Calcium for Out-of-Hospital Cardiac Arrest - A Randomized, Double-Blind, Placebo-Controlled Trial
Phase: PHASE2
Conditions: Heart Arrest, Out-Of-Hospital
Sponsor: Lars Wiuff Andersen

 
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Calcium for Out-of-Hospital Cardiac Arrest 
– A Randomized, Double-Blind, Placebo-Controlled Trial  
 
Acronym: COCA 
 
TRIAL PROTOCOL  
 
Version 1.2 
December 21, 2020 
 
EudraCT number: 2019-003387-46 
ClinicalTrials.gov number: NCT04153435 
 
Principal investigator and sponsor: 
Lars W. Andersen, M.D., M.P.H., Ph.D., D.M.Sc. 
Associate Professor  
Phone: +4551781511 
Email: lwandersen@clin.au.dk 
Research Center for Emergency Medicine 
Department of Clinical Medicine 
Aarhus University and Aarhus University Hospital 
Palle Juul Jensens Boulevard 99, Bygning J, Plan 1 
8200 Aarhus N, Denmark 
 
Research and Development  
Prehospital Emergency Medical Services 
Central Denmark Region 
Olof Palmes Allé 34, 1. sal 
8200 Aarhus N, Denmark 

 
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Content 
Preface ..................................................................................................................................................................6 
List of abbreviations .............................................................................................................................................7 
Overview...............................................................................................................................................................8 
Trial flow chart......................................................................................................................................................9 
Steering committee ........................................................................................................................................... 10 
Representatives for the physician-manned ambulances .................................................................................. 11 
International advisory board ............................................................................................................................. 12 
Trial site ............................................................................................................................................................. 13 
Pharmacy ........................................................................................................................................................... 13 
Amendments ..................................................................................................................................................... 14 
1. BACKGROUND ............................................................................................................................................... 16 
1.1 Out-of-hospital cardiac arrest ................................................................................................................. 16 
1.1.1 Incidence and mortality .................................................................................................................... 16 
1.1.2 Lack of high-quality randomized trials ............................................................................................. 16 
1.1.3 Pathophysiology ............................................................................................................................... 16 
1.2 Calcium .................................................................................................................................................... 17 
1.2.1 Pharmacology ................................................................................................................................... 17 
1.2.2 Use outside cardiac arrest ................................................................................................................ 17 
1.2.3 Use in cardiac arrest ......................................................................................................................... 18 
1.2.4 Hyperkalemia and hypocalcemia in cardiac arrest .......................................................................... 18 
1.3 Randomized controlled trials concerning calcium for OHCA .................................................................. 19 
1.4 Guidelines regarding calcium .................................................................................................................. 19 
1.5 Standard of care ...................................................................................................................................... 19 
2. TRIAL OBJECTIVES AND HYPOTHESES ............................................................................................................ 21 
3. TRIAL DESIGN ................................................................................................................................................. 22 
3.1 Overview .................................................................................................................................................. 22 
3.2 Allocation ................................................................................................................................................. 22 
3.3 Interventions ........................................................................................................................................... 22 
3.3.1 Calcium ............................................................................................................................................. 22 
3.3.2 Placebo ............................................................................................................................................. 22 
3.3.3 Procedures ........................................................................................................................................ 22 

 
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3.3.4 Overview of study medication ......................................................................................................... 23 
3.4 Blinding .................................................................................................................................................... 23 
3.5 Trial procedures ....................................................................................................................................... 24 
3.5.1 Patients ............................................................................................................................................. 24 
3.5.2 Clinical personnel ............................................................................................................................. 24 
4.  SETTING AND PATIENT POPULATION ........................................................................................................... 24 
4.1 Setting ...................................................................................................................................................... 24 
4.2 Inclusion criteria ...................................................................................................................................... 24 
4.3 Exclusion criteria ..................................................................................................................................... 25 
4.4 Co-enrollment ......................................................................................................................................... 26 
5. OUTCOMES .................................................................................................................................................... 26 
5.1 Primary outcome ..................................................................................................................................... 26 
5.1.1 Original definition ............................................................................................................................. 26 
5.1.2 Updated definition ........................................................................................................................... 26 
5.1.3 Rationale ........................................................................................................................................... 26 
5.2 Secondary outcomes ............................................................................................................................... 27 
5.2.1 Definitions ........................................................................................................................................ 27 
5.2.2 Rationale ........................................................................................................................................... 27 
5.3 Tertiary outcomes ................................................................................................................................... 28 
5.4 Harm ........................................................................................................................................................ 29 
5.4.1 General consideration ...................................................................................................................... 29 
5.4.2 Subcutaneous injection .................................................................................................................... 29 
5.4.3 Hypercalcemia and arrhythmias ...................................................................................................... 30 
5.4.4 Digitalis glycoside toxicity ................................................................................................................. 30 
5.4.5 Acute kidney injury ........................................................................................................................... 30 
5.4.6 Peptic ulcer disease .......................................................................................................................... 31 
5.4.7 Acute pancreatitis............................................................................................................................. 31 
5.4.8 Definitions ........................................................................................................................................ 32 
5.4.9 Specific adverse events .................................................................................................................... 32 
5.4.10 Timeline .......................................................................................................................................... 33 
5.4.11 Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................................................... 33 
5.4.12 Reporting ........................................................................................................................................ 33 
5.5 Additional follow-up ................................................................................................................................ 34 
6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN ................................................................... 34 

 
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6.1 Sample size calculation ............................................................................................................................ 34 
6.1.1 Original sample size calculation ....................................................................................................... 34 
6.1.2 Updated sample size calculation ...................................................................................................... 34 
6.2 Statistical analysis plan ............................................................................................................................ 35 
6.2.1 General considerations..................................................................................................................... 35 
6.2.2 Primary and secondary outcomes .................................................................................................... 35 
6.2.3 Subgroup analyses ............................................................................................................................ 36 
6.2.4 Additional analyses and outcomes ................................................................................................... 36 
6.2.5 Missing data ..................................................................................................................................... 36 
6.2.6 Multiple comparisons ....................................................................................................................... 36 
6.2.7 Statistical stopping criteria ............................................................................................................... 37 
6.2.8 Secondary Bayesian analyses ........................................................................................................... 37 
7. DATA COLLECTION AND MANAGEMENT ....................................................................................................... 37 
7.1 Data collection process ........................................................................................................................... 37 
7.2 Variables .................................................................................................................................................. 38 
7.2.1 Overview ........................................................................................................................................... 38 
7.2.2 Pre-cardiac arrest characteristics ..................................................................................................... 38 
7.2.3 Cardiac arrest characteristics ........................................................................................................... 39 
7.2.3 Post-cardiac arrest characteristics ................................................................................................... 40 
7.2.4 Outcomes ......................................................................................................................................... 40 
7.3 Data quality and validity .......................................................................................................................... 41 
7.3.1 Central monitoring ........................................................................................................................... 41 
7.3.2 On-site monitoring ........................................................................................................................... 41 
7.4 Data storage and security ........................................................................................................................ 41 
7.5 Data access .............................................................................................................................................. 41 
8. CLINICAL TREATMENT ................................................................................................................................... 42 
9. ETHICAL CONSIDERATIONS............................................................................................................................ 42 
9.1 Clinical equipoise ..................................................................................................................................... 42 
9.1.1 Potential benefits ............................................................................................................................. 42 
9.1.2 Potential harms ................................................................................................................................ 42 
9.1.3 Risk/benefit ratio .............................................................................................................................. 42 
9.2 Research in cardiac arrest ....................................................................................................................... 43 
9.2.1 General considerations..................................................................................................................... 43 
9.2.2 Danish regulations ............................................................................................................................ 43 

 
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9.2.3 Regulations in relation to the current trial ....................................................................................... 44 
9.3 Procedures ............................................................................................................................................... 45 
9.3.1 Ethical review committee ................................................................................................................. 45 
9.3.2 Trial-specific procedures .................................................................................................................. 45 
9.3.3 Insurance .......................................................................................................................................... 46 
10. MONITORING .............................................................................................................................................. 46 
10.1 Good Clinical Practice monitoring ......................................................................................................... 46 
10.2 Independent data-monitoring committee (IDMC) ................................................................................ 46 
11. TIMELINE AND ENROLLMENT ...................................................................................................................... 47 
11.1 Timeline ................................................................................................................................................. 47 
11.2 Feasibility ............................................................................................................................................... 48 
11.3 Enrollment ............................................................................................................................................. 48 
11.4 Additional sites ...................................................................................................................................... 48 
12. PUBLICATION PLAN ..................................................................................................................................... 48 
13. DATA SHARING ............................................................................................................................................ 49 
14. FUNDING ..................................................................................................................................................... 49 
15. TASKS AND RESPONSIBILITIES ..................................................................................................................... 49 
References ......................................................................................................................................................... 51 
Appendices ........................................................................................................................................................ 63 
Appendix 1: Conflict of interest disclosures for the steering committee members ..................................... 63 
Appendix 2: Study kit and drug labeling (Danish) ......................................................................................... 66 
Appendix 3: Draft of CONSORT flow diagram ............................................................................................... 67 
Appendix 4: Charter for the independent data-monitoring committee (IDMC) ........................................... 68 
 
 
 

 
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Preface 
The “Calcium for Out-of-Hospital Cardiac Arrest – A Randomized, Double-Blind, Placebo-Controlled Trial” 
(COCA) will be conducted according to this protocol. The trial will be conducted in accordance with all 
applicable national and international laws, regulations, and guidelines including the revised version of the 
Declaration of Helsinki,1 European regulations,2 and the international Good Clinical Practice guidelines.3 The 
trial and this protocol are developed in accordance with the International Conference on Harmonization 
(ICH) guidelines3-5 and the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 
statement.6,7 Mikael Fink Vallentin and Lars W. Andersen wrote the protocol with input from the steering 
committee. Any substantial changes or amendments to the protocol will be clearly documented and 
communicated to all relevant parties.  
 
 
 
                                 
_________________________________________________________ 
                                                                         Lars W. Andersen, M.D., M.P.H., Ph.D., D.M.Sc.     Date: 21/12 - 2020 
    

 
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List of abbreviations  
AED:  
 
Automated external defibrillator 
AHA:  
 
American Heart Association 
CaCl:  
 
Calcium Chloride 
COCA: 
 
Calcium for Out-of-Hospital Cardiac Arrest 
CONSORT:  Consolidated Standards of Reporting Trials 
COSCA:  
Core Outcome Set for Cardiac Arrest 
CPC:   
 
Cerebral performance category 
CPR:   
 
Cardiopulmonary resuscitation 
ECG:  
 
Electrocardiogram 
ECPR:  
 
Extracorporeal cardiopulmonary resuscitation 
EMS:   
 
Emergency medical services 
EudraCT:  
European Union Drug Regulating Authorities Clinical Trials Database 
HEMS: 
 
Helicopter emergency medical services 
ICH:   
 
International Conference on Harmonization 
IDMC:  
 
Independent data-monitoring committee  
IHCA:   
 
In-hospital cardiac arrest 
ILCOR:  
 
International Liaison Committee on Resuscitation 
mRS:   
 
modified Rankin Scale 
NaCl:  
 
Sodium Chloride 
OHCA:  
 
Out-of-hospital cardiac arrest 
PEA:  
 
Pulseless electrical activity 
REDCap:  
Research Electronic Data Capture 
ROSC:  
 
Return of spontaneous circulation  
SINE:  
 
“Sikkerhedsnettet” 
SOFA:  
 
Sequential Organ Failure Assessment 
SOP:  
 
Standard operating procedure 
SPIRIT:   
Standard Protocol Items: Recommendations for Interventional Trials 
SUSAR:  
Suspected Unexpected Serious Adverse Reaction 
 
VAM-IHCA: Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest 
 

 
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Overview  
Registry and trial number 
EudraCT number: 2019-003387-46, ClinicalTrials.gov number: NCT04153435 
Date of registration 
EudraCT: October 28, 2019, ClinicalTrials.gov: November 6, 2019 
Funding 
The Novo Nordic Foundation, Aarhus University, Central Denmark Region, and 
the Tryg Foundation 
Primary sponsor 
Lars W. Andersen, Aarhus University 
Contact  
Lars W. Andersen, lwandersen@clin.au.dk 
Title 
Calcium for Out-of-Hospital Cardiac Arrest (COCA) – A Randomized, Double-
Blind, Placebo-Controlled Trial 
Country of recruitment 
Denmark 
Condition studied 
Out-of-hospital cardiac arrest 
Intervention 
Calcium chloride (CaCl) (5-10 mmol) 
Comparator  
Placebo in the form of 0.9% sodium chloride (NaCl) (10-20 mL) 
Inclusion criteria 
1) Out-of-hospital cardiac arrest 
2) Age ≥18 years 
3) Received at least one dose of adrenaline during CPR 
Exclusion criteria 
1) Traumatic cardiac arrest 
2) Known or strong suspicion of pregnancy 
3) Prior enrollment in the trial 
4) Received adrenaline during CPR before arrival of prehospital personnel with 
the study drug 
5) Clinical indication for calcium administration during the cardiac arrest 
Study type 
Interventional 
Allocation: Randomized (1:1) 
Intervention model: Parallel group 
Masking: Double-blind 
Date of first screening  
January 20, 2020 
Target sample size 
674 
Recruitment status 
Recruiting 
Primary outcomes 
Return of spontaneous circulation (ROSC) 
Key secondary outcomes 
Survival at 30 days 
Survival at 30 days with a favorable neurological outcome (modified Rankin 
Scale, mRS, of 0-3) 

 
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Trial flow chart 
 
 
 
 
 
 
 
Out-of-hospital cardiac arrest (OHCA) 
Cardiopulmonary resuscitation (CPR) 
Physician/paramedic unit deployed 
Assessment of rhythm  
Shockable rhythm  
Non-shockable rhythm   
CPR   
CPR   
Defibrillation 
Adrenaline  
Adrenaline  
3 defibrillations 
5 mmol of calcium chloride 
or 
Placebo 
CPR 
CPR 
After 2nd adrenaline dose: 
5 mmol of calcium chloride 
or 
Placebo 
Primary outcome:  
Return of spontaneous circulation (ROSC) 
 
Secondary outcomes:  
Survival at 30 days 
Survival at 30 days with a favorable neurological outcome 

 
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Steering committee  
Lars W. Andersen, M.D., M.P.H., Ph.D., D.M.Sc. 
Sponsor and principal investigator 
Associate Professor  
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University Hospital 
Mikael Fink Vallentin, M.D. 
Ph.D.-fellow / Coordinating investigator 
Prehospital Emergency Medical Services 
Central Denmark Region 
Department of Clinical Medicine 
Aarhus University 
Hans Kirkegaard, M.D., Ph.D., D.M.Sc. 
Director, Professor  
Research Center for Emergency Medicine  
Department of Clinical Medicine  
Aarhus University and Aarhus University Hospital 
Christian Fynbo Christiansen, M.D., Ph.D. 
Associate professor 
Department of Clinical Epidemiology  
Department of Clinical Medicine 
Aarhus University 
Thomas Dissing, M.D., Ph.D. 
Staff specialist 
Prehospital Emergency Medical Services 
Central Denmark Region 
Asger Granfeldt, M.D., Ph.D., D.M.Sc. 
Associate Professor  
Department of Anesthesiology 
Aarhus University Hospital 
Christian Juhl Terkelsen, M.D., Ph.D., D.M.Sc. 
Associate professor 
Department of Cardiology  
Aarhus University Hospital 
Steffen Christensen, M.D., Ph.D.  
Associate professor 
Department of Anesthesiology 
Aarhus University Hospital 
Carsten Meilandt, B.Sc. 
Paramedic  
Prehospital Emergency Medical Services 
Central Denmark Region 
Conflicts of interest 
The members of the steering committee have no conflicts of interest related to the current trial. A list of all 
conflict of interests is provided in Appendix 1.  

 
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Representatives for the physician-manned ambulances 
 
 
 
 
Bo Nees Iversen, M.D. 
Aarhus 
Mads Partridge Vandborg, M.D. 
Viborg / Ringkøbing 
Rikke Mærkedahl, M.D. 
Herning 
Maren Tarpgaard, M.D. 
Holstebro / Lemvig 
Lone Mortensen, M.D. 
Randers / Grenå 
Charlotte Runge, M.D., Ph.D. 
Silkeborg 
Anette Hostrup, M.D. 
Horsens 

 
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International advisory board 
Michael Donnino, M.D.  
Professor  
Center for Resuscitation Science 
Department of Emergency Medicine  
Beth Israel Deaconess Medical Center 
 
Clifton Callaway, M.D., Ph.D.  
Professor  
Department of Emergency Medicine  
University of Pittsburg  
 
Markus Skrifvars, M.D., Ph.D.  
Professor  
Department of Emergency Care and Services 
Helsinki University Hospital and University of Helsinki 
 
 

 
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Trial site 
Prehospital Emergency Medical Services 
Central Denmark Region 
Olof Palmes Allé 34, 1. 
8200 Aarhus N 
Denmark 
 
Pharmacy  
Skanderborg Pharmacy  
Adelgade 27 
8660 Skanderborg 
Denmark 
Contact: Heidi Svith, hei@skanderborg-apotek.dk 
 
 
 
 

 
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Amendments 
Version 1.1 to 1.2 
• 
Changed the primary outcome; please see sections 5.1.2 and 5.1.3 for details 
• 
Increased sample size from 430 to 674; please see section 6.1.2 for details 
o The trial’s feasibility has been updated based on the new sample size and current enrollment 
rate (section 11.2) 
• 
Clarified two exclusion criteria without changing their meaning (section 4.3) 
• 
Multiple changes to the statistical analyses plan including (section 6): 
o Change of the primary analysis  
o Addition of a sensitivity analysis for the primary outcome  
o Subgroup analyses on both the relative and absolute scale 
o Only reporting P-values for certain key outcomes  
o Analysis of survival to 90 days as a binary outcome  
• 
Updated information on the steering committee (section “Steering Committee”) 
• 
Updated the contact information for the pharmacy (section “Pharmacy”) 
• 
Added dates of registration for EUDRA-CT and clinicaltrials.gov 
• 
Added date of first screening 
• 
Updated section “Representatives for the physician-manned ambulances” 
• 
Updated section 1.1.1 in accordance with the newest data 
• 
Clarified the format of the study ID (section 3.3.4) 
• 
Clarified the role of cardinal signs of death in the definition of cardiac arrest (section 4.2) 
• 
Clarified that there are other trials in OHCA in Denmark, but in another region (section 4.4) 
• 
Added description of a secondary safety parameter assessing early hypercalcemia (section 5.4.9)  
• 
Clarified the extent of source data (section 7.1) 
• 
Clarified the roles of central and on-site monitoring (section 7.3) 
• 
Clarified that the consent forms are separate for each role (section 9.3.2) 
• 
Added an extra IDMC interim analysis at 400 patients (section 10.2 and appendix 4) 
• 
Clarified result sharing with participating patients (section 12) 
• 
Added additional funding (section 14) 
• 
Added picture of the study drug kit as well as labelling (appendix 2) 
• 
Added three additional variables to the IDMC data set (appendix 4) 
• 
Added “Research ethical committee no.” (appendix 4) 

 
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Version 1.0 to 1.1 
• 
Clarification that the sponsor will be notified about the occurrence of any serious adverse event 
within 24 hours (section 5.4.9) 
• 
Clarification to data storage and security (section 7.4) 
• 
Clarification related to the potential role of digitalis glycoside toxicity (section 9.1.2) 
• 
Additional details related to the consent process (section 9.3.2) 
• 
Clarification that the trial findings will be published irrespective of the results (section 12) 
• 
Clarification related to funding (section 14) 

 
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1. BACKGROUND 
1.1 Out-of-hospital cardiac arrest 
1.1.1 Incidence and mortality  
Out-of-hospital cardiac arrest (OHCA) occurs in an estimated 4 million people each year globally of which 
approximately 5000 are in Denmark.8,9 Unfortunately, survival following OHCA is extremely poor with only 
approximately 15% being alive after 30 days in Denmark.8,10 Of those with a non-shockable rhythm, which 
account for more than 80% of all OHCA, less than 10% are alive after 30 days and, in contrast to those with a 
shockable rhythm, survival has not improved substantially over the last decade.8,10 Furthermore, many 
survivors of OHCA have debilitating long-term sequelae such as neurological deficits, cognitive problems, 
depression, or anxiety.  
 
1.1.2 Lack of high-quality randomized trials 
Multiple medical interventions are used during cardiac arrest.11 However, there are currently none of these 
that have shown to definitively improve 30-day survival with a favorable neurological outcome.11-13 This may 
be caused by the fact that relatively few randomized trials are conducted in OHCA compared to other high-
mortality conditions.14 Furthermore, cardiac arrest, and critical care in general, has been challenged by 
multiple neutral trials over the last decade. To advance cardiac arrest science, and thereby improve patient 
outcomes, it is therefore important that interventions are tested in rigorously performed randomized clinical 
trials. 
 
1.1.3 Pathophysiology  
In broad terms, cardiac arrest can be divided into three phases: pre-cardiac arrest, intra-cardiac arrest, and 
post-cardiac arrest, where intra-cardiac arrest can be further divided into a no-flow (no circulation) and a 
low-flow (circulation induced by chest compressions) phase. One of the main drivers of poor outcomes after 
cardiac arrest is the duration of the cardiac arrest (i.e. no-flow and low-flow time); for each minute increase 
in the length of the cardiac arrest, mortality substantially increases.15,16 Because of this, and since return of 
spontaneous circulation (ROSC) is a prerequisite for more long-term survival, the main goal of intra-cardiac 
arrest interventions is to establish ROSC and limit the duration of the cardiac arrest.       
The pathophysiology of cardiac arrest and the post-cardiac arrest syndrome is complex and has been 
described in extensive details elsewhere.17-19 Ischemia during the cardiac arrest and subsequent ischemia-
reperfusion injury activates multiple harmful pathways including systemic inflammation, endothelial 
activation, activation of immunological and coagulation pathways, adrenal insufficiency, mitochondrial 

 
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damage, and microvascular dysfunction.17 Consequently this leads to a clinical state (the post-cardiac arrest 
syndrome) with potential global brain injury, impaired myocardial function, macrocirculatory failure, and 
increased susceptibility to infections.17 Patients are often hemodynamically unstable following a cardiac 
arrest, and early post-cardiac arrest hypotension is strongly associated with poor outcomes.20 
 
1.2 Calcium 
1.2.1 Pharmacology  
Calcium is the most abundant mineral in the body with more than 99% residing in the teeth and bones as 
hydroxyapatite, an essential molecule for these organs’ strength. This enormous quantity also makes up an 
ample reservoir for a smaller amount of serum calcium, which is tightly regulated mainly through 
parathyroid hormone, vitamin D3, and calcitonin from the thyroid. Serum calcium exists in three forms: 
protein-bound (40%), chelated (9%), and ionized (51%, “free calcium”), the latter being the physiologic 
active. 
 
Ionized calcium serves many important biochemical functions for example for enzymes and intracellular 
signaling, but its greatest role is in muscle contraction. In short, in the cardiac muscle cell, depolarization 
leads to a small influx of extracellular calcium that causes a much larger influx from the sarcoplasmic 
reticulum (calcium-induced calcium release). On the intracellular actin-myosin complexes, calcium binds to 
tropomyosin exposing actin’s active site, which then triggers the molecular cross bridge action. On the larger 
scale, this leads to muscle contraction. This role in muscle contraction explains exogenous calcium 
administration’s well-recognized effect as an inotropic agent.21,22  
 
When calcium chloride (CaCl) is given as a rapid intravenous injection, plasma ionized calcium peaks after 
30 seconds and then falls quickly the next 30 seconds to settle at a more stable concentration falling slowly 
over the course of hours.23,24 In a 70 kg patient, a rapid dose of 5 mmol CaCl is expected to lead to a 30-
second peak in ionized calcium of Δ1.2-1.5 mmol/L falling to Δ0.4 mmol/L and Δ0.3 mmol/L after three and 
five minutes, respectively.24 
 
1.2.2 Use outside cardiac arrest  
Since hypocalcemia is frequent in the critical ill,25,26 calcium is closely monitored in the intensive care unit, 
and it is common to give day-to-day intravenous calcium doses, if ionized calcium drops below a determined 
threshold (e.g., <1.1 mmol/L). Calcium administration is always recommended in symptomatic 
hypocalcemia, which can manifest as focal muscle cramps, distal extremity paresthesia, circumoral 
numbness, or – in severe cases – generalized cramps.27 

 
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Lastly, calcium is closely monitored in situations where iatrogenic hypocalcemia is expected: transfusion 
with citrate-containing products (erythrocytes and fresh frozen plasma), iatrogenic hypoparathyroidism 
(thyroidectomy), or plasma dilution (fluid administration). For example, in a hemodynamically unstable 
patient with hemorrhage, it is recommended to routinely give intravenous calcium along with blood 
products. 
 
1.2.3 Use in cardiac arrest 
Calcium is currently recommended as a therapy during cardiac arrest, when pulseless electrical activity (PEA) 
is present along with one of the following conditions: 1) hyperkalemia, 2) hypocalcemia, or 3) calcium 
channel blocker overdose.11 The rationale is based on expert opinion that has its foundation in calcium’s 
physiology rather than clinical evidence.  
Previously, calcium was recommended broadly for cardiac arrest, but the evidence was contradictory, 
and it has since been limited to the above-mentioned conditions. A few small observational studies of 
limited quality found no association between calcium administration and outcomes in cardiac arrest,28-30 
while two studies found an association with worse outcomes.31,32 However, since calcium are most likely 
administered in cardiac arrests that are prolonged, these studies might be severely biased towards a harmful 
effect of calcium.33 In fact, one study found that early as compared to late calcium administration was 
associated with improved outcomes.32  
 
Despite the lack of new evidence in the field, the rate of calcium administration in in-hospital cardiac 
arrest (IHCA) has increased over time: in an American cohort of patients with a non-shockable rhythm, 20% 
received calcium in 2001 increasing to around 30% in 2016.34 
 
1.2.4 Hyperkalemia and hypocalcemia in cardiac arrest 
In the face of hyperkalemia, calcium is thought to increase cardiac myocytes’ resting membrane potential 
back towards normal.35 Potassium is released from cells in the presence of ischemia. Both animal models36-38 
and human studies39-41 have shown that potassium levels increase during cardiac arrest and often reach high 
levels (i.e., hyperkalemia). Secondly, several studies have found hypocalcemia in cardiac arrest patients upon 
admission, and there is an inverse correlation between serum ionized calcium and time until hospital 
admission as well as no flow time.21,28,29,42 These findings indicate a relative hyperkalemic and hypocalcemic 
state during and immediately after cardiac arrest.   
 
 

 
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1.3 Randomized controlled trials concerning calcium for OHCA 
In two trials, published in 1985, Stueven et al. examined the effect of adding calcium to the standard OHCA-
treatment at that time.43,44 In these American, randomized, double-blind trials, the authors compared 
placebo (0.9% saline) with a single dose of 500 mg (≈4.5 mmol) CaCl to treat refractory PEA and asystole, 
respectively. Refractory PEA was defined as continued PEA despite cardiopulmonary resuscitation (CPR), 
oxygenation, adrenaline, and bicarbonate. Refractory asystole was defined correspondingly, but with an 
asystolic cardiac rhythm and the addition of 1 mg of atropine. The primary outcome was in-field ROSC 
defined as palpable pulse and a heart rhythm at hospital arrival. 
 
The results showed a combined rate of ROSC of 11/87 (13%) in the intervention group and 3/76 (4%) in 
the control arm (fixed-effect meta-analysis, Figure 1, p = 0.06). Only one patient survived until hospital 
discharge (PEA, placebo). In patients with PEA and an electrocardiogram displaying either wide QRS-
complexes (>0.12 mm) or ischemia (peaked T-wave or ST-elevations) there was a significantly higher rate of 
ROSC in the calcium group than in the placebo group (8/39 [21%] vs. 1/31 [3%], p = 0.03). 
 
Figure 1 
 
1.4 Guidelines regarding calcium  
Calcium was initially recommended broadly in the 1974 guidelines from the American Heart Association 
(AHA),45 but after a series of neutral and negative cohort studies (see section 1.2.3), its use was limited to 
patients with PEA due to either hyperkalemia, hypermagnesemia, hypocalcemia, or calcium channel blocker 
toxicity.11,46 The International Liaison Committee on Resuscitation (ILCOR) elaborates: “More data are 
needed on the administration of calcium for specific circumstances, such as hyperkalemia, documented 
hypocalcemia, hypermagnesemia, calcium channel blocker overdose, or wide QRS complexes”.47 
 
1.5 Standard of care  
The standard of care during cardiac arrest is described by guidelines from the European Resuscitation 
Council (ERC) and the AHA.48,49 Pharmacological treatment is generally limited to amiodarone/lidocaine and 
adrenaline for patients with a refractory shockable rhythm and adrenaline for patients with a non-shockable 
rhythm.11,50 Although the evidence for amiodarone/lidocaine and adrenaline is limited and controversial,12,13 

 
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these drugs are currently recommended and are given, when applicable, to most patients with cardiac 
arrest. The intervention of the current trial (CaCl) will therefore be compared to a placebo and both groups 
will receive the established standard of care.  

 
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2. TRIAL OBJECTIVES AND HYPOTHESES  
Primary objective: To determine whether calcium administration during adult OHCA will improve ROSC.  
 
Hypothesis, primary: Calcium administration administered during OHCA will increase ROSC.  
 
Secondary objective: To determine whether calcium administration during adult OHCA will increase survival 
at 30 days and survival at 30 days with a favorable neurological outcome (modified Rankin Scale, mRS)  
 
Hypotheses, secondary: Calcium administration during adult OHCA will increase survival at 30 days and 
survival at 30 days with a favorable neurological outcome (mRS) 
 

 
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3. TRIAL DESIGN  
3.1 Overview 
The COCA trial will be an investigator-initiated, randomized, placebo-controlled, parallel group, double-blind, 
superiority trial of calcium administration during adult OHCA. The trial will be conducted in the Central 
Denmark Region. The primary outcome will be ROSC, and 674 patients will be included. Key secondary 
outcomes include survival at 30 days and survival at 30 days with a favorable neurological outcome.  
 
3.2 Allocation 
Patients will be randomized in a 1:1 ratio to either calcium or placebo in blocks with random sizes of 2, 4 or 
6. The randomization will be stratified according to each ambulance station (hereon forth “stations”).51 An 
independent statistician will create the randomized allocation list using a random number generator. The list 
will only be shared with the pharmacy, which will not be involved in clinical care. The pharmacy and the 
independent statistician will both store the randomization list. As described in section 3.3 and section 3.4, 
stations will be provided with numbered blinded ampoule bundles containing either CaCl or placebo 
ensuring allocation concealment.   
 
3.3 Interventions 
3.3.1 Calcium 
The intervention will consist of 5 mmol (10 mL ampoule) of CaCl administered immediately after the first 
dose of adrenaline and again after the second dose of adrenaline. No further doses will be administered, and 
the study has no other interventions. The drugs will be produced, managed, and stored according to all 
relevant guidelines and regulations.  
 
3.3.2 Placebo  
The placebo will consist of 10 mL of 9 mg/mL sodium chloride (NaCl, “normal saline”) from a 10 mL ampoule 
identical to the CaCl ampoules.  
 
3.3.3 Procedures   
The study drugs will be contained in two bundled ampoules of 10 mL (Appendix 2). The ampoules will be 
prepared at Skanderborg Pharmacy – a company that specializes in the production of medicine and is 
approved by the Danish Health authorities –, shipped to the participating stations regularly, and brought to 
the OHCA by a member of the prehospital team. Once it is anticipated that the patient will receive at least one 

 
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dose of adrenaline, the ampoules will be split and opened consecutively. Once the first ampoule is opened, 
the patient will be considered randomized. A designated member of the prehospital team will then prepare 
the study drugs. We expect that study drug preparation and administration will take approximately 30 
seconds, and that this will not interfere with clinical management. Once prepared, the drug will be 
administered as soon as possible after the first dose of adrenaline either through an intravenous or 
intraosseous line. An additional dose will be administered with the second dose of adrenaline given after 3-5 
minutes irrespective of the underlying rhythm.11 A maximum of two doses will be administered.  
 
3.3.4 Overview of study medication  
Ampoules will be produced and labelled centrally (Skanderborg Pharmacy). Ampoule bundles will be labelled 
with a unique ID consecutively according to the stations (e.g., 10XXX for station 1, 11XXX for station 2, etc.). 
Ampoule bundles will be clearly labelled according to standard practices for clinical trials (Appendix 2). 
Ampoule bundles will be prepared and shipped to the participating stations on a regular basis. Once an 
ampoule is opened, the station investigator and the coordinating investigator will be informed. The 
coordinating investigator will keep tally of all ampoule bundles and make sure, along with the station 
investigator, that stations are always equipped with enough ampoule bundles. The coordinating investigator 
will contact the central pharmacy when extra ampoule bundles are needed. Data on actual drug 
administration (see section 3.3.3) will be entered on an electronic case form (see section 7). This will ensure 
optimal tracking of study drug delivery.           
 
3.4 Blinding  
The trial will be double-blind; patients, investigators, and the clinical team will be blinded to the allocation. 
Only the pharmacy providing the blinded, numbered ampoules will be aware of the allocation. The pharmacy 
will not be involved with clinical care or outcome evaluation.  
 
Placebo will consist of normal saline which is indistinguishable from CaCl in that it is colorless and without 
any identifying features. The normal saline will be stored in 10 mL ampoules that are identical to the CaCl 
ampoules. Furthermore, except for potential slight and temporary hypercalcemia, CaCl has no distinctive 
rapid effects resulting in possible identification. The risk of unblinding is therefore at an absolute minimum. 
The emergency medical services (EMS) dispatch center will keep sealed opaque envelopes containing the 
allocation assignment for each ampoule bundle’s unique ID – this will allow for emergency unblinding. The 
dispatch center is available at all times to both the prehospital as well as the in-hospital team through either 
a direct phone call or radio communication on a specialized network (“Sikkerhedsnettet”, SINE). The decision 

 
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to unblind will be at the complete discretion of the treating physician. However, we do not expect scenarios 
where emergency unblinding will be necessary. In case unblinding occurs, the reason(s) will be clearly 
documented in the case report form. The patient will remain in the trial.  
 
3.5 Trial procedures 
3.5.1 Patients  
The trial procedures will be limited to the interventions given during the cardiac arrest (see section 3.3) and 
the telephone interviews for long-term follow-up (see section 5.3 and 5.5). There will be no planned blood 
draws, other interventions, or additional procedures. Data will be obtained from the study-specific case 
report form as well as prehospital- and in-hospital electronic medical records.  
 
3.5.2 Clinical personnel  
Prior to the beginning of patient enrollment and continuously throughout the enrollment period, the clinical 
teams involved in OHCA resuscitation at the participating stations will be informed about the trial. This 
includes the trial’s background, objectives, the inclusion/exclusion criteria, the interventions, and the trial 
procedures they are involved in (see section 3.3.3 and 9.3.2). A demonstration of correct procedures using 
the ampoule bundles will be included.  
 
4.  SETTING AND PATIENT POPULATION 
4.1 Setting 
The trial will be conducted in the Central Denmark Region’s prehospital setting, where three distinct units 
can give adrenaline to a patient with OHCA: physician-manned ambulances, paramedic-manned ambulances, 
and helicopter-based emergency medical services (HEMS). Patients, where HEMS are the first to give 
adrenaline, will not be enrolled in our study, since the unit is often manned by personnel from outside the 
region. Moreover, HEMS very rarely attend OHCA as the primary unit. 
 
Participating stations will be any regional ambulance station which holds one or more physician- and/or 
paramedic-manned ambulances. 
 
4.2 Inclusion criteria 
Inclusion criteria:  
1) OHCA 
2) Age ≥ 18 years 
3) Received at least one dose of adrenaline during CPR 

 
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Cardiac arrest is defined as unconsciousness, abnormal breathing, and a loss of pulses requiring chest 
compressions and/or defibrillation. If a member of the prehospital personnel determines either rigor mortis, 
livor mortis, maceration, or putrefaction, the patient will be considered to have been found dead and not in 
cardiac arrest even though CPR has been initiated by lay responders. This is in accordance with the Danish 
Cardiac Arrest Registry.8 
OHCA is defined as any individual with a cardiac arrest outside hospital grounds where the prehospital 
system is activated. These broad inclusion criteria were chosen to reflect the pragmatic scope of the trial and 
to allow for optimal external validity. 
 
4.3 Exclusion criteria  
Exclusion criteria: 
1) Traumatic cardiac arrest – including drowning and external asphyxia (e.g., hanging, strangulation, or 
foreign object airway obstruction) 
2) Known or strongly suspected pregnancy 
3) Prior enrollment in the trial 
4) Received adrenaline during CPR before arrival of prehospital personnel with the study drug 
5) Clinical indication for calcium administration during the cardiac arrest 
 
Traumatic OHCA will be excluded, because the patient population and the pathophysiology are vastly 
different from those of medical OHCA. 
OHCA during pregnancy is exceedingly rare,52 and we expect that this exclusion criterion will lead to only 
few, if any, exclusions. If pregnant patients are included (i.e., if the pregnancy is not known and not obvious), 
we do not expect our intervention or trial in general to put the patient or fetus at harm. Guidelines 
recommend that cardiac arrest in pregnancy is treated according to usual guidelines including intra-cardiac 
arrest medications.53  
Patients previously included in the trial will be excluded to avoid statistical complexity related to 
correlated data. Since this is documented (but might not be known by the cardiac arrest team) prior to the 
cardiac arrest and the intervention, any post-randomization exclusions will not lead to bias.54  
OHCA-patients in our setting could on rare occasions receive adrenaline by a non-participating 
prehospital unit (see section 4.1). These patients will be excluded to avoid excessive time to study drug 
administration.  

 
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Calcium is recommended in certain scenarios of cardiac arrest (see section 1.2.3). These patients are 
excluded to avoid that they do not receive guideline-based therapy. A clinical indication for calcium is 
determined by the treating clinician.    
 
 
4.4 Co-enrollment  
There will be no general restrictions on entry into other (post-cardiac arrest) clinical trials although this will 
be evaluated on a case-by-case basis.55 We are not aware of any ongoing or planned intra-cardiac arrest 
trials in this patient population in the Central Denmark Region.  
 
5. OUTCOMES 
5.1 Primary outcome 
5.1.1 Original definition  
The original primary outcome was ROSC at hospital arrival defined as palpable pulses or other signs of 
circulation at time of hospital arrival consistent with the Danish Cardiac Arrest Registry10 and other large 
trials.56,57  
 
5.1.2 Updated definition 
As per December 21st, 2020 (time stamp of protocol version 1.2), the definition of the primary outcome has 
been changed to sustained ROSC. Sustained ROSC is defined as palpable pulses or other signs of circulation 
without a need for chest compressions lasting at least 20 minutes.  
 
5.1.3 Rationale  
The rationale for any intra-cardiac arrest intervention is primarily to increase the rate of ROSC to 
subsequently improve the rate of meaningful survival. Since ROSC is a prerequisite for more long-term 
survival and since the focus of this investigation is an intra-cardiac arrest intervention, ROSC is a logical and 
meaningful primary outcome. ROSC is a core outcome measure in both the IHCA58 and OHCA11 Utstein 
guidelines and is suggested as a potential primary outcome measure by the AHA.59 
 
The original definition of the primary outcome, ROSC at hospital arrival, was chosen to ensure full data 
completeness, which was uncertain for sustained ROSC. Yet, at 294 patients included, there is no missing 
data on sustained ROSC. ROSC at hospital arrival has the disadvantage of being cross-sectional, while 
sustained ROSC better represents what clinicians are trying to achieve. The change of the primary outcome 
to sustained ROSC was made based on blinded data.  

 
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5.2 Secondary outcomes 
5.2.1 Definitions  
Key secondary outcomes will include survival as well as neurological outcome at 30 days. Neurological 
outcome will be assessed with the modified Rankin Scale (mRS, Table 1); scores 0-6 will be presented as 
counts and percentages, while the outcome will be dichotomized as favorable (mRS 0-3) vs. unfavorable 
(mRS 4-6). 
 
Table 1. modified Rankin Scale (mRS)60 
Score Definition 
0 
No symptoms 
1 
No significant disability  
Able to carry out all usual activities, despite some symptoms 
2 
Slight disability 
Able to look after own affairs without assistance, but unable to carry out all previous activities 
3 
Moderate disability 
Requires some help, but able to walk unassisted 
4 
Moderately severe disability 
Unable to attend to own bodily needs without assistance or unable to walk unassisted 
5 
Severe disability 
Requires constant nursing care and attention, bedridden, incontinent 
6 
Death 
 
5.2.2 Rationale  
Survival at 30 days and survival at 30 days with a favorable neurological outcome are considered key 
outcome measures in cardiac arrest research.11,58,59 All follow-up survival data will be obtained from 
electronical medical records or the Danish Central Personal Register which allows for accurate and virtually 
complete follow-up.61 The use of 30-day outcomes as compared to outcomes at hospital discharge avoids 
limitations related to potential differences in discharge practices.62-64  
A centrally-located, trained researcher will assess mRS using a standardized telephone interview, which 
ensures good reliability.65-67 The dichotomy with favorable at 0-3 and unfavorable at 4-6 is widely used in 
cardiac arrest research and is consistent with a recent large OHCA-trial.68 In case the patient is still 

 
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hospitalized, the interview will be face-to-face. Assessment of neurological outcome by telephone is valid 
and reliable.69  
 In accordance with the recent Core Outcome Set for Cardiac Arrest (COSCA)-initiative, we will also assess 
the Cerebral Performance Category (CPC).70 CPC will not be considered a key outcome of neurological status. 
 
5.3 Tertiary outcomes  
We will include 90-day survival as a measure of long-term survival. 90 days were chosen since it is unlikely 
that later mortality will be directly linked to the cardiac arrest or the trial intervention. 90 days is also 
consistent with recommendations from the AHA.59 
Health-related quality of life at 30 and 90 days will be assessed by the questionnaire EQ-5D-5L,71 which is 
supported by the AHA59 as well as the COSCA-initiative.70 EQ-5D-5L is a generic approach with five items 
covering symptomatic, physical, psychological, and social consequences of a disease. It is preferred to HUI3 
and SF-36, because it is free to use and requires a shorter interview. Assessment of health-related quality of 
life by telephone is valid and reliable.72 EQ-5D-5L allows for potential future cost-effectiveness analyses and 
comparison to the background population.  
During the same 90-day interview, we will reassess neurological outcome (mRS and CPC).  
In addition to the above, we will collect outcome data related to hemodynamics, laboratory values, 
mechanical ventilation, organ failure, and hospital disposition.  
To assess the potential beneficial effects of the intervention on hemodynamics, we will measure 
vasopressor-free days. A vasopressor will be defined as any continuous infusion of noradrenaline, dopamine, 
dobutamine, terlipressin, vasopressin, phenylephrine, and/or adrenaline. Vasopressor-free days will be 
defined as the number of days within the first 7 days after the cardiac arrest where the patient is not 
receiving vasopressors and is alive. Receiving vasopressors for at least 6 hours on a given day is defined as 
receiving vasopressors for that day. Contrary to other vasopressor outcomes, such as time to weaning from 
vasopressors, this outcome accounts for both vasopressor use and mortality.73 Invasive ventilation-free days 
will be defined in a similar manner. Invasive ventilation is defined as mechanical ventilation through an 
endotracheal or tracheostomy tube.  
To assess hemodynamics and organ failure, we will calculate the Sequential Organ Failure Assessment 
(SOFA)-score74 at 2, 24, 48 and 72 hours after the cardiac arrest in those alive. The SOFA score is a validated 
and widely used measure of organ failure assessing the respiratory, nervous, cardiovascular, hepatic, 
coagulation, and renal systems.74 We will assess both the cardiovascular sub score as well as the overall 
SOFA score. The calculation of the SOFA score will be based on available clinical and laboratory data. 

 
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Laboratory and clinical data closest to the given time point will be used. If a given component (e.g., bilirubin) 
is not available it will be assumed to be within normal ranges. If PaO2 values are not available, they will be 
imputed using imputations based on SpO2 values.75,76 
Laboratory values, specifically pH, potassium, calcium, and lactate from the first arterial (or venous) gas 
will be compared between groups.  
Hospital disposition (e.g., home, rehabilitation, nursing home, hospice) will be defined at the time of 
discharge from the initial acute care hospital.    
 
5.4 Harm  
5.4.1 General consideration 
Patients with OHCA have a 85% mortality rate in the first 30 days,8 and survivors will in the adjacent time risk 
complications such as global brain injury, impaired myocardial function, macrocirculatory failure, and 
increased susceptibility to infections.17 Furthermore, OHCA-patients have a high prevalence of pre-
resuscitation morbidity with cardiovascular- and cerebrovascular disease as well as chronic obstructive lung 
disease, diabetes, and psychiatric disease.77 The immediately preceding cause may be circulatory failure 
(coronary heart disease, primary arrhythmia, pulmonary embolism, hypovolemia), respiratory failure 
(medical, drowning, asphyxia), or more rarely neurologic disorders.68 Given this, it is difficult, if not 
impossible, to comprehensively report all adverse events and assess their possible relationship with the 
intervention.  
Generally, CaCl is considered safe and is commonly used in clinical practice (see section 1.2.2). The overall 
benefit and potential harm will be captured in our primary and secondary outcomes, and the clinical team 
will document any specific adverse events suspected to be related to the intervention.  
In an awake patient, CaCl is normally given slowly due to risk of brief paresthesia, calcium taste, and/or 
flushing. This is not a concern for our population group, who will be unconscious at the time of 
administration.  
 
5.4.2 Subcutaneous injection 
Accidental subcutaneous injection of CaCl can result in necrosis. However, the study drug – if given 
intravenously – is given immediately after adrenaline, which carries a similar risk and hence the same 
precautions; a misplaced peripheral catheter should be recognized here. The risk of necrosis due to the 
intervention is therefore minimal. 
 

 
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5.4.3 Hypercalcemia and arrhythmias 
There is concern that hypercalcemia can cause tachyarrhythmias, but this is only based on physiological 
theory78 and a few case reports concerning prolonged and often severe hypercalcemia seen in primary 
hyperparathyroidism and malignancy.79-84 There are, to our knowledge, no case reports of arrhythmias 
following short-lived hypercalcemia. Secondly, a recent cohort study of 31 patients admitted to the 
emergency department with severe hypercalcemia (albumin-corrected total calcium >4 mmol/L, median 4.3 
mmol/L) found no life-threatening cardiac arrhythmias or neurological complications during the patients’ 
admissions.85  
Potentially hypercalcemic patients will therefore not be excluded. This keeps the pragmatic scope of the 
trial, as hypercalcemia will hardly ever be recognized in the prehospital setting. Also, hypercalcemia has a 
general prevalence of 1/1000 and should be a rare encounter.86 If a hypercalcemic patient should receive 5-
10 mmol of CaCl, the serum ionized calcium peak is very short-lived (≈30 seconds), while the expected effect 
over the course of hours is Δ<0.3 mmol/L (see section 1.2.1). Consequently, we consider the risk of 
significant hypercalcemia low and the risk of tachyarrhythmias very low. 
 
5.4.4 Digitalis glycoside toxicity 
Similar caution exists regarding calcium administrations in patients treated with digitalis glycosides (e.g. 
Digoxin®) due to the “stone heart” theory: in digitalis glycoside toxicity, calcium excess may lead to impaired 
diastolic relaxation and hence a non-contractile state. This is based on physiological theory, a few case 
reports, and an animal model that found a pro-arrhythmic effect of serum calcium >15 mmol/L in the face of 
digitalis glycoside toxicity.87,88 A 2011 retrospective cohort study identified 161 patients with chronic digitalis 
glycoside toxicity (>2.0 ng/dL) and found that those who received intravenous calcium (n=23) did not have 
increased odds of mortality (adjusted OR 0.76, 95% confidence interval 0.24-2.5).89 Also, no arrhythmias 
occurred within 1 hour of intravenous calcium administration. A 1983 chart review of 480 OHCA patients 
receiving intravenous calcium, found no arrhythmias in seven patients taking digitalis.90 
Patients treated with digitalis glycosides will therefore not be excluded. This keeps the pragmatic scope 
of the trial, as a reliable drug list will rarely be available in the prehospital setting. Lastly, digitalis glycoside 
toxicity should be a rare encounter. 
 
5.4.5 Acute kidney injury 
There is a well-established association between prolonged (“chronic”) hypercalcemia and acute kidney injury 
with numerous case reports in primary hyperparathyroidism,91-93 malignancy,94,95 sarcoidosis,96-98 infection,99 
and milk-alkali syndrome.100-102 Likewise, the association has been established in iatrogenic hypercalcemia 

 
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after long-term overdose of vitamin D, calcium supplement, or denosumab.103-106 A recent study of 12,784 
patients found an association between total calcium at admission and the risk of developing acute kidney 
injury during admission.107 There are, to our knowledge, no case reports of short-lived hypercalcemia 
associated with acute kidney injury.  
 
The pathogenesis has been hypothesized in animal models of chronic severe hypercalcemia108-110 as well 
as through human renal biopsies taken from patients with severe disease of the calcium metabolism.111 Only 
a few animal models of renal arterial flow have studied the effect of short-lived hypercalcemia, yet only in 
ranges with ionized calcium >1.88 mmol/L: at this level, the relative effects on renal arterial flow and 
glomerular filtration rate were small.112-115 
 
Hypercalcemia is unwanted in chronic kidney failure due in part to the above-mentioned associations, 
but mostly because renal calcium excretion can be affected, and chronic hypercalcemia can – besides the 
already mentioned risks – lead to nausea, vomiting, obstipation, fatigue, and confusion.116 However, calcium 
administration is of particular interest in OHCA patients with kidney failure as it may help to treat a possible 
hyperkalemia. Therefore, patients with known or suspected kidney failure will not be excluded from the 
study. 
 
5.4.6 Peptic ulcer disease 
In patients with diagnosed peptic ulcer disease, hypercalcemia is associated with a hypergastrinemia-
induced increase in gastric secretion volume as well as acid secretion – yet, this is not the case for patients 
without diagnosed peptic ulcer disease.117-122 Also, the hypersecretion returns to normal within a few hours, 
when hypercalcemia is corrected.120 Chronic hypercalcemia due to primary hyperparathyroidism has been 
linked to de novo peptic ulcer disease, and parathyroidectomy seems to relieve the symptoms.123,124 To our 
knowledge, short-lived hypercalcemia has not been associated with de novo peptic ulcer disease, nor has it 
been linked to aggravating symptoms or prognosis in patients who already have the diagnosis. 
 
5.4.7 Acute pancreatitis 
Calcium is essential for intracellular messaging in the exocrine pancreas. However, in vitro studies show that 
hypercalcemia can lead to pancreatitis through raised trypsinogen activity, acinar cell apoptosis, and ductal 
outflow obstruction.125 Primary hyperparathyroidism has been associated with acute pancreatitis responsive 
to parathyroidectomy,126 while there are case reports with similar associations for other conditions with 
prolonged hypercalcemia.127-130 To our knowledge, short-lived hypercalcemia has not been associated with 
de novo pancreatitis, nor has it been linked to aggravating symptoms or prognosis in patients who already 
have the diagnosis. 

 
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5.4.8 Definitions  
The following definitions will be used:2  
 
Adverse event: any untoward medical occurrence in a subject to whom a medicinal product is administered 
and which does not necessarily have a causal relationship with this treatment. 
 
Serious adverse event: any untoward medical occurrence that at any dose requires inpatient hospitalization 
or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, results 
in a congenital anomaly or birth defect, is life-threatening, or results in death. 
 
Unexpected serious adverse reaction: a serious adverse reaction, the nature, severity or outcome of which is 
not consistent with the reference safety information. 
 
5.4.9 Specific adverse events 
To assess specific adverse and potentially serious adverse events, we will collect data on hypercalcemia, 
arrhythmias, acute kidney failure requiring dialysis, ulcers, and acute pancreatitis. Assessment of adverse 
events will be based on available laboratory values and clinical data. No specific procedures or blood draws 
will be performed. Other potential adverse events or serious adverse events will not be collected (see 
section 5.4.1). The sponsor will be notified about the occurrence of any serious adverse event within 24 
hours.  
The normal range of serum ionized calcium is 1.18-1.32 mmol/L.131 Hypercalcemia is rarely symptomatic 
and does not affect kidney function until albumin-corrected total plasma calcium rises to >3.2 mmol/L 
(ionized calcium >1.46 mmol/L).132 A hypercalcemic crisis is defined as a) >3.7 mmol/L (ionized calcium >1.8 
mmol/L) with acute kidney failure and/or poor general condition or b) >4.0 mmol/L (ionized calcium >2.0 
mmol/L.). Hypercalcemia will be defined by the peak serum pH-corrected ionized calcium concentration 
within the first 24 hours of hospital admission and – in line with the above-mentioned definitions – stratified 
in to mild (1.33-1.46 mmol/L), moderate (1.47-2.0 mmol/L), and severe (>2.0 mmol/L). As a secondary safety 
parameter, we will assess the uncorrected ionized calcium concentration in the first blood sample taken 
upon hospital arrival. 
 
Arrhythmia will be defined as any supraventricular or ventricular tachyarrhythmia requiring an 
intervention from the time of ROSC until 24 hours after hospital admission. Supraventricular 
tachyarrhythmias will not include sinus tachycardia.  

 
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Acute kidney injury will be defined as the need for acute dialysis (continuous veno-venous hemofiltration 
or acute hemodialysis) within the first week of hospital admission. Acute dialysis for conditions not related 
to failing kidney function (e.g. removal of toxins) will not be included in this parameter. 
 
Peptic ulcer disease will be defined as gastroscopy-confirmed ulcerative disease of the stomach or 
duodenum within the first week of hospital admission. 
 
Acute pancreatitis will be defined as plasma amylase levels >360 units/L within the first week of hospital 
admission. 
 
5.4.10 Timeline 
Data on hypercalcemia and tachyarrhythmias will be collected from the time of sustained ROSC and through 
the first 24 hours of hospital admission, as a patient without calcium metabolism disease should be able to 
correct a slight iatrogenic hypercalcemia within this time frame. We will collect data on delayed potential 
adverse events (acute dialysis, peptic ulcer disease, and acute pancreatitis) in the first week of hospital 
admission since any event after this time frame will have poor association with our intervention. We do not 
expect any survivors to be discharged within one week, as OHCA survivors usually have longer hospital 
admissions.133 
 
5.4.11 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Suspected Unexpected Serious Adverse Reactions (SUSAR) will be reported to the independent data-
monitoring committee (IDMC) (see section 10.2) and the regulatory authorities as applicable. Given the 
consideration outlined in section 5.4.1, most events or conditions, including but not limited to organ failure, 
infection, tissue ischemia, brain damage, cardiac arrest, and death, will not be considered SUSARs. This 
approach is compatible with an ongoing international, multicenter trial in post-cardiac arrest 
(ClinicalTrials.gov Identifier: NCT02908308) and the ongoing Danish trial Vasopressin and 
Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) (ClinicalTrials.gov Identifier: NCT03640949). 
No events, including those outlined in section 5.4.3, will automatically lead to unblinding.  
 
5.4.12 Reporting  
Once a year the sponsor will submit a list of all registered adverse events that have occurred during the trial 
period as well as a report on safety of the trial subjects to the Danish Medicines Agency and the National 
Committee on Health Research Ethics. The sponsor will notify both agencies when the trial has been 
completed (no later than 90 days thereafter) or if earlier than planned, the reasons for stopping the trial will 
be given. The results from the trial including important adverse events will be recorded on EudraCT. 

 
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5.5 Additional follow-up  
The primary trial and publication will be related to the study outcomes (section 5.1, 5.2, and 5.3). However, 
extended follow-up at 180 days and 1 year, including overall survival, neurological outcomes, and health-
related quality of life, will be collected and reported. Data will be collected and analyzed like the 90-day 
outcomes and will be reported in a separate publication. Although the overall trial will be unblinded after 
the collection of the 90-day outcomes, the person assessing 180 days and 1-year outcomes will be blinded to 
treatment assignment.  
 
6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN  
6.1 Sample size calculation 
6.1.1 Original sample size calculation 
The original sample size was based on the primary outcome of ROSC at hospital arrival. Based on the best 
available data,10,134 we assumed that the ROSC rate would be 25.0% in the placebo group. We anticipated a 
ROSC rate of 37.5% in the calcium group corresponding to an absolute treatment effect of 12.5% and a 
relative treatment effect of 50%. Based on a chi-squared test and an alpha of 0.05, a sample size of 430 was 
needed to obtain 80% power.  
 
6.1.2 Updated sample size calculation 
From Jan. 20th to November 18th, 61 out of 270 patients (23% [95%CI 14, 26]) met the updated primary 
outcome of sustained ROSC. This is lower than anticipated.  
 
We have re-estimated the sample size based on this lower combined ROSC proportion. We anticipate a 
ROSC proportion of 18% in the placebo group and 27% in the calcium group, corresponding to an absolute 
treatment effect of 9% and a relative treatment effect of 50%. With  a chi-squared test, an alpha of 0.05, and 
80% power, a sample size of 674 patients is needed.   
We anticipate no loss to follow-up for the primary outcome.  
 
Of note, a recent trial of adrenaline administration during OHCA found that this increased ROSC 
approximately 3-fold68 illustrating that intra-cardiac arrest interventions have the potential to substantially 
increase the rate of ROSC. Similarly, the 1985-trials found a 3-fold increase in ROSC with calcium 
administration (section 1.3).43,44 
 

 
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6.2 Statistical analysis plan 
6.2.1 General considerations 
The statistical analyses and reporting will adhere to the Consolidated Standards of Reporting Trials 
(CONSORT)-guidelines.135,136 All tests will be two-sided, a p-value <0.05 will be considered significant, and all 
confidence intervals will have 95% coverage. P-values will only be reported for the primary outcome and the 
two key secondary outcomes. 
Patient inclusion and exclusion will be illustrated in a CONSORT flow diagram (see Appendix 3 for a draft). 
All analyses will be conducted on a modified intention-to-treat basis only including patients receiving at 
least one dose of the study drug and meeting all inclusion criteria and no known exclusion criteria at the 
time of drug administration. In a double-blind trial, this approach is unbiased while increasing precision.54  
The two groups will be compared in relation to baseline patient and cardiac arrest characteristics using 
descriptive statistics.  
The persons conducting the statistical analysis will be blinded to the randomized allocation and the 
statistical analysis will be performed separately by two investigators. Groups will be designated as “A” and 
“B” until all pre-specified analyses are performed and shared with all authors and the IDMC (see section 
10.2).    
 
6.2.2 Primary and secondary outcomes  
The primary and secondary outcomes (binary variables) will be presented as counts and proportions in each 
group. Results will be reported as both risk ratios and risk differences. 95% confidence intervals will be 
obtained using methods described by Miettinen and Nurmimen.137 In the case where results are significantly 
different between groups, the number needed to treat (with 95% confidence intervals) will also be provided. 
P-values will be obtained from Fisher’s Exact test.  
 
As a sensitivity analysis, we will estimate the risk ratio with 95% confidence intervals for the primary 
outcome while adjusting for station (stratification variable) and strong prognostic factors as covariates: this 
includes age, whether the cardiac arrest was witnessed, whether bystander CPR was initiated or not, and the 
initial rhythm.138-141 Small stations (i.e. those with less than 30 patients included) will be combined. The risk 
ratio will be estimated from a log-binomial regression model.142 If this model fails to converge, a modified 
Poisson regression model will be used instead.142,143 Age will be included as a linear continuous variable, and 
witness-status, bystander CPR as well as the initial rhythm will be included as binary variables (i.e. witnessed 
vs. unwitnessed, bystander CPR vs. no bystander CPR, and shockable vs. non-shockable, respectively). 
 

 
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6.2.3 Subgroup analyses  
Subgroup analyses will be performed on both the absolute and relative scale. The analyses will be performed 
according to the initial rhythm (shockable vs. non-shockable), the timing of the drug administration 
(dichotomized by the median), intravenous vs. intraosseous administration, whether or not the OHCA was 
witnessed by a bystander, whether the OHCA was witnessed by the ambulance staff, and whether bystander 
CPR was performed. The trial is not powered to detect subgroup differences, and these will be considered 
exploratory and hypothesis generating.   
 
Additional exploratory subgroup analyses will be performed in patients with PEA as the presenting 
rhythm. These will include subgroup analyses related to electrocardiogram (ECG) characteristic (e.g., QT 
length) and will be presented in a separate manuscript.  
 
6.2.4 Additional analyses and outcomes  
Continuous outcomes (e.g. health-related quality-of-life) will be compared using linear regression with 
station included as a random effect.145 Health-related quality of life and SOFA-scores will only be assessed in 
those alive at the time of measurement.  
Survival until 90 days will be presented with Kaplan-Meier curves,146 but will otherwise be analyzed as a 
binary outcome as described section 6.2.2.  
Adverse events and other binary outcomes will be presented and analyzed like the primary and 
secondary outcomes.     
 
6.2.5 Missing data 
Missing data will be reported in the relevant publications. We do not expect any missing data for the primary 
outcome or the key secondary outcomes. For mortality up to 90 days, there may be some very limited loss to 
follow-up.  
There might be some limited missing data for neurological outcomes and health-related quality of life at 
90 days due to loss to follow-up. Multiple imputation using known risk factors for outcomes after OHCA will 
be used to impute values for patients with missing data if missing data is substantial (>10%).  
 
6.2.6 Multiple comparisons  
No adjustments will be made for multiple comparisons. The rationale for this approach is three-fold. First, 
the trial has a clearly defined primary outcome which will ensure that the risk of a Type I error (i.e. false 
positives) is equal to the set alpha (i.e. 0.05) for this outcome. Second, the simplest procedure to control the 
family-wise error rate is the Bonferroni correction where the alpha is divided by the number of tests 

 
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performed within the “family” of tests. However, defining the “family” is difficult and at best arbitrary.149,150 
Third, any adjustment for multiple comparisons to control the family-wise error rate increases the chance of 
Type II errors (i.e. false negatives).150  
Given that the risk of Type I errors is not well defined when conducting multiple secondary analyses, 
these specific analyses should be considered exploratory and hypothesis generating.      
 
6.2.7 Statistical stopping criteria  
Since the primary outcome is not mortality, there will be no formal stopping criteria for efficacy. There will 
be no predefined stopping criteria for futility since enrollment of the full cohort might allow for detection of 
efficacy in subgroups or in other outcomes even if the primary outcome is negative. Furthermore, since two 
previous randomized clinical trials have shown a potential pooled efficacy,43,44 a negative trial with an 
adequate sample size will be important. For potential stopping due to safety concerns, see section 10.2.  
 
6.2.8 Secondary Bayesian analyses  
We will perform secondary Bayesian analyses for the primary and key secondary outcomes in order to aid 
interpretation of the results.151 Given the limited evidence on calcium use in cardiac arrest, we will primarily 
use noninformative prior probability distributions and the results obtained from the trial to obtain posterior 
probability distributions for both risk differences and risk ratios. More skeptical neutral prior probability 
distributions will also be used. These will be based on an assumed trial of a quarter of the sample size with 
no treatment effect.151 For the outcome ROSC, an analysis will also be made using a prior probability 
distribution based on the previous two calcium trials (section 1.3). The posterior probability distributions will 
be illustrated graphically, and the probability that the true treatment effect is larger than various thresholds 
for risk ratios and differences will be provided. Lastly, we will provide the median risk ratio and risk 
difference with 95% credibility intervals.  
 
7. DATA COLLECTION AND MANAGEMENT  
7.1 Data collection process  
A trained member of the research team, along with the station investigators, will be responsible for data 
collection and entry. Very limited data will be obtained by the prehospital team on an electronic case report 
form. This will include the patient identifier (i.e., Danish Central Personal Register number), study ID, timing 
of the first adrenaline and calcium dose, route of administration, number of doses, and name of the 
prehospital personnel responsible for inclusion. This, along with the telephone interviews for long-term 

 
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follow-up, will be the only source data; all additional data will be obtained from pre- and in-hospital 
electronical medical records, as well as linkage with relevant registries, and will be based on measurements 
and assessments made by the clinical team. All ECG-data from monitors and defibrillators will be uploaded 
to a safe electronic database.  
 
7.2 Variables 
7.2.1 Overview 
Based on the definitions in section 4.2, all OHCAs will be entered into a screening log. OHCAs will be 
identified by review of prehospital records and logs. For those not randomized, a specific reason for non-
inclusion/exclusion will be documented. All randomized patients (i.e., those where the ampoule is opened) 
will be entered into the main database. For those randomized that did not receive the study intervention, 
only a very limited amount of data will be collected.    
A detailed data dictionary that clearly defines all included variables will be created prior to patient 
enrollment. The data dictionary will provide the name of the variable (including the code used in the 
database), a detailed definition of the variable, categories for categorical variables, and units and ranges for 
continuous variables.  
 
The number of collected variables will be kept relatively small to limit resource use and data entry 
mistakes. The included variables largely follow the OHCA Utstein guidelines from 2015.11 Below is provided a 
brief overview of the included variables, but details are reserved for the data dictionary.  
 
7.2.2 Pre-cardiac arrest characteristics 
Patient demographics and characteristics  
• 
Name 
• 
Unique patient identifier (Danish Central Personal Register number) 
• 
Age  
• 
Sex 
• 
Race 
• 
Height 
• 
Weight  
 
Conditions/medications prior to the cardiac arrest 
• 
Co-morbidities 

 
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o Cardiac 
o Non-cardiac 
• 
mRS (and CPC) prior to cardiac arrest  
• 
Clinical fragility index 
 
7.2.3 Cardiac arrest characteristics  
Pre-intervention variables 
• 
Date and time of the cardiac arrest 
• 
Location of the cardiac arrest 
• 
Witnessed (bystander, EMS, none) 
• 
Bystander CPR 
• 
Bystander shock with automated external defibrillator (AED) 
• 
Date and time of the first dose of adrenaline 
• 
Initial rhythm 
• 
Rhythm when intervention administered  
• 
Date and time of first defibrillation  
• 
Response time by EMS 
o Primary ambulance 
o Physician-manned- or paramedic ambulance 
 
Post-intervention variables 
• 
Date and time of the end of resuscitation (ROSC or termination without ROSC) 
• 
Extracorporeal cardiopulmonary resuscitation (ECPR) 
 
Other variables 
• 
Other drugs during resuscitation 
• 
Pathogenesis 
o Medical 
o Drug overdose 
o Drowning 
o Electrocution 
o Asphyxia 

 
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Trial related variables 
• 
Study ID 
• 
Station 
• 
Receipt of study medication  
o If no, reason for no study medication provided  
• 
Paramedic or physician  
• 
Intravenous vs. intraosseous administration  
• 
Timing of study drug administration 
• 
Doses of study medication provided 
• 
Requirement for emergency unblinding 
• 
Inclusion criteria 
• 
Exclusion criteria 
• 
Date and time consent for data collection is obtained  
 
7.2.3 Post-cardiac arrest characteristics  
• 
Targeted temperature management 
o If yes: Temperature target, duration 
• 
Coronary reperfusion attempted 
o If yes: Type and timing 
• 
Adverse events (see section 5.4.3) 
 
7.2.4 Outcomes  
• 
ROSC 
• 
Laboratory values 
• 
Vasopressor-free days 
• 
Ventilator-free days 
• 
SOFA scores at 2, 24, 48 and 72 hours 
• 
Survival at 30 days, 90 days, 180 days and 1 year 
• 
mRS and CPC at 30 days, 90 days, 180 days and 1 year  
• 
EQ-5D-5L at 30 days, 90 days, 180 days and 1 year 
 

 
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7.3 Data quality and validity  
7.3.1 Central monitoring 
Data quality and validity will be optimized by having trained researchers enter all data according to a 
detailed data dictionary. Research Electronic Data Capture (REDCap) (see section 7.4) is designed such that 
data forms contain field-specific validation checks ensuring that mandatory fields are filled out and that 
continuous variables are within predefined ranges. Furthermore, REDCap allows for data quality rules 
warning of potential incorrect data (e.g., administration of study drug before arrival of prehospital 
personnel); this data is assessed and – if relevant – corrected. 
Given its limited utility, double-data entry will not be performed.152,153  
 
7.3.2 On-site monitoring 
On-site monitoring will be performed by the Good Clinical Practice unit according to the developed 
monitoring plan. Please see section 10.1. 
 
7.4 Data storage and security  
The database application we will use is REDCap.154 REDCap is a professional database that provides a user-
friendly interface. The REDCap data management system is secure, fully compliant with all regulatory 
guidelines and includes a complete audit-trail for data entry validation. Through these mechanisms, as well 
as relevant training for all involved parties, patient confidentiality will be safeguarded. REDCap is available 
for free at Aarhus University. The case report form will be digital. 
 
Data will be handled according to all relevant Danish laws including the General Data Protection 
Regulation (“Databeskyttelsesforordningen”) and the Data Protection Act (“Databeskyttelsesloven”).  The 
project will be registered with the Central Denmark Region’s internal list of research projects.  
 
7.5 Data access  
During the trial, relevant members of the steering committee along with the station investigators will have 
access to the entire database. Once the database is locked, a deidentified version of the database will be 
made available to the members of the steering committee. The IDMC, the Good Clinical Practice unit, 
regulatory agencies, and other relevant monitoring entities will have direct access to patients’ records and to 
all relevant trial data including all source data as applicable.  
 

 
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8. CLINICAL TREATMENT  
The clinical management of included patients will be at the complete discretion of the treating prehospital 
and in-hospital teams in order to test the interventions in a real-life clinical scenario. In general, 
management will adhere to the intra- and post-cardiac arrest guidelines provided by the ERC49 and the 
Danish Resuscitation Council,155 but no specific treatments will be prohibited or mandated. The stations will 
be informed about the most recent guidelines for intra-cardiac arrest care and will be encouraged to limit 
premature termination of resuscitation efforts.156 Hospitals will also be encouraged to follow ERC post-
cardiac arrest guidelines including appropriate neurological prognostication.157 
 
9. ETHICAL CONSIDERATIONS  
9.1 Clinical equipoise  
9.1.1 Potential benefits 
Details about the potential benefits of the intervention are provided in the background section (section 1.2 
and 1.3). In brief, two randomized, double-blind trials found that calcium might lead to a clinically 
meaningful increase in ROSC in patients with OHCA and a refractory non-shockable rhythm.43,44 
 
9.1.2 Potential harms  
The two trials with intravenous calcium administration in OHCA found no signs of significant harm.43,44 Based 
on case reports, there is concern that hypercalcemia could lead to tachyarrhythmia or – in the setting of 
digitalis glycoside toxicity – impaired diastolic relaxation, but the clinical evidence indicates that it is safe 
(section 5.4.3 and 5.4.4). There is an association with gastric hypersecretion, but only in patients who 
already have peptic ulcer disease, and even in these patients there are no data showing calcium should 
worsen symptoms or outcomes (section 5.4.6). Lastly, prolonged hypercalcemia has been linked with acute 
kidney injury and acute pancreatitis, but no evidence shows an association with short-lived hypercalcemia 
(section 5.4.5 and 5.4.7). 
 
9.1.3 Risk/benefit ratio  
From the data provided above in section 9.1.1. and 9.1.2 and in the background section (section 1.2 and 1.3), 
the current risk/benefit ratio is encouraging for calcium administered during OHCA. However, due to the 
previous trials’ non-significant result (p=0.06), their small sample size (n=163), and some contrary evidence 
from observational studies,30,31 international guidelines are calling for additional clinical trials.47 Taken 
together, there is clear clinical equipoise for calcium administration during OHCA. 
 

 
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9.2 Research in cardiac arrest   
9.2.1 General considerations  
Research in cardiac arrest is ethically challenging for two reasons: 1) Patients are unconscious and can 
therefore not provide informed consent and 2) treatment must be administered within minutes limiting the 
possibility of obtaining informed consent from a legally authorized representative.158,159 Despite these 
challenges, there is an ongoing need to conduct research in this, and similar, patient populations to improve 
outcomes. International guidelines, such as the revised Declaration of Helsinki,1 European regulations,2 and 
the Good Clinical Practice guidelines,3 clearly supports research in such populations. For example, the 
revised Declaration of Helsinki states:  
 
“Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed 
consent is a necessary characteristic of the research group. In such circumstances the physician must seek 
informed consent from the legally authorised representative. If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed consent have been 
stated in the research protocol and the study has been approved by a research ethics committee. Consent to 
remain in the research must be obtained as soon as possible from the subject or a legally authorised 
representative.”1 
 
The current trial will adhere to the revised Declaration of Helsinki as well as all applicable laws and 
regulatory guidelines.  
 
9.2.2 Danish regulations 
Danish law allows research without informed consent in situation where the following criteria are met:160,161  
 
1) The research can only be conducted in the given acute situation 
2) The patient is incapable of providing informed consent 
3) Consent cannot be obtained from a surrogate given the urgency of the intervention   
4) The research specifically involves the patient’s current condition  
5) There is a possibility of benefit to the patient  
 

 
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The current trial fulfils all the above criteria as described in section 9.2.3 for #1-4 and for #5 in section 9.1. 
Under these circumstances, research with pharmacological interventions is allowed if the following is 
obtained:160-162  
 
1) Consent is obtained from a designated “legal guardian” (“forsøgsværge” in Danish)  
2) Informed consent is obtained from the patient or a surrogate as soon as feasible  
 
A “legal guardian” is a physician not involved in the research related to the specific patient and who is not in 
an inferior/superior position to the investigator/sponsor. The “legal guardian” should act according to the 
interest of the research participant.  
 
9.2.3 Regulations in relation to the current trial  
#1. The research can only be conducted in the given acute situation 
Given the high morbidity and mortality of OHCA (see section 1.1.1), clinical trials are highly needed to 
improve patient outcomes. Animal studies do not adequately reflect the clinical condition of cardiac 
arrest,163 and human trials are needed to advance the treatment of cardiac arrest patients. There is no other 
clinical condition that reflects cardiac arrest, and any study aimed to improve outcomes for cardiac arrest 
patients can therefore only be conducted in this population.      
 
#2. The patient is incapable of providing informed consent 
OHCA is an unpredictable and sudden event. It is therefore impossible to obtain consent prior to the event. 
During the cardiac arrest, patients are unconscious and therefore not able to provide consent.   
 
#3. Consent cannot be obtained from a surrogate given the urgency of the intervention   
Cardiac arrest is an acute event that often lasts for less than 30 minutes. The intervention will be 
administered as soon as possible after the first adrenaline dose, which is given as soon as possible in patients 
with a non-shockable rhythm (most often <20 minutes from cardiac arrest onset), and after the third 
defibrillation in patients with a shockable rhythm (approximately 6-7 minutes after the beginning of 
advanced resuscitation efforts11). Given these time frames, it would be impossible to obtain consent from a 
surrogate.  
 
#4. The research specifically involves the patient’s current condition 

 
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The interventions in this trial is specifically targeted for OHCA patients and if proven effective, will benefit 
this patient population. 
 
9.3 Procedures 
9.3.1 Ethical review committee  
The trial will be sent for approval by the regional ethics committee. 
 
9.3.2 Trial-specific procedures 
The “legal guardian” will be a prehospital physician not involved in trial procedures related to the specific 
patient. Consent for enrolment from the “legal guardian” will be obtained either through direct conversation 
or a phone call, while written consent will be obtained as soon as possible thereafter. As the “legal guardian” 
could be from a station involved in trial enrollment, he/she could be involved in trial procedures for other 
unrelated patients. All potential “legal guardians” will be made aware of the trial including background, 
significance, inclusion- and exclusion criteria, as well as potential risks and benefits. This allows for an 
informed and prompt decision about patient enrollment.  
As soon as possible, a physician will obtain consent for further data collection from the patient or – if the 
patient is not able to provide consent – by a secondary “legal guardian” and a surrogate. The physician 
obtaining consent will be a member of the steering committee or a physician with sufficient knowledge 
about the patient, the condition, and the trial (i.e., a member of the clinical team who has been formally 
educated about the trial and relevant procedures). Trial information and the consent request will take place 
in an undisturbed room, and the patient or the surrogate will have the opportunity to request an assessor. 
Between the trial information and the consent request, the patient or surrogate will be provided with an 
appropriate amount of time for consideration, and further time can be requested as needed. 
The patient, surrogate, the person obtaining the consent, and the secondary “legal guardian” will sign 
individual digital consent forms as appropriate. If a patient dies before it is possible to obtain consent (we 
anticipate that approximately 75-80% will not achieve ROSC, see section 6.1), patient data will be included in 
the trial.164 If a patient denies future participation in the trial, no additional data will be collected but all data 
collected up until the point of withdrawal will be included consistent with Danish law.165 
 
When approached, the patient or a surrogate will be informed, verbally and in writing, about the 
background and significance of the study, inclusion criteria, potential risks and benefits, as well as a brief 
description of the study protocol. They will be informed that no additional interventions or procedures, 
except the telephone interviews for long-term follow-up, will be performed and that future participation will 
only include data collection. The patient or the surrogate will then provide written informed consent 

 
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through the informed consent form approved by the ethical review committee. When consent is obtained 
from participants or a surrogate, information about potential deidentified data sharing will also be included.  
 
The consent forms will be digital, and all signatures will be written on a smart phone or tablet using 
REDCap which has dedicated functionalities for written consent.  
 
9.3.3 Insurance 
The patients in the study are covered by the Danish patient insurance.166  
 
10. MONITORING 
10.1 Good Clinical Practice monitoring 
The trial will be monitored by the regional Good Clinical Practice monitoring unit. A detailed monitoring plan 
will be developed prior to trial commencement. The monitoring unit will have full access to all data in the 
trial.  
 
10.2 Independent data-monitoring committee (IDMC) 
The IDMC will be responsible for safeguarding the interests of trial participants, assessing the safety and 
efficacy of the interventions during the trial, and for monitoring the overall conduct of the clinical trial. The 
IDMC will consist of three clinicians/trialist with expertise in cardiac arrest research. The IDMC members are 
chosen such to avoid any financial or intellectual conflicts of interest. The IDMC will be independent from 
the sponsor and the trial investigators. The IDMC will review deidentified data for safety at three 
predetermined milestones (50, 200, and 400 enrolled patients, respectively), but can – at any time – require 
extra reviews. Unless there are group differences necessitating unblinding (as determined by the IDMC), the 
IDMC will be blinded to treatment groups. The trial will continue while the IDMC review data. After the 
reviews, the IDMC will create a short report to the steering committee with recommendations for 
continuation, modifications, or termination of the trial. As noted in section 6.2.7, there will be no formal 
stopping criteria for efficacy or futility. Criteria for recommending termination will be at the discretion of the 
IDMC, and there will be no formal statistical criteria for termination due to safety. The final decision 
regarding potential modifications or termination will rest with the steering committee and the principal 
investigator. A detailed charter for the IDMC is provided in Appendix 4.  

 
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11. TIMELINE AND ENROLLMENT  
11.1 Timeline  
 
Pre-trial 
Year 1 
Year 2 
Year 3 
Funding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol development 
and modifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Development of the 
statistical analysis plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethical/regulatory 
approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of data 
dictionary and SOPs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of study drug 
kits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial registration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of 
randomization list 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Education of 
ambulance staff  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Good Clinical Practice 
and IDMC monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient inclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Writing and publication 
of methodology article 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cleaning and closing of 
the final database 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main manuscript 
writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblinding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Publication and 
presentation of results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Planning of the next 
study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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11.2 Feasibility  
From Jan. 20th, 2020 to December 10th, 2020, we have included 294 patients corresponding to nearly 1 
patient per day. We therefore anticipate that we will be able to enroll 330 patients per year. Based on the 
current enrollment rate, we will reach the updated sample size of 674 patients by spring of 2022. 
 
11.3 Enrollment  
Enrollment at each station will be continuously monitored by the station investigator, the coordinating 
investigator, and the principal investigator. Formal reports outlining the number of OHCA and the proportion 
of those enrolled at each station will be shared with the steering committee monthly. In case multiple 
eligible OHCA are not enrolled, a root cause analysis will be performed, and efforts will be made to avoid 
such issues in the future. Given the urgency of OHCA, we do not expect 100% enrollment rate. However, we 
will aim for enrollment of >50% of eligible OHCA. In case that a station continuously underperforms despite 
troubleshooting and feedback, the steering committee will evaluate whether enrollment will continue at 
that station.  
 
11.4 Additional sites 
In case target enrollments are not met after 6 months to 1 year of enrollment, additional regions of 
Denmark will be approached regarding participation in the trial.  
 
12. PUBLICATION PLAN  
Four manuscripts are planned from the current trial. Prior to unblinding of the results, a methodology article 
will be published including a detailed description of the trial and the statistical analysis plan. The second and 
primary manuscript will include the main results including pre-defined primary, secondary, and tertiary 
outcomes. The manuscript will adhere to the CONSORT guidelines.135,136 The coordinating investigator will be 
the first author, and the principal investigator will be the last and corresponding author. Additional 
authorship will follow authorship guidelines from the International Committee of Medical Journal Editors167 
and will include members of the steering committee and representatives from the stations as appropriate. 
The trial results will be shared with participating stations and via press releases, as well as with participating 
patients if they requested so on their consent form. The third manuscript will include long-term follow-up at 
180 days and 1 year (see section 5.5). The fourth manuscript will focus on the subgroup of patients with PEA. 
Study findings will be published irrespective of the results. Trial findings will be published irrespective of the 
results.    

 
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13. DATA SHARING 
Six months after the publication of the last results, all deidentified individual patient data will be made 
available for data sharing.168 Procedures, including re-coding of key variables, will be put in place to allow for 
complete deidentification of the data. Data will be completely anonymized according to Danish law.  
All relevant trial-related documents, including the protocol, data dictionary, and the main statistical code, 
will be shared along with the data. There will be no predetermined end date for the data sharing. Data will 
be available for any research purpose to all interested parties who have approval from an independent 
review committee and who have a methodological sound proposal as determined by the steering committee 
of the current trial. Only the methodological qualities and not the purpose or objective of the proposal will 
be considered. Interested parties will be able to request the data by contacting the principal investigator. 
Authorship of publications emerging from the shared data will follow standard authorship guidelines from 
the International Committee of Medical Journal Editors167 and might or might not include authors from the 
steering committee depending on the nature of their involvement.  
 
14. FUNDING  
Funding for the trial is provided by the Novo Nordic Foundation (DKK 2,942,996), Aarhus University (DKK 
180,000), the Health Research Foundation of Central Denmark Region (DKK 782,449), and the Tryg 
Foundation (DKK 271,349). Funding is administered at the Prehospital Emergency Medical Services, Central 
Denmark Region and is used for salary support, pharmacy and medications costs, monitoring, and additional 
operational expenses. Additional funding will be applied for at various private and public foundations. The 
funding agencies will have no role in the design and conduct of the study; collection, management, analysis, 
and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit 
the manuscript for publication.  
 
15. TASKS AND RESPONSIBILITIES  
Principal investigator, sponsor, and coordinating investigator: Overall responsibility for protocol 
development, funding, budget overview, data dictionary development, ethical approval, trial registration, 
daily management, trial oversight, contact to the pharmacy, contact to Good Clinical Practice monitoring 
unit and the data and safety monitoring board, assessment of overall recruitments, potential recruitment of 
additional sites, data analysis, and dissemination and presentation of results. Also, the responsibility to 

 
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educate station personnel, evaluation of eligible patients not included, data entry and management, and 
patient follow-up. 
 
Steering committee: Protocol development, funding, budget overview, data dictionary development, trial 
oversight, dissemination of results, responsibilities as principal investigator for short time periods.  
 
Station investigators: Responsible for station-specific enrollment, evaluation of eligible patients not included, 
education of personnel at participating stations, reporting of station-specific issues or challenges to the 
principal investigator, participant consent for data collection. 
 
Clinical team: Administration of the study drug, participant consent for data collection  
 
Good Clinical Practice-unit: See section 10.1. 
 
IDMC: See section 10.2.  

 
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Ringgren KB, Christensen HC, Schønau L, et al. Rapport for Dansk Hjertestopregister 2018 [Danish]. 
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Appendices 
Appendix 1: Conflict of interest disclosures for the steering committee members 
Lars W. Andersen  
Industry:  
• 
None 
 
Other:  
• 
None 
 
Hans Kirkegaard  
Industry:  
• 
None 
 
Other:  
• 
None 
 
Asger Granfeldt 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Mikael Fink Vallentin 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Thomas Dissing 
Industry:  

 
COCA Protocol – version 1.2 
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• 
None 
 
Other:  
• 
None 
 
Christian Fynbo Christiansen 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Christian Juhl Terkelsen 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Steffen Christensen 
Industry:  
• 
None 
 
Other:  
• 
None 
 
 
Carsten Meilandt  
Industry:  
• 
None 
 
Other:  
• 
None 

 
COCA Protocol – version 1.2 
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COCA Protocol – version 1.2 
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Appendix 2: Study kit and drug labeling (Danish)  
 

 
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Appendix 3: Draft of CONSORT flow diagram 
 
 
 
 
 
 
 
OHCA  
Excluded (n= ) 
1) Traumatic cardiac arrest  
2) Known or strongly suspected pregnancy 
3) Prior enrollment in the trial 
4) Received adrenaline during CPR before 
arrival of prehospital personnel with the 
study drug 
5) Clinical indication for calcium 
administration during the cardiac arrest  
 
Analyzed for ROSC (n= ) 
 
Lost to follow-up (n= ) 
Analyzed for 30-day survival (n= ) 
 
Lost to follow-up (n= )  
Analyzed for 30-day favorable neurological outcome (n= ) 
 
Lost to follow-up (n= ) 
Allocated to calcium (n= ) 
 
Received calcium and eligible for analysis (n= ) 
 
Received calcium but not eligible for analysis (n= ) 
o 
Reasons (n= ) 
 
Did not receive calcium (n= ) 
o 
ROSC prior to drug delivery (n= ) 
o 
Patient declared dead prior to drug delivery 
(n= )  
o 
Logistical reason (n= )  
Randomized (n=  ) 
Allocated to placebo (n= ) 
 
Received placebo and eligible for analysis (n= ) 
 
Received placebo but not eligible for analysis (n= ) 
o 
Reasons (n= ) 
 
Did not receive placebo (n= ) 
o 
ROSC prior to drug delivery (n= ) 
o 
Patient declared dead prior to drug delivery 
(n= )  
o 
Logistical reason (n= )  
Analyzed for ROSC (n= ) 
 
Lost to follow-up (n= ) 
Analyzed for 30-day survival (n= ) 
 
Lost to follow-up (n= )  
Analyzed for 30-day favorable neurological outcome (n= ) 
 
Lost to follow-up (n= ) 
Not included (n= ) 
1)  < 18 years 
2) Did not receive at least one dose of 
adrenaline during CPR 

 
COCA Protocol – version 1.2 
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Appendix 4: Charter for the independent data-monitoring committee (IDMC) 
 
 
 
Charter for the independent data-monitoring committee (IDMC) for the COCA trial 
 
 
Trial name: Calcium for Out-of-Hospital Cardiac Arrest – A Randomized, Double-Blind, Placebo-Controlled 
Trial 
 
Principal investigator and sponsor: Associate professor Lars W. Andersen, M.D., M.P.H., Ph.D., D.M.Sc. 
 
EudraCT Number: 2019-003387-46 
 
Research ethical committee no.: 1-10-72-215-19 
 
 
 

 
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Introduction  
This charter will define the primary responsibilities of the IDMC, its relationship with other trial 
components, its membership, and the purpose and timing of its meetings. The charter will also 
provide the procedures for ensuring confidentiality and proper communication, the statistical 
monitoring guidelines to be implemented by the IDMC, and an outline of the content of the data that will be 
provided to the IDMC. 
 
Responsibilities of the IDMC 
The IDMC will be responsible for safeguarding the interests of trial participants, assessing the safety and 
efficacy of the interventions during the trial, and for monitoring the overall conduct of the clinical trial. The 
IDMC will provide recommendations about stopping or continuing the trial to the steering committee of the 
COCA trial. To contribute to enhancing the integrity of the trial, the IDMC may decide to also formulate 
recommendations relating to the selection/recruitment/retention of participants, their management, 
improving adherence to protocol-specified regimens and retention of participants, and the procedures for 
data management and quality control. Any such recommendations will be at the discretion of the IDMC.   
The IDMC will be advisory to the steering committee. The steering committee will be responsible for 
promptly reviewing the IDMC recommendations, to decide whether to continue or terminate the trial, and 
to determine whether amendments to the protocol or changes in trial conduct are required. 
The IDMC will be notified of all changes to the trial protocol or conduct. The IDMC concurrence 
will be sought on all substantive recommendations or changes to the protocol or trial conduct prior 
to their implementation.   
 
The members of the IDMC will be unpaid.  
 
Members of the IDMC 
The IDMC is an independent multidisciplinary group consisting of physicians with epidemiological expertise 
that, collectively, has experience in the management of cardiac arrest patients and in the conduct, 
monitoring and analysis of randomized clinical trials. 
 
 
 
 
 
 

 
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The members of the IDMC are:  
Jesper Kjærgaard, M.D., Ph.D., D.M.Sc. (chairman) 
Consultant 
Department of Cardiology 
Rigshospitalet, Copenhagen, Denmark  
 
Jerry P. Nolan, FRCA, FRCP, FFICM, FCEM (Hon.) 
Professor, Consultant 
Anesthesia and Intensive Care 
Royal United Hospitals, Bath, United Kingdom 
 
Theresa M. Olasveengen, M.D., Ph.D. 
Consultant 
Division of Emergencies and Critical Care 
Oslo University Hospital, Oslo, Norway 
 
Conflicts of interest 
IDMC membership has been restricted to individuals free of conflicts of interest. The source of 
these conflicts may be financial, scientific, or regulatory in nature. The IDMC members will disclose to fellow 
members any consulting agreements or financial interests they have with the sponsor of the trial or with 
other sponsors having products that are being evaluated or having products that are competitive with those 
being evaluated in the trial. The IDMC will be responsible for deciding whether these consulting agreements 
or financial interests materially impact their objectivity. The IDMC members will be responsible for advising 
fellow members of any changes in these consulting agreements and financial interests that occur during the 
trial. Any IDMC members who develop significant conflicts of interest during the trial should resign from the 
IDMC. 
IDMC membership is to be for the duration of the clinical trial. If any members leave the IDMC 
during the trial, the steering committee will appoint the replacement(s). 
 
Evaluations of trial data 
The IDMC will review deidentified data for safety at three predetermined milestones (50, 200, and 400 
enrolled patients, respectively), but can – at any time – require extra reviews; unless there are group 
differences necessitating unblinding (as determined by the IDMC), the IDMC will be blinded to treatment 

 
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groups. The trial will continue while the IDMC review data. After the review, the IDMC will create a short 
report to the steering committee with recommendations for continuation, modifications, or termination of 
the trial. There will be no formal stopping criteria for efficacy or futility. Criteria for recommending 
termination will be at the discretion of the IDMC, and there will be no formal statistical criteria for 
termination due to safety. 
 
Raw data will be provided to the IDMC in Excel in the following format:  
 
Row 1 contains the names of the variables (to be defined below) 
 
Row 2 to N (where N-1 is the number of patients who have entered the trial) each contains the data 
of one patient 
 
Column 1 to p (where p is the number of variables to be defined below) each contains in row 1 the 
name of a variable and in the next N-1 rows the values of this variable. 
 
The values of the following variables will be included: 
1: id: a number that uniquely identifies the patient. 
2: group: The randomization code (group A or B)  
3: rosc_sustained: The primary outcome return of spontaneous circulation (ROSC) (1 for ROSC, 0 for no 
ROSC) 
4: surv_30: Survival at 30 days (1 for survival at 30 days, 0 for death prior to 30 days)  
5: mrs_30:  modified Rankin Scale (mRS) at 30 days (0-6) 
 
Specific adverse events (see section 5.4.3 in the protocol):  
6: hyp_cal: Hypercalcemia (3 for severe, 2 for moderate, 1 for mild, 0 for no) 
7: tac_arr: Tachyarrhythmia (1 for yes, 0 for no) 
8: aki: Acute kidney injury (1 for yes, 0 for no) 
9: pud: Peptic ulcer disease (1 for yes, 0 for no) 
10: panc: Acute pancreatitis (1 for yes, 0 for no) 
11: ca_peak_corrected_24h: Peak pH-corrected calcium ion plasma concentration within the first 24 hours 
after sustained ROSC (the numeric value on which hyp_cal is based) 

 
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12: hyp_cal_blood_0: Hypercalcemia based on the uncorrected calcium ion plasma concentration in the first 
in-hospital arterial blood sample (3 for severe, 2 for moderate, 1 for mild, 0 for no) 
13: ca_uncorrected_blood_0: Uncorrected calcium ion concentration in the first in-hospital arterial blood 
sample (the numeric value in which hyp_cal_blood_0 is based) 
 
Variables #1 and #3-13 will be provided by the steering committee and item #2 will be provided by the 
pharmacy.  
 
An independent biostatistician or a member of the IDMC will provide aggregate data for each of the 
variables #3-13 stratified by treatment group (variable #2) in two-by-two tables. No statistical tests will be 
performed unless explicitly requested by the IDMC.  
 
In addition to the above, the steering committee will provide the IDMC with data on the number of patients 
screened (i.e., all OHCA at participating stations), number of patients included, and the number of patients 
who have provided consent for additional data collection and long-term follow-up. Data will be provided on 
the specific reasons for non-inclusion and exclusion.  
  
All data will be provided to the IDMC at least 5 days prior to their meeting.  
 
Meeting, communication, and reports  
The steering committee, along with the IDMC chairman, will be responsible for scheduling and arranging the 
IDMC meeting. The meeting will start with a study overview provided by the principal investigator. This will 
include an overview of recruitment and potential problems and issues. The remainder of the meeting, which 
will only be attended by the IDMC members, will be related to evaluations of trial data as described above.  
The IDMC is not planned to meet physically to evaluate data. In addition to the scheduled meeting, the 
IDMC may, whenever they decide, contact each other by telephone, videoconference, or e-mail to discuss 
the safety for trial participants. The recommendations of the IDMC regarding stopping, continuing, or 
changing the design of the trial should be communicated in writing without delay to the steering committee. 
The steering committee has the responsibility to inform, as fast as possible, and no later than 72 hours, all 
investigators of the trial and the stations including patients in the trial about the recommendation of the 
IDMC and the steering committee decision hereof. 
The IDMC will prepare minutes of their meetings. The closed minutes will describe the 
proceedings from all sessions of the IDMC meeting, including the listing of recommendations by 

 
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the committee. Because it is possible that these minutes may contain unblinded information, it is 
important that they are not made available to anyone outside the IDMC. The IDMC and the independent 
biostatistician are obligated to keep all patient-level data confidential.