrillator.32-34 Moreover, the outcome measure have 
shown a significant linear association between all-cause mortality and both lower global 
HRQoL (HR = 1.67, 95% CI: 1.26-2.23) and physical HRQoL scores (HR=1.71, 1.33-2.21) 
and between readmission and both lower HRQoL global (HR=1.73, 1.41-2.12) and physical 
HRQoL scores (HR = 1.63, 1.35-1.96) in patients with ischemic heart disease.33 
 
The 5-level EuroQol-5 (EQ-5D-5L) 
 The EQ-5D-5L is a generic Health-Related Quality of Life (HRQoL)  measurement tool de-
veloped as a generic instrument for HRQoL.35 EQ-5D-5L consists of five dimensions (mo-
bility, self-care, usual activities, pain/discomfort and anxiety/depression), each of which has 
five levels (no problems, slight problems, moderate problems, severe problems or unable 
to), and a visual analogue scale (EQ VAS). The EQ VAS records the patient’s self-rated 
health on a visual analogue scale (0-100), where the endpoints are labelled ‘The best health 
you can imagine’ and ‘The worst health you can imagine’. The EQ-5D-5L is translated to 
Danish but no psychometric evaluation of the Danish version has been published. However, 
several studies have evaluated the English version and found acceptable psychometric 
properties for convergent validity and test-retest reliability. An overall Cronbach's α of 0.73 
has been found in a population of coronary heart disease patients.36 
 
Anxiety and Depression Scale (HADS) 
The Hospital Anxiety and Depression Scale (HADS), a 14-item questionnaire is designed to 
detect the presence of mild degrees of mood disorders in non-psychiatric hospital outpa-
tients.37 The HADS consists of 2 sub-scales: depression and anxiety. Higher scores 

Protocol version 2.7.6 
17 
represent more emotional problems. The scale has a concurrent validity of 0.73 compared 
with the Beck Depression Inventory and alpha is 0.83 (anxiety subscale) and 0.82 (depres-
sion subscale). The HADS is a valid and internally consistent measure, with a mean 
Cronbach's α of 0.83 and 0.82 for the HADS-A and HADS-D, respectively. Scores of 0–7 for 
either subscale are regarded as normal and scores of 8–10 suggest the presence of a mood 
disorder.38 Scores of 11 and above indicate the probable presence of a mood disorder.39 
Questionnaires will be administered at baseline and after three months. The questionnaires 
in the trial will be completed electronically in the questionnaire system Redcap with 'single 
user', which meets the data legislation for logging. If patients do not complete the question-
naire electronically, the material can be administered in paper form and independent trial 
personnel then enters the responses into the database. 
 
CLINICAL CHARACTERISTICS  
 
Cognitive status 
 
Montreal Cognitive Assessment (MoCA) 
 To evaluate the patient’s cognitive status the Montreal Cognitive Assessment tool (MoCA) 
will be used.40 The MoCA is a one-page 30-point brief stand-alone cognitive six-dimensional 
screening test administered in approximately 10 minutes. The MoCA evaluates six cognitive 
domains for detecting even mild cognitive impairment: Attention, visuospatial, construction, 
executive functioning, memory, language and orientation. MoCA is validated in a Danish 
cohort age above 65. The maximum score is 30 points. A summary score of ≥26-30 is con-
sidered normal. 

Protocol version 2.7.6 
18 
 
Frailty 
Frailty is measured by the Clinical Frailty Scale developed by Rockwood and colleges.41 It 
is a cumulative deficit model consisting of a 9-point scale where patients’ frailty is measured 
based on clinical judgement – clinical signs, symptoms, diseases and disabilities. A frailty 
index (FI) score is calculated as a proportion of the number of deficits present. Each 1-
category increment of the scale significantly increased the risk of death. It is recommended 
for use in AMI populations.42 
 
The Clinical Frailty Scale is supplemented by the Study of Osteoporotic Fractures of Frailty 
(SOF index).43 It comprises three items and assesses weight loss, inability to rise from a 
chair five times without using the arms and self-reported poor energy. Frailty defined by the 
SOF index is identified by the presence of 2 or more of the following 3 components: (1) 
weight loss (irrespective of intent to lose weight) of 5% or more between (2) the subject's 
inability to rise from a chair 5 times without using her arms; and (3) reduced energy level, 
as identified by an answer of “no” to the question “Do you feel full of energy?”. Patients with 
none of these components are considered to be robust, and those having 1 component are 
considered to be in an intermediate of pre-frail stage.  
 
Grip strength 
Is measured by the SAEHAN Digital Hand Dynamometer. The SAEHAN Digital Hand Dyna-
mometer is a Highly accurate grip strength measurement. It measures from 0-200 pounds 
(lbs.) or from 0-90 kilograms (kg).  
 
 

Protocol version 2.7.6 
19 
SAFETY 
Patients included in the present study are as indicated by the ORBI risk score high-risk AMI 
patients, but not in overt shock when included. Therapeutic agents aiming to reduce the risk 
of cardiogenic shock and thereby a high risk of death are needed, but at the same time 
without compromising the safety of the patient. The present study investigates the effect of 
anti-inflammatory treatment prior to PCI with a single IV dose of 280 mg Tocilizumab vs 
placebo and the vasoactive and inotropic agent dobutamine vs. placebo for hemodynamic 
support following PCI. 
Tocilizumab is a humanized monoclonal antibody targeting the IL-6 receptor. It is ap-
proved for treatment of rheumatoid arthritis but has shown promising results when adminis-
tered to patients with AMI.21 22 In addition, a previous small trial on Tocilizumab vs. placebo 
administered to AMI-patients revealed no safety concerns.44 Furthermore, in rheumatoid ar-
thritis patients, Tocilizumab was evaluated in a systematic review of 19 studies (11 RCTs) 
and appeared safe compared to other treatments with regards to risk of AMI, stroke and 
major adverse cardiac events (MACE)45, and Tocilizumab was not seen causing QTc-pro-
longation.46 A recent randomized pilot trial from our group in 80 comatose patients resusci-
tated from OHCA with Tocilizumab vs. placebo for modulation of the systemic inflammatory 
response (SIRS) showed no increased occurrence of adverse- or serious adverse events.23 
47 Especially no increased frequency of infections using the same dosage of Tocilizumab as 
planned for the present study were found.23 Tocilizumab has also been tested as a potential 
treatment for the ongoing Covid19-pandemic, and a review of its efficacy and safety likewise 
found no increased risk of infections and adverse events.48 
 
With regards to hemodynamic support in high-risk AMI patients dobutamine was chosen 
for its ionotropic properties with increased cardiac contractility and reduction of systemic 

Protocol version 2.7.6 
20 
vascular resistance and thereby unloading of the left ventricle.49 Concerns regarding the use 
of classic inotropic agents stimulating the beta-receptor–cAMP pathway for patients not ex-
periencing acute heart failure with hypoperfusion have been raised, due to a possible in-
creased risk of arrhythmia, progression of myocardial ischemia and potentially increased 
mortality.50 Dobutamine is contraindicated in patients with hypertrophic obstructive cardio-
myopathy and may be less effective in patients receiving betablockers, which we will inves-
tigate as a supplementary interaction analysis. The adverse effects of dobutamine are dose-
related, facilitating atrioventricular conduction, with possible rapid ventricular response in 
patients developing atrial fibrillation.  
Clinical parameters including blood pressure will be measured every hour during the first 
three hours and if stable every three hours during the first 24 hours of admission or accord-
ing to Early Warning Score (EWS) algorithm. Patients will be monitored by telemetry during 
admission and during dobutamine infusion additional continuous cardiac monitoring will be 
performed. From this device, mean, maximum and minimum heart rate frequency will be 
recorded. This will give us the opportunity for registration of detailed ectopic activity including 
supraventricular and ventricular ectopic beats, runs and sustained arrhythmias.  
 
TREATMENT PROCEDURES AND IMP BLINDING 
The IL-6 receptor antagonist tocilizumab and placebo will both be administered intrave-
nously over a period of one hour starting as soon as possible after admission. Prepared 
study drug must be kept refrigerated until used and must be administered within 8 hours of 
production. The study drug administration schedule will be identical for subjects receiving 
tocilizumab and placebo. Qualified healthcare personnel will perform all infusions of the 
study drug, and subject self-administration will not occur. 

Protocol version 2.7.6 
21 
The site will establish a formal, documented collaboration with a near-by ward with 24/7 
service for preparation of the study drug. The attending nurse at the preparation ward will 
be notified to prepare a set of study drug and placebo. Identification, mixing, dilution and 
labeling of the investigational products will be cross-checked within the collaborating ward 
according to an agreed, documented, two-person workflow under the sponsor’s responsibil-
ity to assure that safety, registration and blinding criteria are met, and unintentional unblind-
ing is avoided. 
The prepared drug kits will be delivered to the investigation ward with the study labels as 
sole means of reference. 
Personnel will be specifically trained prior to and have access to written, printed instructions 
concerning all details regarding preparation, administration, and monitoring procedures 
available with the kits of study drugs. All personnel will be qualified and trained in accord-
ance with GCP, and the sponsor will maintain documentation pertaining to everyone’s qual-
ifications and consent to registration. IMP storage, handling and any discarding will be sub-
ject to mandatory record keeping in agreement with the institution GCP unit’s standard op-
erating procedure guidelines. 
Record keeping will include timed interval temperature measurements of storage as well as 
inventory management with the purpose of obtaining full traceability of batch identification 
and amount dispensed. Inventory will also be kept at a center-level, comprising name, 
strength and packaging size of the medication, the amount received, date of receival, batch 
number, date of expiry, amount available on location, date and initials of the record-keeping 
individual. 
 

Protocol version 2.7.6 
22 
INVESTIGATIONAL PRODUCT DOSAGE  
The single dose Tocilizumab (RoActemra®, Roche) of 280 mg will be added isotonic (9%) 
normal saline to a total volume of 100 ml. This treatment regimen is similar to the regimen 
used for rheumatoid arthritis and recently used in a clinical trial in STEMI patients.22 The 
placebo kit will contain 100 mL of isotonic (0.9% normal saline). Tocilizumab infusion is 
administered within one hour. The infusion can be administered in a central or peripheral 
intravenous line. The study drug label (‘A’ or ‘B’) is documented along with time of study 
drug infusion start, time of study drug infusion completion.  
Standard dosage of Dobutamine is initially 2-3 yg/kg/min, which in a daily clinical setting 
can be increased up to 20 yg/kg/min. Due to the possible adverse effects of tachyarrhythmia, 
a low maintenance dose in the current study of 5 yg/kg/min of Dobutamine is chosen. The 
study drug label (‘C’ or ‘D’) is documented along with time of study drug infusion start, time 
of study drug infusion completion.  
The manufacturing nurse will use RedCap confirming his/her identity as investigational 
drug manufacturer and will through the website obtain information as to whether kit ‘A’ or ‘B’ 
will contain Tocilizumab and / or saline and ‘C’ or ‘D’ will contain Dobutamine and/or saline. 
 
TREATMENT DEESCALATION / TERMINATION 
In case of persistent supraventricular tachy-arrhythmia > 130 BPM for > 30 minutes Dobu-
tamine infusion will be diminished to 2.5 yg/kg/min. Hereafter in case of further tachy-ar-
rhythmia dobutamine will be discontinued at the discretion of the treating physician.  
The dose of the Tocilizumab will be fixed. If clinical signs of an allergic reaction or other 
severe side effects are suspected, the infusion will be terminated immediately. No dosage 

Protocol version 2.7.6 
23 
adjustments are intended. A standard operating procedures (SOP) manual will be made 
available to all clinicians involved in the study. 
 
ADVERSE EVENT REPORTING 
Adverse events will be recorded daily for the first 7 days in a pre-specified form in the eCRF. 
Adverse events occurring after day 7 will be evaluated at 30- and 180-day follow-up. At each 
assessment of all adverse events, serious adverse events (SAE) and suspected unexpected 
serious adverse reactions (SUSAR) must be recorded by the investigator and evaluated. 
Each SAE and SUSAR requires the sponsor to fill in the AE form, including the following 
variables: description of event, onset and end of event, severity, relation to the intervention, 
action taken, and outcome. Any adverse events occurring during the study will be treated 
according to established standards, and the subject will be followed until the event has dis-
appeared or stabilized. On a yearly basis, a safety rapport containing information on serious 
adverse events/reactions will be submitted to the Danish Health and Medicines Authority. 
 
Adverse Events (AE) 
Events are defined as any untoward medical occurrence in a patient administered a medic-
inal product and which does not necessarily have a causal relationship with this treatment. 
Adverse events will be reported daily, within 24 hours from awareness, through the eCRF. 
 
Serious Adverse Events (SAE) 
For each AE reporting, there will be an additional question, as to whether there has been a 
serious adverse event. A SAE is an AE that results in death, is life threatening, requires 
hospitalization or prolongation of hospitalization, or results in significant disability, including 

Protocol version 2.7.6 
24 
congenital anomaly or birth defect. Any SAE must be reported to the sponsor within 24 hours 
of awareness.  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
A SUSAR is an unexpected and serious reaction to the investigational drug. The investigator 
assesses potential causality between investigational product, and whether the reaction is 
suspected will be assessed by the sponsor. The Summary of Product Characteristics for 
RoActemra and Dobutrex will be used for this assessment. The sponsor will be responsible 
to report all life-threatening of lethal SUSARS to the Danish Health and Medicines Authority 
as soon as possible and no later than 7 days after being aware of such an event. Non-life 
threatening SUSARs will be reported as soon as possible and no later than 15 days after 
the event.  
 
Severity of Adverse Events 
For each AE, severity will be graded accordingly: 
- 
Mild: Transient symptoms, no interference with subject’s daily activities 
- 
Moderate: Marked symptoms, moderate interference with subject’s daily activities 
- 
Severe: Considerable interference with subject’s daily activities 
 
Relationship of AE to Trial Intervention 
For each AE, relationship to trial intervention will be rated accordingly: 
- 
Probable: Good reason and sufficient documentation to assume a causal relationship 
- 
Possible: A causal relationship is likely and cannot be excluded 
- 
Unlikely: The event is most likely related to an etiology other than the intervention 

Protocol version 2.7.6 
25 
- 
Unknown: Causality is not assessable  
 
For the conditions bleeding, infection and arrythmia, the following definitions will apply in 
reporting:  
Major bleeding: Uncontrolled bleeding (>1 unit of blood/10kg/hour), or any bleeding causing 
fatality or critical organ affection, (e.g. intracranial, intraocular, intraarticular, pericardial), or 
any other bleeding requiring > 2 units of transfused blood or volume replacement. 
Infection: Upper airway infection, pneumonia, sepsis, pyelonephritis, diverticulitis. 
Arrythmia: Ventricular fibrillation (VF), sustained ventricular tachycardia (VT), new-onset 
atrial fibrillation/flutter, persistent supraventricular tachy-arrhythmia (> 130 BPM > 30 
minutes). 
 
Reference Document 
Relationship to trial intervention will be determined according to the manufacturer ‘summary 
of product characteristics (Appendix D, E). 
 
Procedures for Un-Blinding the Treatment Allocation 
The identification of treatment allocation will be maintained at a computer located at 
Rigshospitalet but protected from participants of the study. Authorized site staff will be pro-
vided with a unique Personal Identification Number (PIN) to obtain unblinding information. 
This PIN is unique to the individual and must not be shared.  
A subject’s treatment assignment should only be unblinded by a study site when knowledge 
of the treatment is essential for the further management of the subject or if needed for safety 

Protocol version 2.7.6 
26 
reporting to regulatory authorities. Unblinding at the study site for any other reason will be 
considered a protocol deviation. 
For unblinding at the site, the Principal Investigator should if possible be contacted before 
unblinding any subject’s treatment assignment. At the latest, the principal investigator must 
be notified within 1 working day after the event, and the unblinding must be documented in 
the subject’s case report form.  
 
SAFETY MONITORING 
The trial will be conducted according to the Act No. 593 of 14 June 2011 on Act on Research 
Ethics. Review of Health Research Projects. The investigators will immediately notify the 
regional ethics committee and Danish Medicines Agency in case of occurrence of unex-
pected serious adverse reactions within the interventions period. The report will be accom-
panied by comments on possible implications for the trial, and notification will be made within 
seven days after the investigators have obtained knowledge of the event. Please see the 
supplementary material.  
 
INFORMED CONSENT 
The study will be conducted in adherence to national and international standards of GCP.  
A subject has the right to withdraw from the study at any time, for any reason, without prej-
udice to his or her future medical care by the physician or at the institution. Any subject who 
withdraws consent to participate in the study will immediately be removed from further treat-
ment and/or study observation on the date of request. In addition, the investigator and the 
sponsor have the right to withdraw a subject from the study if any of the following occurs:  
 

Protocol version 2.7.6 
27 
1. Refusal by the subject to continue observations  
2. Decision by the investigator that termination is in the subject’s best medical interest  
 
Should a subject request or decide to withdraw from the study, all efforts will be made to 
complete and report the observations as thoroughly as possible up to the date of withdrawal. 
All information should be reported on the applicable case report forms. A complete final 
evaluation and assessments according to outcome measures will be made at the time of the 
subject’s withdrawal. The End of Study case report form will be completed with an explana-
tion for the withdrawal. If the withdrawal of a subject is due to an adverse event, follow-up 
visits should be scheduled until the adverse event has resolved or stabilized. Unless consent 
has been withdrawn, follow-up data on deaths and hospitalizations will be collected until 
study termination or a maximum of 48 months since enrolment of the subject. Unless spe-
cifically requested by the patient, the patient will be followed for the primary endpoint until 
end of study. 
 
 
 

Protocol version 2.7.6 
28 
ETHICAL CONSIDERATIONS 
All patients will be included after informed (written and oral) consent in accordance with the 
Danish Data Protection Act and the General Data Protection Regulation with electronical 
signature in via RedCap. Neither participation in the trial nor administration of study drug will 
interfere with or delay diagnostic or therapeutic procedures. The trial will investigate the 
beneficial effects of the IL-6RA Tocilizumab and / or dobutamine administered as soon as 
possible after PCI in AMI-patients presenting < 24 hours from chest pain and ORBI risk 
score ≥10.  
 
The ethical justifications for acute administration of Tocilizumab and dobutamine in AMI-
patients are that knowledge of the inflammation reducing effects of IL-6RA in AMI-patients 
cannot be gained outside of the acute setting as proposed. Similar research in a non-acute 
setting is not possible, as we aim to investigate the development of cardiogenic shock after 
hospital admission, which often occurs during the first couple of hours after AMI. The aim of 
the study is to assess the benefit of reducing inflammation in AMI-patients – a response that 
has been proposed associated with poor outcome. Infusion of dobutamine will need to be 
initiated as soon as possible after PCI to alleviate the progressive ischemia-reperfusion in-
jury following AMI and early revascularization.  
Study drug infusion is approved for other medical conditions and is expected to be of 
minimal risk to the subjects. Increased knowledge on the therapeutic potential of Tocili-
zumab would increase scientific knowledge of AMI-patients in general, and the SIRS-like 
response in particular, without exposing the patients to high risk. Inclusion in the study may 
benefit the individual participant as we hypothesize that development of CS and infarct size 
will be diminished, and therefore will be valuable to the group of high-risk AMI-patients, since 
further knowledge is needed to continue to improve treatment in this specific patient group.  

Protocol version 2.7.6 
29 
DATA HANDLING AND RECORD KEEPING 
The patient’s records will be reviewed by study related personnel and the endpoint commit-
tee to assess clinical endpoints. The patient is informed about this and gives informed con-
sent to this when entering the study. The investigators are responsible for ensuring the ac-
curacy, completeness, legibility and timeliness of the data recorded in the eCRFs. The in-
formed consent gives the investigator and possibly control authority direct access to data 
from the patient's journal. These are used to view information on the participant’s medical 
condition necessary for the conduct of the trial and for self-control, quality control and mon-
itoring.  
 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
The principal investigator will permit monitoring, audits, reviews of ethical committees and 
regulatory authorities’ direct access to source data, blinded to treatment allocation. An inde-
pendent Data Monitoring Committee consisting of members with relevant expertise will be 
assembled prior to study commencement. This committee will periodically review safety data 
and enrollment trends. 
 
QUALITY CONTROL AND ASSURANCE 
The trial will be externally monitored by the national GCP unit at the Copenhagen GCP 
center. A monitoring plan will be conducted prior to trial initiation. The frequency of onsite 
monitoring will depend on compliance with the protocol, number of enrolled patients, and 
quality of data handling. There will be mandatory monitoring before and after the trial and at 
least once during the trial. The GCP will monitor inclusion and exclusion criteria, consent 

Protocol version 2.7.6 
30 
obtained in all subjects according to legislation, and data included in the eCRF. The principal 
investigator will be responsible for all data in the eCRFs.  
 
PUBLICATION OF RESULTS 
The results obtained in accordance with the protocol and any amendments in their approved 
form will be uploaded to the EudraCT portal as soon as possible within a 1-year time frame. 
Data will be published to clinicaltrialsregister.eu. 
 
 

Protocol version 2.7.6 
31 
FINANCE 
The study is an investigator-initiated trial conceived and conducted by medical doctors from 
the Heart Centre at Rigshospitalet, Copenhagen University Hospital. When financial support 
has been obtained, the regulatory organs will be notified, and the participant information 
updated accordingly. The funding will cover expenses as listed in the budget overview. The 
financial support will be deposited to a project specific research account, which is adminis-
trated by the hospital and under public revision. The study is independent of commercial 
interests. External sponsors will have no influence on the conduct of the study. Participants 
will not receive any financial compensation. 
 
 
 

Protocol version 2.7.6 
32 
TASKS AND RESPONSIBILITIES 
 
Helle Søholm, MD, PhD and Professor, MD, Dr. Med. Christian Hassager will take respon-
sibility as a primary investigator and sponsor, respectively, according to current legislation 
and regulations.  
 
Joakim Kunkel, MD and Sarah Holle, MD will uptake informed consent from patients and 
perform inclusion in the trial. Additional personnel may be delegated to perform these 
tasks under the provisions specified in the section “Recruiting” (p. 10). 
 
All collaborators are GCP-certified. The sponsor holds documentation thereof. 
 
 
 
 
 
 
 
 
 

Protocol version 2.7.6 
33 
REFERENCES 
 
1. Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 
2008;117(5):686-97. doi: 10.1161/CIRCULATIONAHA.106.613596 
2. Obling L, Frydland M, Hansen R, et al. Risk factors of late cardiogenic shock and mortality in ST-segment elevation 
myocardial infarction patients. Eur Heart J Acute Cardiovasc Care 2018;7(1):7-15. doi: 
10.1177/2048872617706503 
3. De Luca L, Olivari Z, Farina A, et al. Temporal trends in the epidemiology, management, and outcome of patients 
with cardiogenic shock complicating acute coronary syndromes. Eur J Heart Fail 2015;17(11):1124-32. doi: 
10.1002/ejhf.339 
4. Baran DA, Grines CL, Bailey S, et al. SCAI clinical expert consensus statement on the classification of cardiogenic 
shock: This document was endorsed by the American College of Cardiology (ACC), the American Heart 
Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in 
April 2019. Catheter Cardiovasc Interv 2019;94(1):29-37. doi: 10.1002/ccd.28329 [published Online First: 
2019/05/20] 
5. Dietz JR. Release of natriuretic factor from rat heart-lung preparation by atrial distension. Am J Physiol 1984;247(6 
Pt 2):R1093-6. 
6. Toth M, Vuorinen KH, Vuolteenaho O, et al. Hypoxia stimulates release of ANP and BNP from perfused rat 
ventricular myocardium. Am J Physiol 1994;266(4 Pt 2):H1572-80. 
7. Tateishi J, Masutani M, Ohyanagi M, et al. Transient increase in plasma brain (B-type) natriuretic peptide after 
percutaneous transluminal coronary angioplasty. Clin Cardiol 2000;23(10):776-80. 
8. Goetze JP, Christoffersen C, Perko M, et al. Increased cardiac BNP expression associated with myocardial ischemia. 
FASEB J 2003;17(9):1105-7. doi: 10.1096/fj.02-0796fje 
9. Nagaya N, Nishikimi T, Goto Y, et al. Plasma brain natriuretic peptide is a biochemical marker for the prediction of 
progressive ventricular remodeling after acute myocardial infarction. Am Heart J 1998;135(1):21-8. doi: 
10.1016/s0002-8703(98)70338-2 [published Online First: 1998/02/07] 
10. Jarai R, Huber K, Bogaerts K, et al. Plasma N-terminal fragment of the prohormone B-type natriuretic peptide 
concentrations in relation to time to treatment and Thrombolysis in Myocardial Infarction (TIMI) flow: a 
substudy of the Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous 
Coronary Intervention (ASSENT IV-PCI) trial. Am Heart J 2010;159(1):131-40. doi: 10.1016/j.ahj.2009.11.001 
11. Frydland M, Moller JE, Lindholm MG, et al. Biomarkers predictive of late cardiogenic shock development in 
patients with suspected ST-elevation myocardial infarction. Eur Heart J Acute Cardiovasc Care 
2020:2048872619896063. doi: 10.1177/2048872619896063 [published Online First: 2020/01/22] 
12. Katayama T, Nakashima H, Furudono S, et al. Evaluation of neurohumoral activation (adrenomedullin, BNP, 
catecholamines, etc.) in patients with acute myocardial infarction. Intern Med 2004;43(11):1015-22. 
13. Jarai R, Huber K, Bogaerts K, et al. Prediction of cardiogenic shock using plasma B-type natriuretic peptide and the 
N-terminal fragment of its pro-hormone [corrected] concentrations in ST elevation myocardial infarction: an 
analysis from the ASSENT-4 Percutaneous Coronary Intervention Trial. Crit Care Med 2010;38(9):1793-801. 
doi: 10.1097/CCM.0b013e3181eaaf2a 
14. Gillespie TA, Ambos HD, Sobel BE, et al. Effects of dobutamine in patients with acute myocardial infarction. Am J 
Cardiol 1977;39(4):588-94. doi: 10.1016/s0002-9149(77)80170-7 [published Online First: 1977/04/01] 
15. Shah B, Pillinger M, Zhong H, et al. Effects of Acute Colchicine Administration Prior to Percutaneous Coronary 
Intervention: COLCHICINE-PCI Randomized Trial. Circ Cardiovasc Interv 2020;13(4):e008717. doi: 
10.1161/CIRCINTERVENTIONS.119.008717 [published Online First: 2020/04/17] 
16. Giugliano GR, Giugliano RP, Gibson CM, et al. Meta-analysis of corticosteroid treatment in acute myocardial 
infarction. Am J Cardiol 2003;91(9):1055-9. doi: 10.1016/s0002-9149(03)00148-6 [published Online First: 
2003/04/26] 
17. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. 
N Engl J Med 2017;377(12):1119-31. doi: 10.1056/NEJMoa1707914 [published Online First: 2017/08/29] 
18. Tong DC, Quinn S, Nasis A, et al. Colchicine in Patients with Acute Coronary Syndrome: The Australian COPS 
Randomized Clinical Trial. Circulation 2020 doi: 10.1161/CIRCULATIONAHA.120.050771 [published Online 
First: 2020/08/31] 

Protocol version 2.7.6 
34 
19. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J 
Med 2019;381(26):2497-505. doi: 10.1056/NEJMoa1912388 [published Online First: 2019/11/17] 
20. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med 2020 
doi: 10.1056/NEJMoa2021372 [published Online First: 2020/09/01] 
21. Kleveland O, Kunszt G, Bratlie M, et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab 
on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-
blind, randomized, placebo-controlled phase 2 trial. Eur Heart J 2016;37(30):2406-13. doi: 
10.1093/eurheartj/ehw171 [published Online First: 2016/05/11] 
22. Broch K, Anstensrud AK, Woxholt S, et al. Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With 
Acute ST-Segment Elevation Myocardial Infarction. Journal of the American College of Cardiology 
2021;77(15):1845-55. doi: 10.1016/j.jacc.2021.02.049 [published Online First: 2021/04/17] 
23. Meyer MAS, Wiberg S, Grand J, et al. Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the 
Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, 
Placebo-Controlled, Single-Center, Randomized, Clinical Trial. Circulation 2021;143(19):1841-51. doi: 
10.1161/CIRCULATIONAHA.120.053318 [published Online First: 2021/03/23] 
24. Auffret V, Cottin Y, Leurent G, et al. Predicting the development of in-hospital cardiogenic shock in patients with 
ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: the ORBI 
risk score. Eur Heart J 2018 doi: 10.1093/eurheartj/ehy127 
25. Frederiksen KP, Soeholm H, Hassager C, et al. Biomarkers reflecting neurohormonal activation and inflammation 
are correlated with the ORBI Risk Score and predictive of in-hospital cardiogenic shock development in 
STEMI-patients. SESSION ACVC Essentials 4 You - ePublications 2020 
26. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in 
patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial 
infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur 
Heart J 2017 doi: 10.1093/eurheartj/ehx393 
27. Buchner S, Debl K, Barlage S, et al. Dynamic changes in N-terminal pro-brain natriuretic peptide in acute coronary 
syndromes treated with percutaneous coronary intervention: a marker of ischemic burden, reperfusion and 
outcome. Clin Chem Lab Med 2010;48(6):875-81. doi: 10.1515/CCLM.2010.164 [published Online First: 
2010/05/06] 
28. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation 
2018;138(20):e618-e51. doi: 10.1161/CIR.0000000000000617 [published Online First: 2018/12/21] 
29. Trzeciak S, McCoy JV, Phillip Dellinger R, et al. Early increases in microcirculatory perfusion during protocol-
directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. 
Intensive Care Med 2008;34(12):2210-7. doi: 10.1007/s00134-008-1193-6 [published Online First: 
2008/07/03] 
30. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ 
dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of 
Intensive Care Medicine. Intensive Care Med 1996;22(7):707-10. 
31. Oldridge N, Saner H, McGee HM, et al. The Euro Cardio-QoL Project. An international study to develop a core heart 
disease health-related quality of life questionnaire, the HeartQoL. Eur J Cardiovasc Prev Rehabil 
2005;12(2):87-94. doi: 10.1097/01.hjr.0000159408.05180.0e [published Online First: 2005/03/24] 
32. Zangger G, Zwisler AD, Kikkenborg Berg S, et al. Psychometric properties of HeartQoL, a core heart disease-specific 
health-related quality of life questionnaire, in Danish implantable cardioverter defibrillator recipients. Eur J 
Prev Cardiol 2018;25(2):142-49. doi: 10.1177/2047487317733074 [published Online First: 2017/09/28] 
33. Hansen TB, Thygesen LC, Zwisler AD, et al. Self-reported health-related quality of life predicts 5-year mortality and 
hospital readmissions in patients with ischaemic heart disease. Eur J Prev Cardiol 2015;22(7):882-9. doi: 
10.1177/2047487314535682 [published Online First: 2014/05/14] 
34. Gronset CN, Thygesen LC, Berg SK, et al. Measuring HRQoL following heart valve surgery: the HeartQoL 
questionnaire is a valid and reliable core heart disease instrument. Qual Life Res 2019;28(5):1245-53. doi: 
10.1007/s11136-018-02098-1 [published Online First: 2019/01/06] 
35. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 2001;33(5):337-43. doi: 
10.3109/07853890109002087 [published Online First: 2001/08/09] 
36. De Smedt D, Clays E, Doyle F, et al. Validity and reliability of three commonly used quality of life measures in a 
large European population of coronary heart disease patients. Int J Cardiol 2013;167(5):2294-9. doi: 
10.1016/j.ijcard.2012.06.025 [published Online First: 2012/07/04] 

Protocol version 2.7.6 
35 
37. Snaith RP, Zigmond AS. The hospital anxiety and depression scale. Br Med J (Clin Res Ed) 1986;292(6516):344. doi: 
10.1136/bmj.292.6516.344 [published Online First: 1986/02/01] 
38. Bjelland I, Dahl AA, Haug TT, et al. The validity of the Hospital Anxiety and Depression Scale. An updated literature 
review. J Psychosom Res 2002;52(2):69-77. doi: 10.1016/s0022-3999(01)00296-3 [published Online First: 
2002/02/08] 
39. Snaith RP. The Hospital Anxiety And Depression Scale. Health Qual Life Outcomes 2003;1:29. doi: 10.1186/1477-
7525-1-29 [published Online First: 2003/08/14] 
40. Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for 
mild cognitive impairment. J Am Geriatr Soc 2005;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x 
[published Online First: 2005/04/09] 
41. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 
2005;173(5):489-95. doi: 10.1503/cmaj.050051 [published Online First: 2005/09/01] 
42. Bebb O, Smith FG, Clegg A, et al. Frailty and acute coronary syndrome: A structured literature review. Eur Heart J 
Acute Cardiovasc Care 2018;7(2):166-75. doi: 10.1177/2048872617700873 [published Online First: 
2017/10/25] 
43. Ensrud KE, Ewing SK, Taylor BC, et al. Frailty and risk of falls, fracture, and mortality in older women: the study of 
osteoporotic fractures. J Gerontol A Biol Sci Med Sci 2007;62(7):744-51. doi: 10.1093/gerona/62.7.744 
[published Online First: 2007/07/20] 
44. Carroll MB, Haller C, Smith C. Short-term application of tocilizumab during myocardial infarction (STAT-MI). 
Rheumatol Int 2018;38(1):59-66. doi: 10.1007/s00296-017-3842-y [published Online First: 2017/10/27] 
45. Castagne B, Viprey M, Martin J, et al. Cardiovascular safety of tocilizumab: A systematic review and network meta-
analysis. PLoS One 2019;14(8):e0220178. doi: 10.1371/journal.pone.0220178 [published Online First: 
2019/08/02] 
46. Kobayashi H, Kobayashi Y, Yokoe I, et al. Heart Rate-corrected QT Interval Duration in Rheumatoid Arthritis and Its 
Reduction with Treatment with the Interleukin 6 Inhibitor Tocilizumab. J Rheumatol 2018;45(12):1620-27. 
doi: 10.3899/jrheum.180065 [published Online First: 2018/09/03] 
47. Meyer MAS, Wiberg S, Grand J, et al. Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory 
Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a double-blinded, placebo-
controlled, single-center, randomized clinical trial. Trials 2020;21(1):868. doi: 10.1186/s13063-020-04783-4 
[published Online First: 2020/10/22] 
48. Tleyjeh IM, Kashour Z, Damlaj M, et al. Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic 
review and meta-analysis. Clin Microbiol Infect 2020 doi: 10.1016/j.cmi.2020.10.036 [published Online First: 
2020/11/09] 
49. Schumann J, Henrich EC, Strobl H, et al. Inotropic agents and vasodilator strategies for the treatment of 
cardiogenic shock or low cardiac output syndrome. Cochrane Database Syst Rev 2018;1:CD009669. doi: 
10.1002/14651858.CD009669.pub3 [published Online First: 2018/01/30] 
50. Landmesser U, Drexler H. Update on inotropic therapy in the management of acute heart failure. Curr Treat 
Options Cardiovasc Med 2007;9(6):443-9. doi: 10.1007/s11936-007-0039-9 [published Online First: 
2008/01/29]