Clinical trial NCT03640949
Conditions: Heart Arrest
Sponsor: Lars Wiuff Andersen
Start date: 2018-09-17; Completion date: 2022-01-21
Enrollment: 501 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an investigator-initiated, multicenter, randomized, placebo-controlled, parallel group, double-blind, superiority trial of vasopressin and methylprednisolone during adult in-hospital cardiac arrest. There will be ten enrolling sites in Denmark. 492 adult patients with in-hospital cardiac arrest receiving at least one dose of adrenaline will be enrolled. The primary outcome is return of spontaneous circulation and key secondary outcomes include survival at 30 days and survival at 30 days with a favorable neurological outcome.

Detailed description:

Arms: arm 1: The study drugs will consist of 40 mg methylprednisolone (Solu-medrol®, Pfizer) and 20 IU of vasopressin (Empressin®, Amomed Pharma GmbH) given as soon as possible after the first dose of adrenaline. Additional doses of vasopressin (20 IU) will be administered after each adrenaline dose for a maximum of four doses (80 IU). arm 2: The placebo for vasopressin will consist of 1 mL of 9 mg/mL NaCl ("normal saline") from 2 mL ampules identical to the vasopressin ampules. The placebo for methylprednisolone will also consist of 1 mL of 9 mg/mL NaCl.
Interventions: intervention 1: Vasopressin, Arginine intervention 2: Methylprednisolone intervention 3: NaCl
Intervention descriptions: intervention 1: 20 IE of vasopressin per dose for a maximum of four doses (80 IU) intervention 2: 40 mg methylprednisolone once intervention 3: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
VAM-IHCA Protocol – version 1.8 
Page 1 of 80 
 
Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest  
– A Randomized, Double-Blind, Placebo-Controlled Trial  
 
Acronym: VAM-IHCA 
 
TRIAL PROTOCOL  
 
Version 1.8 
Oct 30, 2020  
 
EudraCT number: 2017-004773-13 
ClinicalTrials.gov number: NCT03640949  
 
Principal investigator and sponsor: 
Lars W. Andersen, M.D., M.P.H., Ph.D., D.M.Sc. 
Associate Professor  
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 
Phone: +4551781511 
Email: lwandersen@clin.au.dk 


 
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Content 
Preface ..................................................................................................................................................................6 
List of abbreviations .............................................................................................................................................7 
Overview...............................................................................................................................................................8 
Trial flow chart......................................................................................................................................................9 
Steering committee ........................................................................................................................................... 10 
Trial sites ............................................................................................................................................................ 12 
Pharmacy ........................................................................................................................................................... 14 
Amendments ..................................................................................................................................................... 15 
1. BACKGROUND ............................................................................................................................................... 19 
1.1 In-hospital cardiac arrest ......................................................................................................................... 19 
1.1.1 Incidence and mortality .................................................................................................................... 19 
1.1.2 An understudied entity ..................................................................................................................... 19 
1.1.3 Pathophysiology ............................................................................................................................... 19 
1.2 Vasopressin ............................................................................................................................................. 20 
1.2.1 Pharmacology ................................................................................................................................... 20 
1.2.2 Use outside cardiac arrest ................................................................................................................ 20 
1.2.3 Use in cardiac arrest ......................................................................................................................... 20 
1.3 Methylprednisolone ................................................................................................................................ 21 
1.3.1 Pharmacology ................................................................................................................................... 21 
1.3.2 Use outside cardiac arrest ................................................................................................................ 21 
1.3.3 Use in cardiac arrest ......................................................................................................................... 21 
1.4 The vasopressin, steroids, and epinephrine (VSE) trials ......................................................................... 22 
1.5 Guidelines regarding vasopressin and glucocorticoids ........................................................................... 22 
1.6 Standard of care ...................................................................................................................................... 23 
1.7 Post-cardiac arrest glucocorticoids ......................................................................................................... 23 
2. TRIAL OBJECTIVES AND HYPOTHESES ............................................................................................................ 24 
3. TRIAL DESIGN ................................................................................................................................................. 25 
3.1 Overview .................................................................................................................................................. 25 
3.2 Allocation ................................................................................................................................................. 25 
3.3 Interventions ........................................................................................................................................... 25 
3.3.1 Methylprednisolone and vasopressin .............................................................................................. 25 
3.3.2 Placebo ............................................................................................................................................. 25 


 
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3.3.3 Procedures ........................................................................................................................................ 26 
3.3.4 Overview of study medication ......................................................................................................... 26 
3.4 Blinding .................................................................................................................................................... 27 
3.5 Trial procedures ....................................................................................................................................... 27 
3.5.1 Patients ............................................................................................................................................. 27 
3.5.2 Clinical personnel ............................................................................................................................. 28 
4.  SETTING AND PATIENT POPULATION ........................................................................................................... 28 
4.1 Setting ...................................................................................................................................................... 28 
4.2 Inclusion criteria ...................................................................................................................................... 28 
4.3 Exclusion criteria ..................................................................................................................................... 28 
4.4 Co-enrollment ......................................................................................................................................... 29 
5. OUTCOMES .................................................................................................................................................... 29 
5.1 Primary outcome ..................................................................................................................................... 29 
5.1.1 Definition .......................................................................................................................................... 29 
5.1.2 Rationale ........................................................................................................................................... 30 
5.2 Secondary outcomes ............................................................................................................................... 30 
5.2.1 Definitions ........................................................................................................................................ 30 
5.2.2 Rationale ........................................................................................................................................... 31 
5.3 Tertiary outcomes ................................................................................................................................... 31 
5.4 Harm ........................................................................................................................................................ 33 
5.4.1 General consideration ...................................................................................................................... 33 
5.4.2 Definitions ........................................................................................................................................ 33 
5.4.3 Specific adverse events .................................................................................................................... 34 
5.4.4 Timeline ............................................................................................................................................ 35 
5.4.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................................................. 35 
5.5 Additional follow-up ................................................................................................................................ 35 
6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN ................................................................... 36 
6.1 Sample size calculation ............................................................................................................................ 36 
6.2 Statistical analysis plan ............................................................................................................................ 37 
6.2.1 General considerations..................................................................................................................... 37 
6.2.2 Primary and secondary outcomes .................................................................................................... 37 
6.2.3 Subgroup analyses ............................................................................................................................ 37 
6.2.4 Addition analyses and outcomes ..................................................................................................... 38 
6.2.5 Missing data ..................................................................................................................................... 38 


 
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6.2.6 Multiple comparisons ....................................................................................................................... 38 
6.2.7 Statistical stopping criteria ............................................................................................................... 39 
7. DATA COLLECTION AND MANAGEMENT ....................................................................................................... 39 
7.1 Data collection process ........................................................................................................................... 39 
7.2 Variables .................................................................................................................................................. 39 
7.2.1 Overview ........................................................................................................................................... 39 
7.2.2 Pre-cardiac arrest characteristics ..................................................................................................... 40 
7.2.3 Cardiac arrest characteristics ........................................................................................................... 41 
7.2.3 Post-cardiac arrest characteristics ................................................................................................... 41 
7.2.4 Outcomes ......................................................................................................................................... 42 
7.3 Data quality and validity .......................................................................................................................... 42 
7.4 Data storage and security ........................................................................................................................ 42 
7.5 Data access .............................................................................................................................................. 43 
7.6 DANARREST ............................................................................................................................................. 43 
8. CLINICAL TREATMENT ................................................................................................................................... 43 
9. ETHICAL CONSIDERATIONS............................................................................................................................ 43 
9.1 Clinical equipoise ..................................................................................................................................... 43 
9.1.1 Potential benefits ............................................................................................................................. 43 
9.1.2 Potential harms ................................................................................................................................ 44 
9.1.3 Risk/benefit ratio .............................................................................................................................. 44 
9.2 Research in cardiac arrest ....................................................................................................................... 44 
9.2.1 General considerations..................................................................................................................... 44 
9.2.2 Danish regulations ............................................................................................................................ 45 
9.2.3 Regulations in relation to the current trial ....................................................................................... 46 
9.3 Procedures ............................................................................................................................................... 46 
9.3.1 Ethical review committee ................................................................................................................. 46 
9.3.2 Trial-specific procedures .................................................................................................................. 47 
9.3.3 Insurance .......................................................................................................................................... 47 
10. MONITORING .............................................................................................................................................. 47 
10.1 Good Clinical Practice monitoring ......................................................................................................... 47 
10.2 Independent data-monitoring committee (IDMC) ................................................................................ 48 
11. TIMELINE AND ENROLLMENT ...................................................................................................................... 49 
11.1 Timeline ................................................................................................................................................. 49 
11.2 Feasibility ............................................................................................................................................... 50 


 
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11.3 Enrollment ............................................................................................................................................. 50 
11.4 Additional sites ...................................................................................................................................... 51 
12. PUBLICATION PLAN ..................................................................................................................................... 51 
13. DATA SHARING ............................................................................................................................................ 51 
14. FUNDING ..................................................................................................................................................... 52 
15. TASKS AND RESPONSIBILITIES ..................................................................................................................... 52 
References ......................................................................................................................................................... 53 
Appendices ........................................................................................................................................................ 64 
Appendix 1: Conflict of interest disclosures for the steering committee members ..................................... 64 
Appendix 2: Study kit and drug labeling (Danish) ......................................................................................... 70 
Appendix 3: Draft of CONSORT flow diagram ............................................................................................... 71 
Appendix 4: Case report form (Danish) ......................................................................................................... 72 
Appendix 5: DANARREST case report form (Danish) ..................................................................................... 73 
Appendix 6: Charter for the independent data-monitoring committee (IDMC) ........................................... 75 
 
 
 


 
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Preface 
The “Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest – A Randomized, Double-Blind, 
Placebo-Controlled Trial” (VAM-IHCA) 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 Helsinki1, European regulations2, and the international 
Good Clinical Practice guidelines3. The trial and this protocol is developed in accordance with the 
International Conference on Harmonization (ICH) guidelines3-5 and the Standard Protocol Items: 
Recommendations for Interventional Trials (SPIRIT) statement6,7. The principal investigator 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 
 
 
 
 
 
 
 
 
 
 
 
 
   30/10 - 2020 


 
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List of abbreviations  
CPC:   
Cerebral performance category 
CPR:   
Cardiopulmonary resuscitation  
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 
OHCA:  
Out-of-hospital cardiac arrest 
ROSC:  
Return of spontaneous circulation  
SOFA:  
Sequential organ failure assessment  
SPIRIT:  Standard Protocol Items: Recommendations for Interventional Trials 
VSE:   
Vasopressin, steroids, and epinephrine  
 
 


 
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Overview  
Registry and trial number 
EudraCT number: 2017-004773-13, ClinicalTrials.gov number: NCT03640949 
Date of registration 
EudraCT: 25/1-2018, ClinicalTrials.gov: 21/8-2018 
Sources of monetary or 
material support 
Aarhus University Research Foundation 
Department of Clinical Medicine, Aarhus University 
Independent Research Fund Denmark 
Amomed Pharma GmbH (only vasopressin) 
Primary sponsor 
Lars W. Andersen, Aarhus University 
Contact  
Lars W. Andersen, lwandersen@clin.au.dk 
Title 
Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest – A 
Randomized, Double-Blind, Placebo-Controlled Trial 
Country of recruitment 
Denmark 
Condition studied 
In-hospital cardiac arrest 
Interventions 
Methylprednisolone (40 mg) combined with 
Vasopressin (20 IU per adrenaline dose, maximum 80 IU)  
Comparator  
Placebo (for both methylprednisolone and vasopressin) 
Inclusion criteria 
1) In-hospital cardiac arrest 
2) Age ≥ 18 years 
3) Received at least one dose of adrenaline during CPR 
Exclusion criteria 
1) Clearly documented “do-not-resuscitate” order prior to the cardiac arrest 
2) Prior enrollment in the trial 
3) Invasive mechanical circulatory support at the time of the cardiac arrest  
4) Known or suspected pregnancy at the time of the cardiac arrest 
Study type 
Interventional  
 
 
 
 
 
 
 
Allocation: Randomized (1:1) 
Intervention model: Parallel group  
 
Masking: Double-blind 
Date of first screening  
Sept. 17, 2018 
Target sample size 
492 
Recruitment status 
Recruiting  
Primary outcomes 
Return of spontaneous circulation 
Key secondary outcomes 
Survival at 30 days 
Survival at 30 days with a favorable neurological outcome (cerebral 
performance category 1 or 2) 


 
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Trial flow chart 
 
In-hospital cardiac arrest (IHCA) 
Cardiopulmonary resuscitation (CPR) 
Activation of cardiac arrest team 
Assessment of rhythm  
Shockable rhythm  
Non-shockable rhythm   
CPR   
CPR   
Defibrillation 
Adrenaline  
Adrenaline  
3 defibrillations 
20 IU Vasopressin and 
40 mg Methylprednisolon 
or 
Placebo 
CPR 
CPR 
For each dose of adrenaline 
20 IU Vasopressin 
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. 
Associate Professor  
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University Hospital 
Michael Donnino, M.D.  
Director, Professor 
Center for Resuscitation Science  
Beth Israel Deaconess Medical Center 
Harvard Medical School  
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 
Tobias Kurth, M.D., Sc.D.  
Director, Professor 
Institute of Public Health 
Charité Universitätsmedizin Berlin 
Bodil S. Rasmussen, M.D., Ph.D. 
Professor 
Department of Anesthesiology and Intensive Care 
Medicine, Aalborg University Hospital  
Department of Clinical Medicine, Aalborg University 
Jesper Kjærgaard, M.D., Ph.D., D.M.Sc.  
Department of Cardiology  
Rigshospitalet 
Copenhagen University Hospital 
Bo Løfgren, M.D., Ph.D.  
Professor  
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University Hospital 
Dan Isbye, M.D., Ph.D.  
Clinical Associate Professor  
Department of Anesthesiology 
Copenhagen University Hospital - Rigshospitalet 
Jacob Moesgaard Larsen, M.D., Ph.D.  
Department of Cardiology  
Aalborg University Hospital  
Asger Granfeldt, M.D., Ph.D., D.M.Sc. 
Associate Professor  
Department of Anesthesiology 
Aarhus University Hospital 


 
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Stine Thorhauge Zwisler, M.D., Ph.D.  
Department of Anesthesiology 
Odense University Hospital 
Søren Darling, M.D.  
Department of Anesthesiology 
Odense University Hospital 
Kasper Glerup Lauridsen, M.D.  
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University Hospital 
Kim B. Pælestik, M.D.  
Department of Anesthesiology 
Viborg Regional Hospital 
Christoffer Sølling, M.D., Ph.D.   
Department of Anesthesiology 
Viborg Regional Hospital 
Anders Kjærgaard, M.D., Ph.D.  
Department of Anesthesiology 
Horsens Regional Hospital 
Dorte Due-Rasmussen, M.D.  
Department of Anesthesiology 
Horsens Regional Hospital 
Martin Schultz, M.D., Ph.D.  
Department of Internal Medicine 
Copenhagen University Hospital – Herlev 
Fredrik Folke, M.D., Ph.D.  
Professor 
Department of Cardiology  
Copenhagen University Hospital – Gentofte 
Kasper Iversen, M.D., D.M.Sc.  
Professor  
Department of Cardiology  
Copenhagen University Hospital – Herlev 
Mette Gitz Charlot, M.D., Ph.D.  
Department of Cardiology  
Copenhagen University Hospital – Gentofte 
Sebastian Wiberg, M.D., Ph.D.  
Department of Anesthesiology 
Zealand University Hospital - Køge 
Mathias Holmberg, M.D., M.P.H, Ph.D. 
Research Center for Emergency Medicine  
Department of Clinical Medicine 
Aarhus University and Aarhus University Hospital 
Rikke Malene Jepsen, M.D., Ph.D.  
Department of Anesthesiology 
Zealand University Hospital - Køge 
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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Trial sites  
 
Aarhus University Hospital – Skejby  
Palle Juul-Jensens Boulevard 99 
8200 Aarhus N 
Denmark  
Site investigator: Asger Granfeldt, granfeldt@clin.au.dk 
 
Aalborg University Hospital – South 
Hobrovej 18 – 22 
9000 Aalborg  
Denmark  
Site investigator: Jacob Moesgaard Larsen, jaml@rn.dk 
 
Randers Regional Hospital  
Skovlyvej 15 
8930 Randers NØ 
Denmark  
Site investigator: Kasper Glerup Lauridsen, kglerup@clin.au.dk 
 
Copenhagen University Hospital - Rigshospitalet  
Blegdamsvej 9 
2100 Copenhagen 
Denmark 
Site investigator: Dan Isbye, dan.lou.isbye@regionh.dk 
 
Odense University Hospital  
J. B. Winsløws Vej 4 
5000 Odense C 
Denmark 
Site investigator: Søren Darling, sorendarling@gmail.com 
 


 
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Horsens Regional Hospital 
Sundvej 30 
8700 Horsens 
Denmark  
Site investigator: Anders Kjærgaard, andekjae@rm.dk 
 
Viborg Regional Hospital  
Heibergs Alle 4 
8800 Viborg 
Denmark  
Site investigator: Christoffer Sølling, chrsoell@rm.dk 
 
Copenhagen University Hospital – Gentofte 
Kildegårdsvej 28 
2900 Hellerup  
Denmark  
Site investigator: Fredrik Folke, fredrik.folke@regionh.dk 
 
Copenhagen University Hospital – Herlev 
Herlev Ringvej 75 
2730 Herlev 
Denmark  
Site investigator: Kasper Iversen, Kasper.Karmark.Iversen@regionh.dk 
 
Zealand University Hospital - Køge 
Lykkebækvej 1 
4600 Køge 
Denmark 
Site investigator: Rikke Malene Jepsen, rimj@regionsjaelland.dk 
 
 
 
 


 
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Pharmacy  
Skanderborg Pharmacy  
Adelgade 27 
8660 Skanderborg 
Denmark 
Contact: Heidi Svith, hei@skanderborg-apotek.dk 


 
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Amendments  
Version 1.7 (May 14, 2020) to 1.8 (Oct. 30, 2020) 
• 
Corrections of minor typos and grammatical issues as well as minor clarifications  
• 
Minor change to the publication plan (section 12)  
• 
Removal of three sites including site investigators (multiple sections) 
• 
Multiple changes to the statistical analyses plan including (section 6): 
• 
Change of the primary analysis  
• 
Addition of a sensitivity analysis for the primary outcome  
• 
Subgroup analyses on both the relative and absolute scale 
• 
Only reporting P values for certain key outcomes  
• 
Removal of two subgroup analyses and addition of two  
• 
Analysis of survival to 90 days as a binary outcome  
 
Version 1.6 (Nov. 11, 2019) to 1.7 (May 14, 2020)  
• 
Addition of four new sites (multiple sections)  
• 
Change of site investigator in Viborg from Therese Straarup to Kim B. Pælestik (multiple sections) 
• 
Addition of Mathias Holmberg to the steering committee (multiple sections)   
• 
Corrections of minor typos and grammatical issues  
 
Version 1.5 (Apr. 4, 2019) to 1.6 (Nov. 11, 2019) 
• 
Change of site investigator in Aalborg from Signe Juul Riddersholm to Jacob Moesgaard Larsen 
(multiple sections) 
• 
Addition of a subgroup analysis based on time from adrenaline administration to first study drug and 
removal of the site subgroup analysis (section 6.2.3) 
• 
Addition of funding (section 14) 
 
Version 1.4 (Sep. 12, 2018) to 1.5 (Apr. 4, 2019) 
• 
Addition of four sites + site investigators (multiple sections) 
 
Version 1.3 (Mar. 19, 2018) to 1.4 (Sep. 12, 2018)  
• 
Corrections of minor typos and grammatical issues  
• 
Change of address for the principal investigator (title page) 


 
VAM-IHCA Protocol – version 1.8 
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• 
Addition of EudraCT and ClinicalTrials.gov numbers (title page) 
• 
Update of the overview table  
• 
Addition of Kasper Glerup Lauridsen as a site investigator in Randers (multiple sections) 
• 
Change of site investigator in Aalborg from Jacob Moesgaard Larsen to Signe Juul Riddersholm 
(multiple sections) 
• 
Reference to Appendix 2 in section 3.3.3  
• 
Clarification that the study kits will be created at Skanderborg Pharmacy (section 3.3.3 + 3.3.4) 
• 
Clarification that the site investigator and the research nurse will also be responsible for study kits at 
each site (section 3.3.4) 
• 
Change in exclusion criteria from “Extracorporeal circulation at the time of the cardiac arrest” to 
“Invasive mechanical circulatory support at the time of the cardiac arrest” (section 4.3) 
• 
Minor change in the definition of hospital disposition (section 5.3) 
• 
Addition of a reference to COSCA (section 5.3) 
• 
Change in definition of vasopressor-free days (section 5.3) 
• 
Addition of invasive ventilation-free days as a tertiary outcome (section 5.3) 
• 
Change in the timepoints of SOFA score calculation from 4 and 24 hours to 24, 48, and 72 hours 
(section 5.3 + 7.2.4) 
• 
Change in the definition of hyperglycemia (section 5.4.3) 
• 
Change in definition of prior use of glucocorticoids from 5 days to 14 days (section 6.2.3) 
• 
Addition of a subgroup analysis related to time from cardiac arrest to first study drug (section 6.2.3) 
• 
Clarification that multiple imputation will only be performed if missing data is substantial (< 10%) 
(section 6.2.5) 
• 
Clarification that data collection will not include the timing of the methylprednisolone dose (section 
7.1)  
• 
Removal of ethnicity as a variable (section 7.2.2) 
• 
Removal of the reference to the updated IHCA Ustein guidelines (section 7.2.1) 
• 
Addition of the Glasgow Outcome Scale Extended (section 7.2.4) 
• 
Change in terminology from “legally authorized surrogate” and “next of kin” to “surrogate” (section 
9.2.2 + 9.3.2) 
• 
Clarification that the legal guardian cannot be related to trial procedures for the specific patient but 
can be involved in trial procedures for other unrelated patients (section 9.2.3 + 9.3.2) 
• 
Update indicating approval by the regional ethics committee (section 9.3) 


 
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• 
Removal of sentence stating that data on non-enrollled patients can be obtained from DANARREST 
(section 11.3)  
• 
Addition of Appendix 2  
• 
Minor updates to Appendix 3  
• 
Addition of Appendix 4 
• 
Removal of Appendix 6 and 7  
• 
Appendix 8 renumbered as Appendix 6 and updated  
 
Version 1.2 (Jan. 24, 2018) to 1.3 (Mar. 19, 2018) 
• 
Change of the primary pharmacy to Skanderborg Pharmacy 
• 
Addition details provided on the follow-up telephone interview (section 5.3) 
• 
Clarification that the trial has been reported to the Danish Data Protection Agency (section 7.4) 
• 
Clarification that consent after the cardiac arrest will be obtained by a physician (section 9.3.2) 
• 
Addition of feasibility data from Odense (section 11.2) 
• 
Clarification that shared data will be completely anonymized according to Danish law (section 13) 
 
Version 1.1 (Jan. 24, 2018) to 1.2 (Jan. 24, 2018)    
• 
Change of the primary pharmacy to Pharma Skan ApS  
• 
Addition of Odense University Hospital as a site (multiple sections)   
 
Version 1.0 (Aug. 31, 2017) to 1.1 (Jan. 24, 2018) 
• 
Corrections of minor typos and grammatical issues  
• 
Clarification of the intervention being the combination of methylprednisolone and vasopressin 
(Overview, Trial flow chart)  
• 
Clarification that the vasopressin placebo ampules and vasopressin ampules are identical (section 
3.3.2) 
• 
Production and labelling of the study kits at Pharma Skan ApS instead of the university pharmacy 
(section 3.3.3 and 3.3.4) 
• 
Clarification that that the unblinded pharmacy staff will not be involved in outcome evaluation 
(section 3.4) 
• 
Storage of medicine at room temperature as oppose to 2°C to 8°C (section 3.3.3)  
• 
Clarification that the site investigator will keep track of study kits at each site (section 3.3.4)  


 
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• 
Clarification that data will also be obtained from the case report forms (section 3.5.1)  
• 
Removal of E-Learning as a modality for education of study personnel (section 3.5.2) 
• 
Clarification that patients who re-arrest in the emergency department can be included if they had 
sustained ROSC prior to the cardiac arrest (section 4.2) 
• 
Definition of ROSC when patients are put on extracorporeal circulation redefined (section 5.1.1)  
• 
Addition of the Glasgow Outcome Scale Extended for neurological outcome (section 5.3) 
• 
Addition of a section of reporting of adverse events (section 5.4.6) 
• 
Clarification of the follow-up after 90 days (section 5.5) 
• 
Addition of a draft of the CONSORT flow diagram (section 6.2.1 + Appendix 3)  
• 
Addition of two subgroup analyses according to the location of the cardiac arrest and the prior use of 
glucocorticoids (section 6.2.3) 
• 
Addition of ordinal logistic regression (section 6.2.4) 
• 
Various additions to the data collection (section 7.2) 
• 
Clarification that the IDMC, the Good Clinical Practice unit, and regulatory agencies will have access 
to all relevant trial data (section 7.5) 
• 
Clarification of the “legal guardian” (section 9) 
• 
Clarification that consent for future data collection will be obtained from the legal guardian and the 
patient’s next of kin if the patient is not able to provide consent (section 9.3.2)  
• 
Clarification that the study results will be published irrespective of the results (section 12) 
• 
Funding updates (overview and section 14) 
• 
Removal of the section on potential expansion of the trial (section 15) 
• 
Addition of Appendix 8: Charter for the independent data-monitoring committee (IDMC) 


 
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1. BACKGROUND 
1.1 In-hospital cardiac arrest 
1.1.1 Incidence and mortality  
In-hospital cardiac arrest (IHCA) is relatively common with an estimated 200,000 treated cases in the United 
States each year.8 Although no published data is currently available on the incidence of IHCA in Denmark, we 
estimate that approximately 2500-3000 IHCA occur each year. Unfortunately, outcomes remain poor with 
approximately 60% achieving return of spontaneous circulation (ROSC) and only 20-30% surviving to hospital 
discharge.9-11 Furthermore, in initial survivors, there are substantial post-discharge morbidity and early 
mortality.10,12-14 
 
1.1.2 An understudied entity  
Clinical trials are sparse in cardiac arrest15,16, and especially in IHCA17, relative to the burden of the condition. 
In a systematic review of all randomized clinical trials involving cardiac arrest from 1995 to 2014, Sinha et al. 
found that 81 (88%) were exclusively in out of hospital cardiac arrest (OHCA), 7 (8%) involved OHCA and 
IHCA, and only 4 (4%) involved exclusively IHCA. The total number of included patients were 83 times higher 
in OHCA studies as compared to IHCA studies.18  
Currently, there is a scarcity of evidence-based pharmacological interventions for IHCA.19-21 The evidence 
for adrenaline (epinephrine) and amiodarone, the only two drugs currently recommended , is limited and 
based on extrapolation from OHCA.19-23 There is therefore an, currently unmet, need for additional 
randomized clinical trials in IHCA in order to advance the science and improve patient outcomes.  
 
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.24,25 Because of this, and since 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.26-28 Ischemia during the cardiac arrest and subsequent ischemia-
reperfusion injury activates multiple harmful pathways including systemic inflammation, endothelial 


 
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activation, activation of immunological and coagulation pathways, adrenal insufficiency, mitochondrial 
damage, and microvascular dysfunction.26 Consequently this leads to a clinical state (the post-cardiac arrest 
syndrome) with global brain injury, impaired myocardial function, macrocirculatory failure, and increased 
susceptibility to infections.26 Patient are often hemodynamically unstable following a cardiac arrest and early 
post-cardiac arrest hypotension is strongly associated with poor outcomes.29 
 
1.2 Vasopressin 
1.2.1 Pharmacology  
Vasopressin (also known as antidiuretic hormone or arginine vasopressin) is a nonapeptide produced in the 
hypothalamus and secreted into the circulation through the posterior pituitary gland. Vasopressin exerts its 
effects through binding to one of its three receptor subtypes V1-V3. The V1 receptor mediates 
vasoconstriction, while binding to V2 mediates the antidiuretic effects in the kidney and activation of the V3 
receptor in the pituitary gland stimulates the secretion of hormones. During states of shock, levels of 
vasopressin are low and exogenously administered vasopressin exerts profound vasoconstrictive effects. 
Where the vasoconstrictive effects of other vasopressors are reduced in conditions of hypoxia and acidosis 
the vasoconstrictive effects of vasopressin are maintained.30 When administered intravenously, vasopressin 
has a half-life of approximately 10 to 35 minutes31,32 
 
1.2.2 Use outside cardiac arrest  
Vasopressin is licensed in several countries, including the United States, Sweden, Germany, and the United 
Kingdom, to treat refractory shock in patient with sepsis. The 2016 Surviving Sepsis Guidelines recommends 
vasopressin as the second-line vasopressor after noradrenaline.33 Vasopressin might also be beneficial in 
other forms of shock.34 Terlipressin and desmopressin, synthetic vasopressin analogs with slower onset but 
longer duration35,36, are licensed in Denmark for the treatment of esophageal varices bleeding and diabetes 
insipidus, respectively.  
 
1.2.3 Use in cardiac arrest 
The rationale for the use of vasopressin during cardiac arrest is based on studies demonstrating that plasma 
levels of vasopressin are lower in non-survivors compared to survivors37, and that vasopressin, through its 
potent vasoconstrictive properties, increases the coronary perfusion pressure and thereby the chance of 
ROSC.38,39 These properties lead to clinical trials where vasopressin was compared to standard treatment.40-43 
Only one relatively small trial included IHCA patients.44 In a meta-analysis of six randomized clinical trials, 


 
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there was no overall benefit of vasopressin administration during cardiac arrest.41 However, there were a 
potential benefit in subgroups according to a first rhythm of asystole and early (< 20 minutes) drug 
administration.41 In addition, a recent meta-analysis demonstrated that the administration of vasopressin 
increases the rate of ROSC and survival in patients with in-hospital arrest.43 These latest findings are largely 
based on studies by Mentzelopoulos et al.45,46 as described in more detail in section 1.4.   
 
1.3 Methylprednisolone  
1.3.1 Pharmacology  
Methylprednisolone is a synthetic glucocorticoid which is a class of corticosteroids that is part of the larger 
group of steroid hormones. Glucocorticoids are produced in the adrenal cortex and exerts a wide range of 
functions in the body including regulation of metabolism, inflammation, and cell proliferation.47 During 
situations with stress, glucocorticoids are secreted as a defense mechanism exerting widespread 
physiological functions.48 The primary effect of glucocorticoids is exerted through binding to the 
glucocorticoid receptor followed by translocation to the nucleus where it modulates gene transcription 
through binding to glucocorticoid-responsive elements.49 This is termed the genomic effects of 
glucocorticoids and it takes hours for a response to fully develop.50 However, glucocorticoids also possess 
rapid (within minutes) non-genomic effects through interaction with cellular membranes and receptors, 
which are relevant in the setting of cardiac arrest.49-51 Methylprednisolone is administered intravenously and 
has a biological half-life of approximately 12 to 36 hours.52 
 
1.3.2 Use outside cardiac arrest 
Methylprednisolone is primarily licensed in Denmark as Solu-medrol® (Pfizer). Clinically, glucocorticoids have 
been used for decades in the treatment of various diseases due to its anti-inflammatory effects53 and 
methylprednisolone is on the World Health Organization’s list of essential medicines54. Glucocorticoids are 
used in several acute and critical conditions including bacterial meningitis, anaphylactic shock, and severe 
asthma or chronic obstructive pulmonary disease exacerbations. Glucocorticoids have been especially well-
studied in the setting of septic shock where treatment with glucocorticoids increases shock reversal (i.e. 
weaning for vasopressor support) and may lower mortality.55  
 
1.3.3 Use in cardiac arrest 
Studies in patients with cardiac arrest have demonstrated that levels of cortisol are higher in patients that 
are resuscitated when compared to patients that are not resuscitated56 which may illustrate an impaired 


 
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endocrine response in non-survivors. This is supported by animal studies where the administration of 
hydrocortisone during cardiac arrest increases ROSC rates.57 This may relate to the cardiovascular effects of 
glucocorticoids which include increases in enzymes involved in adrenaline synthesis, inhibition of 
catecholamine re-uptake and breakdown, and by enhancement of cardiovascular sensitivity to 
catecholamines by increasing the binding capacity and affinity.48,58 Data on glucocorticoid administration 
during human cardiac arrest is limited and small studies have shown conflicting results.59 
 
1.4 The vasopressin, steroids, and epinephrine (VSE) trials  
In two trials, published in 2009 and 2013, Mentzelopoulos et al. examined the effect of adding vasopressin 
and glucocorticoids to standard treatment in IHCA.45,46 In these two Greek, randomized, double-blind trials, 
the authors compared the addition of vasopressin (20 IU for each dose of adrenaline) and glucocorticoids (40 
mg methylprednisolone) during cardiac arrest to placebo. After the cardiac arrest, patients in the 
intervention arm furthermore received glucocorticoids (300 mg hydrocortisone) if they had vasopressor-
dependent shock. The results, which were published in the Archives of Internal Medicine (now JAMA Internal 
Medicine) and the Journal of the American Medical Association (JAMA), were remarkable. The combined rate 
of ROSC was 148/178 (83%) in the intervention group vs. 118/190 (62%) in the control arm (p < 0.001). In the 
first trial, survival to hospital discharge was higher in the intervention group as compared to the placebo 
group (9/48 [19%] vs. 2/52 [4%], p = 0.02).45 In the second trial, the primary outcome of survival to hospital 
discharge with a favorable neurological outcome (cerebral performance category [CPC] score of 1 or 2) was 
higher in the intervention group as compared to the placebo group (18/130 [14%] vs. 7/138 [5%], p = 0.02).46 
The authors also showed beneficial effects on post-cardiac arrest hemodynamics, organ failure, and 
inflammation.45,46 
 
1.5 Guidelines regarding vasopressin and glucocorticoids 
The VSE trials have received a great deal of attention in the literature with most commentaries arguing for 
external validation studies before clinical implementation.60-63 The International Liaison Committee on 
Resuscitation (ILCOR) reached the same conclusion: “Confidence in the treatment effects from bundled 
treatments [i.e. vasopressin and glucocorticoids] will increase if confirmed in further studies”.19 The current 
American and European guidelines from 2015 do not recommend the routine use of vasopressin and 
glucocorticoids in IHCA primarily due to lack of trials externally validating the findings from the VSE trials.20,21 
The American guidelines recognized the importance of this as a potential therapeutic option but specifically 
state “… further studies are needed before recommending the routine use of this therapeutic strategy”.21  


 
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1.6 Standard of care  
The standard of care during cardiac arrest is described by guidelines from the European Resuscitation 
Council and the American Heart Association.20,21 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.20,21 Although the evidence for amiodarone/lidocaine and adrenaline 
is limited and controversial22,23, these drugs are currently recommended and are given, when applicable, to 
most patients with cardiac arrest. The interventions of the current trial (vasopressin and 
methylprednisolone) will therefore be compared to placebo and both groups will receive the established 
standard of care consistent with the two VSE trials.45,46    
 
1.7 Post-cardiac arrest glucocorticoids 
The intervention in the VSE trials included hydrocortisone for patients with vasopressor dependent shock 4 
hours after the cardiac arrest. 300 mg of hydrocortisone was administered per day until shock reversal or for 
a maximum of 7 days.45,46 For several reasons, this part of the intervention is not included in the current trial. 
First, considerable beneficial effects were seen in the original trials before the hydrocortisone was 
administered. This includes a substantial increase in ROSC as noted above, improvements in early 
hemodynamics, and an increase in 4-hour survival (intervention: 111/194 [57%] vs. placebo: 96/206 [47%], p 
= 0.01).45,46 Second, a separate randomized clinical trial by members of our study team, not including the 
intra-cardiac arrest interventions, found no benefit of hydrocortisone for post-cardiac arrest patients with 
vasopressor dependent shock.64 Third, assessing both intra- and post-cardiac arrest interventions combined 
does not allow for assessment of the individual effects of each intervention. If the current trial is positive, 
future trials are needed to then assess the post-cardiac arrest aspect of the VSE trials. Lastly, the primary 
outcome of the current trial is ROSC which will not be influenced by post-cardiac arrest treatment.   


 
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2. TRIAL OBJECTIVES AND HYPOTHESES  
Primary objective: To determine whether the combination of vasopressin and methylprednisolone, as 
compared to placebo, when administered during IHCA, will increase ROSC 
 
Hypothesis: The combination of vasopressin and methylprednisolone administered during IHCA will increase 
ROSC 
 
Secondary objective: To determine whether the combination of vasopressin and methylprednisolone, as 
compared to placebo, administered during IHCA will increase survival at 30 days and survival at 30 days with 
a favorable neurological outcome (CPC score 1 or 2)  
 
Hypothesis: The combination of vasopressin and methylprednisolone administered during IHCA will increase 
survival at 30 days and survival at 30 days with a favorable neurological outcome (CPC score 1 or 2)  
 


 
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3. TRIAL DESIGN  
3.1 Overview 
This is an investigator-initiated, multicenter, randomized, placebo-controlled, parallel group, double-blind, 
superiority trial of vasopressin and methylprednisolone during adult IHCA. There will be 10 enrolling sites in 
Denmark. 492 adult patients with IHCA receiving at least one dose of adrenaline will be enrolled. The 
primary outcome is ROSC and 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 vasopressin and methylprednisolone or placebo in blocks 
with random sizes of 2, 4, or 6. The randomization will be stratified according to site.65 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, sites will be 
provided with numbered blinded kits including either vasopressin and methylprednisolone or placebo 
ensuring allocation concealment.   
 
3.3 Interventions 
3.3.1 Methylprednisolone and vasopressin 
The study drugs will consist of 40 mg methylprednisolone (Solu-medrol®, Pfizer) and 20 IU of vasopressin 
(Empressin®, Amomed Pharma GmbH) given as soon as possible after the first dose of adrenaline. Additional 
doses of vasopressin (20 IU) will be administered after each adrenaline dose for a maximum of four doses 
(80 IU). The drugs will be produced, managed, and stored according to all relevant guidelines and 
regulations.  
 
These drugs and doses are similar to the original VSE trial.45,46 However, for practical reasons (i.e. that one 
ampule of vasopressin contain two doses) this trial will include a maximum of four doses of vasopressin as 
compared to a maximum of five doses in the original trials.45,46  
 
3.3.2 Placebo  
The placebo for vasopressin will consist of 1 mL of 9 mg/mL NaCl (“normal saline”) from 2 mL ampules 
identical to the vasopressin ampules. The placebo for methylprednisolone will also consist of 1 mL of 9 


 
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mg/mL NaCl. Normal saline is often administered to critically ill patients and have no effects or side-effects 
with these very small volumes.    
 
3.3.3 Procedures   
The study drugs will be placed in a blinded study kit (a small box, see Appendix 2) containing one 40 mg dose 
of methylprednisolone (or placebo) and two 40 IU ampules (i.e. four 20 IU doses) of vasopressin (or placebo). 
The study kits will be prepared at Skanderborg Pharmacy, a company that specializes in the production of 
medicine and is approved by the Danish Health authorities, and shipped to the participating sites regularly. 
The study kit will be stored at room temperature and protected from light according to the manufacturers’ 
instructions and brought to the IHCA by a designated member of the cardiac arrest team. Once it is anticipated 
that the patient will receive at least one dose of adrenaline, the kit will be opened, and the patient will be 
considered randomized. A designated member of the cardiac arrest team will then prepare the study drugs. 
Preparation of methylprednisolone will include mixing of the methylprednisolone powder (or placebo) with 
the solvent in a blinded manner (see section 3.4). The vasopressin (or placebo) will require no mixing. A visual 
guide showing the procedures will be placed in the kit and cardiac arrest team members will have training in 
the procedures (see section 3.5.2). We expect that these procedures will take approximately 1 minute and 
that they will not interfere with the clinical management of the patient. Once prepared, the drugs will be 
administered as soon as possible after the first dose of adrenaline; first the 20 IU (1 mL) vasopressin and then 
the 40 mg (1 mL) methylprednisolone (or their respective placebos). Additional doses of 20 IU vasopressin (or 
placebo) will be administered with each dose of adrenaline which is given every 3-5 minutes irrespective of 
the underlying rhythm.20 A maximum of 4 doses of vasopressin (80 IU) will be administered. Only one dose of 
methylprednisolone will be administered.  
 
3.3.4 Overview of study medication  
Study kits will be produced and labelled centrally (Skanderborg Pharmacy). Study kits will be labelled with a 
unique ID consecutively according to site (e.g. 1XXX for site 1, 2XXX for site 2, etc.). The study kits and drugs 
will be clearly labelled according to standard practices for clinical trials (see Appendix 2). Study kits will be 
prepared and shipped to the participating sites on a regular basis. Once a study kit is opened, the site 
investigator, the research nurse, and the principal investigator will be informed. The central pharmacy will 
keep a tally of all study kits and make sure, along with the site investigator and the research nurse, that sites 
are always equipped with enough kits. The site investigator at each site will keep track of all delivered and 
used study kits. Data on actual drug administration (see section 3.3.3) will be entered in real-time on the 


 
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case report form and subsequently into the online database (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 kits will be aware of the allocation. The pharmacy will 
not be involved with clinical care or outcome evaluation.  
 
Vasopressin placebo will consist of normal saline which, like vasopressin, is colorless and without any 
identifying features. The normal saline will be stored in 2 mL ampules that are identical to the vasopressin 
ampules. Furthermore, vasopressin has no distinctive rapid effects (except those related to the trial) 
resulting in possible identification. We therefore do not anticipate any risk of unblinding.  
Methylprednisolone placebo will consist of an empty vial completely covered such that the clinical team 
cannot distinguish whether the vial is empty or contains the methylprednisolone powder. The 
methylprednisolone solvent or the NaCl placebo, which are identical in appearance, will be injected into the 
vial and the vial will be shaken to immediately dissolve the powder. The mixed solution will then be 
aspirated from the vial and administered to the patient. Since the mixed solution is colorless and without 
any identifying features, the clinical team will remain blinded to the treatment arm. A similar approach is 
being used in the ongoing SUP-ICU trial which is a multicenter, double-blind, randomized trial.66  
In the blinded intervention kit, a sealed opaque envelope will contain the allocation assignment which 
will allow for emergency unblinding. The decision to unblind will be at the complete discretion of the 
treating physician and clinical team. 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, the electronic medical records, and the national Danish IHCA registry (DANARREST) (see section 
7).  
 


 
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3.5.2 Clinical personnel  
Prior to the beginning of patient enrollment and continuously throughout the enrollment period, the clinical 
teams involved in IHCA resuscitation at the participating hospitals will be informed about the trial. Clinical 
personnel will be informed about the background and objectives of the trial, 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 study kits will be included. We anticipate formal, in-person 
didactics quarterly with informal sessions and emails as applicable in between.     
 
4.  SETTING AND PATIENT POPULATION 
4.1 Setting 
The trial will be conducted at 10 hospitals in Denmark. All participating sites have clinical experience and 
expertise in treating IHCA patients.   
 
4.2 Inclusion criteria 
Inclusion criteria:  
1) IHCA 
2) Age ≥ 18 years 
3) Received at least one dose of adrenaline during CPR 
 
Cardiac arrest is defined as unconsciousness, abnormal breathing, and a loss of pulses requiring chest 
compressions and/or defibrillation. IHCA is defined as any individual with a cardiac arrest on hospital 
grounds where the IHCA team is activated. This will include patients who re-arrest in the emergency 
department or elsewhere after an OHCA if they, prior to the re-arrest, had sustained ROSC (i.e. spontaneous 
circulation for at least 20 minutes).  
These broad inclusion criteria were chosen to reflect the inclusion criteria in the two original VSE 
trials.45,46 The original trials included primarily patients with a non-shockable rhythm (84%). However, the 
results were consistent and significant in both those with shockable and non-shockable initial rhythms and 
there was no subgroup difference (p = 0.90, S. Mentzelopoulos, M.D., Ph.D., written communication, July 
2017). We will therefore include IHCA patients with both shockable and non-shockable rhythms.  
 
4.3 Exclusion criteria  
Exclusion criteria: 


 
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1) Clearly documented “do-not-resuscitate” order prior to the cardiac arrest 
2) Prior enrollment in the trial 
3) Invasive mechanical circulatory support at the time of the cardiac arrest  
4) Known or suspected pregnancy at the time of the cardiac arrest 
 
Occasionally CPR is inadvertently started in patients with a pre-existing “do-not-resuscitate” order. If a “do-
not-resuscitate” order is clearly documented in the electronical medical record prior to the cardiac arrest, 
the patient will be excluded. Patients previously included in the trial will be excluded to avoid statistical 
complexity related to correlated data. Since information on “do-not-resuscitate” orders and prior enrollment 
in the trial 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.67 Mechanical circulatory 
support includes extracorporeal circulation and left ventricular assist devises. Patients having an IHCA while 
on mechanical circulatory support constitutes a very specific patient population with different characteristics 
and outcomes. They will therefore be excluded. Given that vasopressin and methylprednisolone are 
generally not recommended in pregnancy, patients with known or suspected pregnancy will be excluded. 
Cardiac arrest during pregnancy is exceedingly rare68 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 any harm to the patient or fetus. Guidelines recommend that cardiac arrest in 
pregnancy is treated according to usual guidelines including intra-cardiac arrest medications.69  
 
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.70 We are not aware of any ongoing or planned trials in this patient 
population in Denmark.  
 
5. OUTCOMES 
5.1 Primary outcome 
5.1.1 Definition  
The primary outcome will be ROSC. ROSC will be defined as spontaneous circulation with no further need for 
chest compressions sustained for at least 20 minutes. This definition is consistent with the second VSE trial46, 
the Get With the Guidelines® – Resuscitation registry11, the Danish registry for IHCA (DANARREST)71, and the 
Utstein guidelines72. If a patient is placed on extracorporeal circulation during the cardiac arrest, the patient 


 
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will only be considered to have ROSC if they are able to be successfully weaned from the extracorporeal 
circulation with spontaneous circulation for at least 20 minutes.73    
 
5.1.2 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 intra-cardiac arrest interventions, ROSC is a logical and 
meaningful primary outcome. ROSC is a core outcome measure in both the IHCA72 and OHCA73 Utstein 
guidelines and is suggested as a potential primary outcome measure by the American Heart Association74. 
 
5.2 Secondary outcomes 
5.2.1 Definitions  
The key secondary outcomes will be survival at 30 days and survival at 30 days with a favorable neurological 
outcome. A favorable neurological outcome will be defined as a CPC score of 1 or 2. The CPC score is a 5-
point scale assessing neurological/functional outcomes after brain damage (Table 1).75 Patients not alive at 
30 days will be categorized as a poor neurological outcome.  
 Table 1. Cerebral performance category (CPC) score  
Score Definition 
1 
Good cerebral performance 
Conscious, alert, able to work, might have mild neurologic or psychologic deficit. 
2 
Moderate cerebral disability  
Conscious, sufficient cerebral function for independent activities of daily life. Able to work in 
sheltered environment. 
3 
Severe cerebral disability 
Conscious, dependent on others for daily support because of impaired brain function. Ranges 
from ambulatory state to severe dementia or paralysis. 
4 
Coma or vegetative state 
Any degree of coma without the presence of all brain death criteria. Unawareness, even if 
appears awake (vegetative state) without interaction with environment; may have 
spontaneous eye opening and sleep/awake cycles. Cerebral unresponsiveness.  
5 
Brain death 
Apnea, areflexia, electroencephalogram silence, etc. 


 
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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.72-74 The use of 30-day outcomes as compared to outcomes at 
hospital discharge avoids limitations related to potential difference in discharge practices.76-78 The use of the 
CPC score is consistent with the second VSE trial46, the Get With the Guidelines® – Resuscitation registry11, 
and recommend by the Utstein guidelines72,73 and the American Heart Association74.  
 
5.3 Tertiary outcomes  
Tertiary outcomes will include:  
1) Vasopressor-free days 
2) Invasive ventilation-free days 
3) Sequential organ failure assessment (SOFA) score at 24, 48 and 72 hours 
4) Hospital disposition 
5) Modified Rankin scale (mRS) and Glasgow Outcome Scale Extended (GOSE) at 30 days   
6) Health-related quality of life (EQ-5D-5L) at 30 days 
7) 90-day outcomes:  
 
Survival 
 
Neurological outcome (CPC, mRS, GOSE) 
  
Health-related quality of life (EQ-5D-5L)  
 
The trial will include additional outcomes focused on hemodynamics, organ failure, additional measures of 
neurological outcome, and long-term outcomes.  
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.79 Invasive ventilation-free days 
will be defined in a similar manner. Invasive ventilation is defined as mechanical ventilation through an 
endotracheal or tracheostomy tube.  


 
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To assess hemodynamics and organ failure, we will calculate SOFA score80 at 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.80 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. 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.81,82  
To further characterize neurological outcome and to allow for comparison with other trials and meta-
analyses, the mRS83 and GOSE84 at 30 days and hospital disposition (e.g. home, rehabilitation, nursing home, 
hospice) will be collected. Hospital disposition will be defined at the time of discharge from the initial acute 
care hospital.    
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 interventions. 90 days is 
also consistent with recommendations from the American Heart Association.74  
Both 30-day and 90-day survival will be obtained from the follow-up phone interview or the Danish Civil 
Personal Register which allows for accurate and virtually complete follow-up.85 Neurological outcome (CPC, 
mRS and GOSE) and health-related quality of life (EQ-5D-5L86) at 30 and 90 days will be assessed via 
telephone communication with the patient or a surrogate. The telephone interview will be semi-structured 
and based on the GOSE and the EQ-5D-5L questionnaires. The interview will be conducted by a centrally 
located and trained member of the research team according to detailed standard operating procedures. In 
case the patient is still in the hospital, this interview will be face-to-face. In addition to CPC, both the mRS 
and health-related quality of life are recommended as outcome measures by the AHA.74 Assessment of 
neurological outcome and health-related quality of life per telephone is valid and reliable.87,88 A structured 
interview will be used to determine CPC, mRS, and GOSE.84 
The mRS is a 7-point scale, ranging from 0 (no symptoms) to 6 (dead), assessing the degree of disability 
and dependence after a neurological injury such as stroke or cardiac arrest. A good outcome will be defined 
as a mRS of 0 to 3 and a poor outcome as 4 to 6. The GOSE is a 8-point scale that is an extension of the 
Glasgow Outcomes Scale (which is identical to the CPC, only with inverse scores) where the scores 1, 2 and 3 
from the CPC score is divided into two.84 The EQ-5D-5L is a well-established measure of health-related 
quality of life that is quantified as a utility (i.e. a measure of quality of life between 0 and 1). In addition to 
being a relevant outcome in itself, this will also allow for potential future cost-effectiveness analyses and 
comparison to the background population.  


 
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All outcomes recommended by the recent COSCA initiative (Core Outcome Set for Cardiac Arrest) are 
included in the current study.89 
 
5.4 Harm  
5.4.1 General consideration 
Patients with IHCA have an in-hospital mortality of 70 to 80% and many patients experience post-cardiac 
arrest complications such as global brain injury, impaired myocardial function, macrocirculatory failure, and 
increased susceptibility to infections.26 Furthermore, patients suffering from IHCA often have multiple 
underlying conditions including heart failure, myocardial infarction, respiratory insufficiency, diabetes, 
infections, and/or renal insufficiency.90 The immediately preceding cause might be related to circulatory 
failure (e.g. cardiogenic shock, sepsis), respiratory failure (e.g. pneumonia, chronic obstructive pulmonary 
disease), arrhythmias (e.g. primary arrhythmias, myocardial infarction), or rarely neurological disorders.91-94 
Given this, it is difficult, if not impossible, to comprehensively report all adverse events and assess their 
possible relationship with the intervention in this patient population. Both vasopressin and 
methylprednisolone are considered safe and are commonly used in clinical practice. The overall benefit and 
potential harm of the interventions will be captured in our primary and secondary outcomes. Any specific 
adverse events suspected by the clinical team to be related to the intervention will be documented.   
 
5.4.2 Definitions  
The following definitions will be used2:  
 
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 
 


 
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5.4.3 Specific adverse events 
To assess specific adverse and potentially serious adverse events (primarily related to methylprednisolone), 
we will collect data on the following:  
 
1) Hyperglycemia (> 180 mg/dL or 10 mmol/L95) within the first 48 hours 
2) Requirement for a continuous insulin infusion (≥ 1 hour) within the first 48 hours 
3) Hypernatremia (> 145 mmol/L96) within the first 48 hours 
4) New infections after the cardiac arrest during the hospital stay (defined below)  
4a) Bacteremia  
4b) Pneumonia 
4c) Urinary tract infections  
5) New or changing antibiotics after the IHCA during the hospital stay 
6) Clinical diagnosis of gastrointestinal bleeding after the IHCA requiring at least one blood transfusion 
during the hospital stay 
7) Acute mesenteric ischemia based on a clinical diagnosis (signs and symptoms, colonoscopy and/or 
radiology findings) leading to surgery97 
8) Peripheral (i.e., limps or digits) ischemia based on a clinical diagnosis (signs and symptoms and/or 
radiology findings) leading to surgery 
 
Assessment of adverse events will be based on available laboratory values and clinical data. No specific 
procedures or blood draws will be performed.  
Given the complexity of the post-cardiac arrest syndrome, it is difficult to diagnose and precisely define 
new infections in this patient population. For example, the new Sepsis-3 definitions98-100 do not readably 
apply since many post-cardiac arrest patients will have a change in SOFA score ≥ 2 irrespective of any 
ongoing infection. Furthermore, fever is difficult to assess during the early post-cardiac arrest period where 
targeted temperature management is often utilized. Infections included here are therefore restricted to 
those that can be, at least partly, objectively defined and those that are the most common after cardiac 
arrest.101,102 Bacteremia will be defined as a positive blood culture (not including presumed contamination or 
non-pathogenic bacteria not leading to antibiotics) obtained after the cardiac arrest. Pneumonia will be 
defined as new or progressive consolidation on a chest radiograph and at least two of the following: fever (> 
38°C), leukocytosis (white blood cell count ≥ 12,000 cells/μL) or leukopenia (white blood cell count < 4,000 
cells/μL), or the presence of purulent tracheobronchial secretions.103,104 Urinary tract infection will be 


 
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defined as a positive urine culture (≥ 100,000 colony-forming units/mL from a pathogenic organism) 
obtained after the cardiac arrest.105  
 
5.4.4 Timeline  
Vasopressin has a half-life of approximately 10 to 35 minutes31 and methylprednisolone has a biological half-
life of approximately 12 to 36 hours52. There is therefore no anticipation of adverse events after hospital 
discharge as patients with IHCA have long hospital stays.106 The above mentioned adverse events will 
therefore only be assessed during the hospital stay.   
 
5.4.5 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). No events, including those outlined in section 5.4.3, will 
automatically lead to unblinding.  
 
5.4.6 Reporting  
Once a year the sponsor will submit a list of all registered adverse events that have occurred during the trial 
period as a well as a report on safety of the trial subjects to the Danish Medicines Agency. The sponsor will 
notify the Danish Medicines Agency when the trial has been completed (no later than 90 days thereafter) or 
if earlier than planned, the reasons for stopping the trial must be given. The results from the clinical trial 
including important adverse events will be recorded on EudraCT. 
 
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 six months 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 six months and 1-year outcomes will be blinded 
to treatment assignment.  


 
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6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN  
6.1 Sample size calculation 
The trial will be powered to the primary outcome of ROSC. In the original trials, the combined rate of ROSC 
was 148/178 (83% [95%CI: 77%, 88%]) in the intervention group and 118/190 (62% [95%CI: 55%, 69%]) in 
the placebo group for an absolute risk difference of 21% and a relative risk of 1.34.45,46 For this trial, we 
assume a ROSC rate of 45% in the control group (based on preliminary data from some of the participating 
sites [see section 11.2]). We assume an absolute difference of 13% between the control and intervention 
group corresponding to a ROSC rate of 58% in the intervention group and a relative risk of 1.29. With these 
estimates, an alpha of 0.05, and the use of the chi-squared test, we will need a total of 492 patients (i.e. 246 
in each group) to have 80% power to detect a statistically significant difference between groups. 
 
With an estimated survival rate of 20% (see section 11.2), an alpha of 0.05, and the use of the chi-
squared test, the power of the trial to detect a significant difference between groups is illustrated in Figure 1 
according to various estimates of treatment effect (i.e. risk ratios). Of note, the risk ratio for survival to 
hospital discharge was 4.87 (95%CI: 1.11, 21.4) in the first VSE trial and 2.73 (95%CI: 1.18, 6.32) for survival 
to hospital discharge with a favorable neurological outcome in the second VSE trial.45,46 The trial will have ≥ 
98% power to detect a risk ratio of ≥ 1.80 with a survival rate of 20% or higher in the placebo group. Sample 
size and power was calculated with PROC POWER in SAS v. 9.4 (SAS Institute, Cary, NC, USA).  
 
Figure 1. Relationship between treatment effect (risk ratio) for survival and trial power 
 


 
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6.2 Statistical analysis plan 
6.2.1 General considerations 
The statistical analyses and reporting will adhere to the CONSORT guidelines.107,108 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 the 
first dose of the study drug and meeting all inclusion criteria and no exclusion criteria (except criteria #4: 
pregnancy). In a double-blind trial, this approach is unbiased while increasing precision.67  
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.109 In case 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 center and strong prognostic factors, specifically age, whether the cardiac arrest 
was witnessed, and the initial rhythm, as covariates.110-113 Small centers (i.e. those with less than 30 patients 
included) will be combined. The risk ratio will be estimated from a log-binomial regression model.114 If this 
model fails to converge, a modified Poisson regression model will be used instead.114,115 Age will be included 
as a linear continuous variable and the initial rhythm as a binary variable (shockable or non-shockable).  
 
6.2.3 Subgroup analyses  
Subgroup analyses will be performed on both the absolute and relative scale. The analyses will include five 
pre-defined subgroup analyses for the primary and key secondary outcomes according to 1) first 


 
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documented rhythm, 2) whether the cardiac arrest was witnessed, 3) patient age (dichotomized by the 
median) , 4) time from cardiac arrest to first study drug (dichotomized by the median), and 5) time from 
adrenaline administration to first study drug (dichotomized by the median). First documented rhythm will be 
categorized as non-shockable (i.e. asystole or pulseless electrical activity) or shockable (i.e. ventricular 
fibrillation or pulseless ventricular tachycardia). The trial is not powered to detect subgroup differences, and 
these will be considered exploratory and hypothesis generating.   
 
6.2.4 Addition analyses and outcomes  
For the tertiary outcomes vasopressor-free days, SOFA scores, and health-related quality of life (continuous 
variables) differences between groups will be estimated using a linear regression model. SOFA scores and 
health-related quality of life will only be assessed in those alive at the time of measurement.   
Survival until 90 days will be presented with Kaplan-Meier curves but will otherwise be analyzed as a 
binary outcome as described in section 6.2.2  
Adverse events and other binary outcomes will be presented and analyzed like the primary and 
secondary outcomes.     
As additional exploratory analyses, ordinal neurological outcomes (i.e. CPC, mRS, GOSE) will be analyzed 
using ordinal logistical regression.124 Before these analyses, the proportional odds assumption will be tested. 
In case the proportional odds assumption is not met, ordinal logistical regression will not be performed, and 
data will be presented descriptively.    
 
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. We do not expect missing data on the vasopressor-free days, SOFA scores, or adverse events. 
There might be some limited missing data for neurological outcomes and health-related quality of life at 90 
days (and potentially at 30 days) due to loss to follow-up. Multiple imputation using known risk factors for 
outcomes after IHCA 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 


 
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family-wise error rate is the Bonferroni correction where the alpha is divided by the number of tests 
performed within the “family” of tests. However, defining the “family” is difficult and at best arbitrary.125,126 
Third, any adjustment for multiple comparisons to control the family-wise error rate increases the chance of 
Type II errors (i.e. false negatives).126 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 neutral. Furthermore, since two 
previous randomized clinical trials have shown efficacy45,46, a neutral trial with an adequate sample size will 
be important. For potential stopping due to safety concerns, see section 10.2.  
 
7. DATA COLLECTION AND MANAGEMENT  
7.1 Data collection process  
A trained research nurse, along with the site investigators, will be responsible for data collection and entry. 
Very limited data will be obtained from the clinical cardiac arrest team in real-time on a numbered case 
report form (see Appendix 4) that accompanies the study kit. This will include the patient identifier (i.e. CPR 
number), timing of the first adrenaline dose, timing of the first vasopressin dose, and the total doses of 
vasopressin administered. This, along with the telephone interviews for long-term follow-up, will be the only 
source data and all additional data will be obtained from the electronical medical records or DANARREST 
(see section 7.6) and will be based on measurements and assessments made by the clinical team. Data will 
be entered directly into the database software (see section 7.4).  
 
7.2 Variables 
7.2.1 Overview 
All IHCA patients at the participating sites will be entered into a screening log. For those not randomized, a 
specific reason for non-inclusion/exclusion will be documented. All randomized patients who received the 
study drug will be entered into the main database.  
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 


 
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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 IHCA Utstein guidelines from 1997.72 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 
Trial related variables 
 
Study ID 
 
Site 
 
Receipt of study medication  
 
 
If no, reason for no study medication provided  
 
Doses of study medication provided 
 
Requirement for emergency unblinding 
 
Inclusion criteria 
 
Exclusion criteria 
 
Date and time consent for data collection is obtained 
 
 
Patient demographics and characteristics  
 
Name 
 
Unique patient identifier (CPR number) 
Age  
 
Sex 
 
Race 
 
Height 
 
Weight  
 
Conditions/medications prior to the cardiac arrest 
 
Co-morbidities (cardiac and non-cardiac) 
 
CPC score and mRS prior to current hospital admission 
 
Reason for admission  
      Length of stay prior to the cardiac arrest 
 
Receipt of glucocorticoids within the last month 


 
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Use of oral or intravenous glucocorticoids during the current admission 
 
Previous IHCA during this admission  
 
7.2.3 Cardiac arrest characteristics  
Location and time 
 
Location of the cardiac arrest 
 
Date and time of the cardiac arrest 
 
Interventions in place 
 
Vasopressors 
 
Mechanical ventilation 
 
Intravenous access  
      Renal replacement therapy 
 
Cardiac arrest variables prior to the intervention 
 
Presumed cause of the cardiac arrest 
 
Initial rhythm  
 
Witnessed  
 
Time to first rhythm analysis  
 
Cardiac arrest variables after the intervention 
 
Date and time of the end of resuscitation (ROSC or termination without ROSC) 
 
7.2.3 Post-cardiac arrest characteristics  
Targeted temperature management  
 
If yes, target temperature and duration 
Cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass grafting   
Procedures related to neurological prognostication (e.g. EEG, imaging, biomarkers)  
Use of intravenous glucocorticoids  
Renal replacement therapy 
Adverse events (see section 5.4.3) 
 


 
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7.2.4 Outcomes  
ROSC 
SOFA scores at 24, 48, and 72 hours 
Vasopressor-free days 
Hospital disposition  
Survival at 30 and 90 days 
CPC score at 30 and 90 days 
mRS at 30 and 90 days 
Glasgow Outcome Scale Extended at 30 and 90 days  
EQ-5D-5L at 30 and 90 days 
 
7.3 Data quality and validity  
Data quality and validity will be optimized by having a single trained research nurses enter all data according 
to a detailed data dictionary. 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. Given its limited utility, double-data entry will not be performed.127,128  
 
7.4 Data storage and security  
The database application we will use is REDCap.129 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 participating sites.  
 
The short paper case report form and the consent form for each patient will initially be stored in a secure, 
locked place at the individual sites. Every half year these will be transported to the Research Center for 
Emergency Medicine in Aarhus while a copy will remain at the sites. Here they will be securely stored in 
locked cabinets, where only the principal investigator and the research nurse will have access. The files will 
be stored for 5 years after the end of the trial, where after they will be destroyed.    
 
The trial has been reported to the Danish Data Protection Agency.  


 
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7.5 Data access  
During the trial, the principal investigator and the research nurse will have access to the entire database, 
while site investigators will have access to data from their own sites. 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 entities will have direct access 
to patients’ records and to all relevant trial data including the case report form as applicable.  
 
7.6 DANARREST 
For the intra-cardiac arrest characteristics, data is captured in real-time by the clinical cardiac arrest team as 
part of a nationwide quality improvement registry (DANARREST).9,71 DANARREST is a quality improvement 
registry that aims to track the epidemiology of IHCA in Denmark. All hospitals in Denmark will participate 
within a few years and the clinical personnel are required to enter data. A Danish version of the DANARREST 
case report form is provided in Appendix 5. 
 
8. CLINICAL TREATMENT  
The clinical management of included patients will be at the complete discretion of the treating clinical team 
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 European Resuscitation Council130 and the Danish 
Resuscitation Council131 but no specific treatments will be prohibited or mandated. The sites will be 
informed about the most recent guidelines for intra-cardiac arrest care and will be encouraged to limit 
premature termination of resuscitation efforts.132 Sites will also be encouraged to follow European 
Resuscitation Council post-cardiac arrest guidelines95 including appropriate neurological prognostication.  
 
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, 
1.3, and 1.4). In brief, randomized controlled trials, primarily in the OHCA setting, have found no benefit or 
harm of sole vasopressin administration.41 The data on steroid administration during cardiac arrest is more 
limited and have shown conflicting results although no study has shown harm.59 The combination of 


 
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vasopressin and glucocorticoids has been tested in two randomized, double-blind trials finding significant 
and meaningful increases in ROSC, survival, and survival with a favorable neurological outcome.45,46   
 
9.1.2 Potential harms  
The two VSE trials found no signs of significant harm with the combination of vasopressin and 
glucocorticoids during cardiac arrest.45,46 In the first VSE trial there was an increase in the number of 
hyperglycemic episodes on day 2 and 3 in the intervention arm.45 In the second VSE trial, there was a small 
increase in the proportion of patients receiving post-cardiac arrest insulin in the intervention arm.46 
Randomized clinical trials in other intensive care unit populations such as those with sepsis have found a 
small increase in hyperglycemia and hypernatremia, but no increased risk of infections, gastrointestinal 
bleeding, or muscular weakness, with small to moderate doses of glucocorticoids.55,133,134 The idea that 
glucocorticoids could impair cardiac healing after myocardial infarction is based on old case reports.135 A 
meta-analysis of controlled trials of glucocorticoids in patients with acute myocardial infarction found no 
association with myocardial rupture and in fact noticed a decrease in mortality with the administration of 
glucocorticoids.136  
 
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, 1.3, and 
1.4), the current risk/benefit ratio is encouraging for vasopressin and methylprednisolone administered 
during IHCA. However, given the potential lack of generalizability of the two VSE trials, international 
guidelines are currently not recommending this treatment but instead calls for additional clinical trials.19-21 
Taken together, there is clear clinical equipoise for the combination of vasopressin and methylprednisolone 
during IHCA. 
 
9.2 Research in cardiac arrest   
9.2.1 General considerations  
Research in cardiac arrest is ethically challenging for two reasons: 1) Patients are unconsciousness 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.137,138 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 Helsinki1, European regulations2, and 


 
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the Good Clinical Practice guidelines3, 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 met139,140:  
 
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  
 
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 
obtained139-141:  
 
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  
 


 
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A “legal guardian” is a physician not involved in the research related to the specific patient and who are not 
in an inferior/superior position to the investigator/sponsor, who 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 IHCA (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 arrest142 
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 
IHCA is an unpredictable and sudden event that often occurs in patients that are already acutely sick. 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.106 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 < 5 minutes from the beginning of the cardiac arrest143) and after 
the third defibrillation in patients with a shockable rhythm (approximately 6-7 minutes after the beginning of 
the cardiac arrest20). Given these time frames, it would be impossible to obtain consent from a surrogate.  
 
#4. The research specifically involves the patient’s current condition 
The interventions in this trial is specifically targeted for IHCA patients and if proven effective, will benefit this 
patient population. 
 
9.3 Procedures 
9.3.1 Ethical review committee  
The trial has been approved by the regional ethics committee (case number: 1-10-72-42-18).  


 
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9.3.2 Trial-specific procedures 
The “legal guardian” will be either a physician member of the cardiac arrest team or a physician on call and 
available 24/7. The physician might be involved in the clinical care of the patient but will not be involved in 
trial procedures related to the specific patient. The legal guardian can be involved in trial procedures for 
other unrelated patients. Through ongoing training and information (see section 3.5.2), the “legal guardian” 
will be aware of the trial including the background and significance, inclusion/exclusion criteria, and 
potential risks and benefits. This way, the “legal guardian” will be able to make an informed and prompt 
decision about patient enrollment. The specific details related to the “legal guardian” (i.e. who will be the 
designated “legal guardian”) will be site-specific.    
As soon as possible, consent for future data collection will be obtained by a physician from the patient or 
if the patient is not able to provide consent, then by the legal guardian and a surrogate. The consent form 
will be signed by the patient or a surrogate and the person obtaining the consent. If a patient dies before it is 
possible to obtain consent (we anticipate that approximately 50% will not survive the cardiac arrest, see 
section 6.1), patient data will be included in the trial.144 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.145  
 
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 utilizing 
the informed consent form approved by the ethical review committee. When consent is obtained from 
participants or a surrogate, information about potential de-identified data sharing will also be included.  
 
9.3.3 Insurance 
The patients in the study are covered by the Danish patient insurance.146  
 
10. MONITORING 
10.1 Good Clinical Practice monitoring 
The sites will be monitored by the regional Good Clinical Practice monitoring units affiliated with the 
participating sites. A detailed monitoring plan will be developed prior to trial commencement.  


 
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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 individuals: two clinicians/trialist with expertise in cardiac arrest/critical care 
research and a biostatistician/epidemiologist. The IDMC members will be 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 on a yearly basis (or more often if determined by the 
IDMC) for safety; 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 
yearly review, 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 6.  


 
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11. TIMELINE AND ENROLLMENT  
11.1 Timeline  
 
Pre-trial 
Year 1 
Year 2 
Year 3 
Year 4 
Funding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol development 
and modifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethical approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration with the 
Danish Medicine Agency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of data 
dictionary  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial registration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of 
randomization list 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Education of site 
personnel  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Good Clinical Practice 
and IDMC monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment and 
assessment of outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Writing and publication 
of methodology article 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cleaning and closing of 
the database 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main manuscript writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblinding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Publication and 
presentation of results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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11.2 Feasibility  
Data from 2016 from five of the participating hospitals are provided in Table 2. As illustrated, we expect that 
approximately 457 patients will be eligible for enrollment each year. Given the acuity of IHCA, we do not 
assume that all eligible patients will be enrolled. However, given the large number of eligible patients, we 
will reach our target sample size over approximately 3 years of active enrollment (see section 11.1) with an 
enrollment rate as low as 35%. With the addition of more sites, we expect enrollment to happen faster.  
 
Table 2. 2016 data from participating hospitals  
Hospital 
IHCA with 
indication for 
CPR 
IHCA with ≥ 1 dose of 
adrenaline given (i.e. 
target population) 
ROSC in IHCA 
with ≥ 1 dose of 
adrenaline given 
30-day survival in 
IHCA with ≥ 1 dose 
of adrenaline given 
Aarhus – Skejby* 
100 
58 
21 (36%) 
11 (19%) 
Randers 
75 
56 
16 (29%) 
7 (13%) 
Aalborg – South 
208 
132 
60 (45%) 
22 (17%) 
Rigshospitalet 
198 
177 
80 (45%) 
33 (19%)** 
Odense 
63 
34 
15 (44%) 
8 (24%) 
Total 
644 
457 
192 (42%) 
81 (18%) 
* This site is currently expanding as it is merging with two other hospitals. We therefore expect a higher 
number of annual IHCA at this site.  
** Estimated based on the ROSC rate and data from the other sites 
  
11.3 Enrollment  
Enrollment at each site will be continuously monitored by the site investigator, the research nurse, and the 
principal investigator. Formal reports outlining the number of IHCA and the proportion of those enrolled at 
each site will be shared with the steering committee quarterly. In case multiple eligible IHCA 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 IHCA, we do not expect 100% enrollment of eligible IHCA. However, we will aim for 
enrollment of > 50% of eligible IHCA. In case that a site continuously underperforms despite troubleshooting 
and feedback, the steering committee will evaluate whether enrollment will continue at that site.  
 
  
 


 
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11.4 Additional sites 
In case target enrollments are not met after 6 months to 1 year of enrollment, additional sites, in Denmark 
or outside Denmark, will be included. The principal investigator and the steering committee have multiple 
national and international ongoing collaborations allowing for recruitment of new sites.     
 
12. PUBLICATION PLAN  
Three 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.107,108 The principal investigator 
will be the first and corresponding author. Additional authorship will follow authorship guidelines from the 
International Committee of Medical Journal Editors147 and will include members of the steering committee. 
In addition, as a guideline, sites enrolling > 50 patients will be entitled one additional author and sites 
enrolling > 100 patients two additional authors in addition to the site investigators and members of the 
steering committee. The trial results will be shared with participating sites and via press releases but not 
directly with the participating patients. The third manuscript will include long-term follow-up at six months 
and 1 year (see section 5.5). Study findings will be published irrespective of the results.   
 
13. DATA SHARING 
Six months after the publication of the last results, all de-identified individual patient data will be made 
available for data sharing.148 Procedures, including re-coding of key variables, will be put in place to allow for 
complete de-identification 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 Editors147 and might or might not include authors from the 
steering committee depending on the nature of their involvement.  
 


 
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14. FUNDING  
Funding for the trial is provided by Aarhus University Research Foundation (kr. 3,000,000), the Department 
of Clinical Medicine, Aarhus University (kr. 950,000), the Central Denmark Region (kr. 55,751), and the 
Independent Research Fund Denmark (kr. 2,343,495). Empressin® and corresponding placebo ampules are 
provided free of charge by Amomed Pharma GmbH. The funding agencies and Amomed Pharma GmbH 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 and sponsor: 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   
 
Steering committee: Protocol development, funding, budget overview, data dictionary development, trial 
oversight, dissemination of results, responsibilities as principal investigator for short time periods  
 
Site investigators: Responsible for site-specific enrollment, evaluation of eligible patients not included, 
education of personnel at participating sites, reporting of site-specific issues or challenges to the principal 
investigator, participant consent for data collection 
 
Research nurse: Daily management, education of personnel at participating sites, contact to pharmacy, 
contact to Good Clinical Practice monitoring unit, data dictionary development, trial registration, data entry 
and management, patient follow-up, budget overview 
 
Clinical team: Administration of the study drug, participant consent for data collection  
 
Good Clinical Practice-unit: See section 10.1. 
 
Data and safety monitoring board: See section 10.2.  


 
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Appendices 
Appendix 1: Conflict of interest disclosures for the steering committee members 
Lars W. Andersen  
Industry:  
• 
None 
 
Other:  
• 
Member of the Advanced Life Support task force at ILCOR 
• 
Editorial board member at Resuscitation  
• 
Member of the steering committee at DANARREST 
• 
Honorarium from JAMA for statistical reviews 
 
Hans Kirkegaard  
Industry:  
• 
None 
 
Other:  
• 
Chairman of the steering committee for DANARREST 
 
Michael Donnino 
Industry:  
• 
Research grants from Kaneka, General Electric, and Bristol-Myers-Squibb 
 
Other:  
• 
Research grants from the American Heart Association and the National Institute of Health 
• 
Vice-chair of the Advanced Life Support task force at ILCOR 
 
Tobias Kurth 
Industry:  
• 
Lecture fees from Novartis 
 
Other:  


 
VAM-IHCA Protocol – version 1.8 
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• 
Honorarium from the BMJ for editorial services 
 
Bodil S. Rasmussen 
Industry:  
• 
Research grant from Ferring  
 
Other: 
 
• 
None 
 
Jesper Kjærgaard  
Industry:  
• 
Lecture fees from Orion Pharma, AstraZeneca, and Bayer 
Other: 
 
• 
None 
 
Bo Løfgren 
Industry:  
• 
Lecture fees from Boehringer Ingelheim, AstraZeneca, and Bayer  
• 
Recipient of a teaching award from the Danish Society of Cardiology sponsored by Merck Sharp and 
Dohme  
 
Other:  
• 
Member of The European Resuscitation Council Basic Life Support and Automated External 
Defibrillation International Course Committee (2010 – 2016) 
• 
Member of the Basic Life Support task force at ILCOR (2017 – 2020) 
 
Asger Granfeldt 
Industry:  
• 
None 
 
Other:  
• 
None 


 
VAM-IHCA Protocol – version 1.8 
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Jacob Moesgaard Larsen Industry:  
• 
None 
 
Other:  
• 
None 
 
Dan Isbye 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Stine Thorhauge Zwisler 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Søren Darling 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Kasper Glerup Lauridsen 
Industry:  
• 
None 
 


 
VAM-IHCA Protocol – version 1.8 
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Other:  
• 
European Resuscitation Council Advanced Life Support (ALS) Science and Educational Committee 
member. 
 
Kim B. Pælestik 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Christoffer Sølling  
Industry:  
• 
None 
 
Other:  
• 
None 
 
Anders Kjærgaard  
Industry:  
• 
None 
 
Other:  
• 
None 
 
Dorte Due-Rasmussen  
Industry:  
• 
None 
 
Other:  
• 
None 
 


 
VAM-IHCA Protocol – version 1.8 
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Kasper Iversen  
Industry:  
• 
None 
 
Other:  
• 
None 
 
Martin Schultz  
Industry:  
• 
None 
 
Other:  
• 
None 
 
Fredrik Folke 
Industry:  
• 
None 
 
Other:  
• 
None 
 
Mette Gitz Charlot  
Industry:  
• 
None 
 
Other:  
• 
None 
 
Sebastian Wiberg 
Industry:  
• 
None 
 


 
VAM-IHCA Protocol – version 1.8 
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Other:  
• 
None 
 
Rikke Malene Jepsen 
Industry:  
• 
None 
 
Other:  
• 
None 
 
 
Mathias Holmberg 
Industry:  
• 
None 
 
Other:  
• 
None 
 
 
 


 
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Appendix 2: Study kit and drug labeling (Danish)  
Example from the Aarhus site.  
 
 
 
 
 
A 
Solu-Medrol/placebo 
SOLVENS 1ml 
til opl. til injektion 1ml 
Randomiseringsnr.  XXXX 
Anv. Inden 00-0000 Batchnr. 0000 
VAM-IHCA 
B 
Solu-Medrol/placebo  
PULVER  
til opl.til i.v. injektion 40mg 
Randomiseringsnr.  XXXX 
Anv. Inden 00-0000 Batchnr. 0000  
VAM-IHCA 
C  
Empressin/placebo 
til i.v. adm. 2ml 
Randomiseringsnr.  XXXX 
Randomiseringsnr.  XXXX 
Anv. Inden 00-0000 Batchnr. 0000 
VAM-IHCA 


 
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Appendix 3: Draft of CONSORT flow diagram 
 
 
 
 
 
Adult IHCA who received ≥ 1 dose 
of adrenaline during CPR 
(n= ) 
Excluded (n= ) 
1) Clearly documented “do-not-resuscitate” 
order prior to the cardiac arrest (n= ) 
2) Prior enrollment in the trial (n= ) 
3) Mechanical circulatory support at the time of 
the cardiac arrest (n= ) 
4) Known or suspected pregnancy at the time of 
the cardiac arrest (n= ) 
5) Logistical reasons (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= ) 
Allocated to vasopressin/methylprednisolone (n= ) 
 
Received vasopressin/methylprednisolone and eligible 
for analysis (n= ) 
 
Received vasopressin/methylprednisolone but not 
eligible for analysis (n= ) 
o 
Reasons (i.e. met exclusion criteria 1-3) (n= ) 
 
Did not receive vasopressin/methylprednisolone (n= ) 
o 
ROSC 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 (i.e. met exclusion criteria 1-3) (n= ) 
 
 
Did not receive placebo (n= ) 
o 
ROSC 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= ) 


 
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Appendix 4: Case report form (Danish)  
 


 
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Appendix 5: DANARREST case report form (Danish)  
 
 
 


 
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Appendix 6: Charter for the independent data-monitoring committee (IDMC) 
 
 
 
Charter for the independent data-monitoring committee (IDMC) for the VAM-IHCA trial 
 
 
Trial name: Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest – A Randomized, Double-
Blind, Placebo-Controlled Trial (VAM-IHCA) 
 
Principal investigator and sponsor: Associate professor Lars W. Andersen, M.D., M.P.H., Ph.D. 
 
EudraCT Number: 2017-004773-13 
 
Research ethical committee no.: 1-10-72-42-18, Central Denmark Region 
 
 
 


 
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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 
VAM-IHCA 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:  
 
Christian Fynbo Christiansen, M.D., Ph.D. (chairman) 
Clinical Associate Professor 
Department of Clinical Epidemiology 
Department of Clinical Medicine 
Aarhus University, Aarhus, Denmark  
 
Hans Friberg, M.D., Ph.D. 
Professor  
Department of Clinical Sciences 
Lund University, Lund, Sweden  
&  
Department of Perioperative and Intensive Care 
Skåne University Hospital, Lund, Sweden  
 
Jasmeet Soar, FRCA, FFICM, FRCP 
Consultant 
Anaesthesia and Intensive Care Medicine 
Southmead Hospital, Bristol, United Kingdom 
 
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). 


 
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Evaluations of trial data 
The IDMC will review deidentified data after six months of patient enrollment and then on a yearly basis (or 
more often if determined by the IDMC) for safety; 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 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: 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: cpc_30: Cerebral performance category (CPC) at hospital discharge (1 to 5) 
 
Specific adverse events (see section 5.4.3 in the protocol):  
6: hyp_gly: Hyperglycemia (1 for yes, 0 for no) 
7: insulin: Requirement for an insulin infusion (1 for yes, 0 for no) 
8: Hyp_na: Hypernatremia (1 for yes, 0 for no) 
9: infect: New infections (1 for yes, 0 for no) 
10: antibio: New or changing antibiotics (1 for yes, 0 for no) 


 
VAM-IHCA Protocol – version 1.8 
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11: gas_bleed: Gastrointestinal bleeding (1 for yes, 0 for no) 
12: mes_ischemia: Mesenteric ischemia (1 for yes, 0 for no) 
13: per_ ischemia: Peripheral ischemia (1 for yes, 0 for no) 
14: susar: Suspected Unexpected Serious Adverse Reactions (1 for yes, 0 for no) 
 
Variables #1 and #3-14 will be provided by the steering committee and item #2 will be provided by the 
pharmacy.  
 
An independent biostatistician (not a member of the IDMC) will provide aggregate data for each of the 
variables #3-12 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 IHCA at participating sites), number of patients included in the studies, 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 
IDCM 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, be 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 sites 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 


 
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proceedings from all sessions of the IDMC meeting, including the listing of recommendations by 
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.