A Cluster Randomized Clinical Trial of Strategic AED Deployment in High-risk Residential Areas Combined With Activation of Local Residents
Phase: NA
Conditions: Out-Of-Hospital Cardiac Arrest
Sponsor: Emergency Medical Services, Capital Region, Denmark

The CARAMBA Trial 
 
January 8th 2022 
NCT ID: 04446585 
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A cluster-randomized clinical trial of strategic AED deployment in high-risk residential 
areas combined with activation of residents: 
The CARAMBA Trial 
Cardiac Arrest in Residential Areas with Mobile First-responder Activation 
General Information  
Primary Investigator and sponsor: Fredrik Folke, MD, PhD, Associate Professor, Head of Research, 
Emergency Medical Services Copenhagen, and Herlev Gentofte Hospital, Department of Cardiology.  
Co-Principal Investigator: Carolina Malta Hansen, MD, PhD 1, 2 
Responsible Investigator: Fredrik Folke, MD, Ph.D., Associate Professor 
Steering Committee 
Freddy K. Lippert, MD2 
Christian Torp-Pedersen, MD, DMSc3 
Annette Kjær Ersbøll, Professor of Statistics5 
Gunnar Gislason, MD, PhD1 
 
 
Christian Hassager, MD, DMSc4 
Jesper Kjærgaard, MD, DMSc4 
Anne Juul Jørgensen, MD, PhD-student2 
Tine Tjørnhøj-Thomsen6
1Department of Cardiology, Copenhagen University Hospital Gentofte, Denmark 
2The Emergency Medical Services, Copenhagen, Copenhagen University, Denmark 
3Department of Clinical Investigation and Cardiology, North Zealand Hospital, Denmark 
4The Heart Centre, Copenhagen University Hospital Rigshospitalet, Denmark 
5Department of Population Health and Morbidity, National Institute of Public Health, Denmark 
6 Department for Health and Social Context, National Institute of Public Health, Denmark 
This is an investigator-initiated study.  
This study will be conducted in accordance with this protocol. The study will comply with regulatory and 
ethical requirements.  
The study will initiate in 2020 and run for up to 5 years after data collection beginns 
This protocol has been developed based on the SPIRIT checklist1.  

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Index 
1 Introduction ................................................................................................................................................ 4 
1.1. Background ......................................................................................................................................... 4 
1.2. Initiatives within Denmark ................................................................................................................. 5 
1.3. Residential areas ................................................................................................................................. 5 
1.4. Research Hypothesis .......................................................................................................................... 6 
1.5. Study Objectives ................................................................................................................................. 6 
1.6. Trial Design ......................................................................................................................................... 6 
2 Methods: Participants, Interventions, and Outcomes ............................................................................... 7 
2.1 Study Setting ........................................................................................................................................ 7 
2.2 Eligibility Criteria .................................................................................................................................. 8 
2.3 Interventions ....................................................................................................................................... 8 
2.4 Study procedure .................................................................................................................................. 9 
2.5. Outcomes.......................................................................................................................................... 10 
2.6. Participant Timeline .......................................................................................................................... 11 
2.7. Sample Size ....................................................................................................................................... 11 
2.8. Recruitment ...................................................................................................................................... 12 
3. Methods: Assignment of Interventions ................................................................................................... 13 
3.1. Pair-matching.................................................................................................................................... 13 
3.2. Allocation .......................................................................................................................................... 13 
3.3. Blinding ............................................................................................................................................. 14 
4. Methods: Data Collection, Management, and Analysis .......................................................................... 14 
4.1. The study sites and data collection area .......................................................................................... 14 
4.2 Data Collection and Management ..................................................................................................... 14 
4.2. Statistical Methods ........................................................................................................................... 15 
5. Safety Monitoring board ......................................................................................................................... 16 
6. Financing and Insurance .......................................................................................................................... 17 
7. Ethics and Dissemination ......................................................................................................................... 17 
7.1. Ethical considerations ....................................................................................................................... 17 
7.2. Declarations of interests ................................................................................................................... 18 
7.3. Access to data ................................................................................................................................... 18 
7.4. Dissemination policy ......................................................................................................................... 19 
8. Trial organization ..................................................................................................................................... 19 

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8.1. Principal investigator ........................................................................................................................ 19 
8.3. Co-principal Investigator .................................................................................................................. 19 
8.2. Executive scientific steering committee: .......................................................................................... 19 
10. References ............................................................................................................................................. 21 
 
 
Abbreviations 
AED 
Automatic External Defibrillator 
CPR 
Cardio Pulmonary Resuscitation 
EMD 
Emergency Medical Dispatch 
EMS 
Emergency Medical Services 
OHCA 
Out-of-hospital Cardiac Arrest 
CARMABA 
Cardiac Arrest in Residential Areas with Mobile First Responder Activation 
ICC 
Intra Class Coefficient 
CV 
Coefficient of Variability 
 
 
 

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1 Introduction 
1.1. Background 
Out-of-hospital cardiac arrest (OHCA) is a major health problem. In Europe and the United States, 
700,000 OHCAs happen annually2, and in Denmark alone, there are 5,000 events every year3. OHCA 
is an acute health emergency and needs to be treated within minutes to ensure survival, and early 
defibrillation is the core of the treatment4, 5. In Denmark, different initiatives have been undertaken 
to increase bystander defibrillation (from here on referred to as defibrillation), but despite these 
initiatives, defibrillation rates remain low in residential areas. Specifically, it has been challenging to 
increase defibrillation in residential areas, which is where 85% of all OHCAs occur6. This study aims 
to increase defibrillation rates and survival after OHCA in residential areas.  
Early defibrillation may be the most critical determinant for survival of out-of-hospital cardiac arrest. 
The chance of survival decreases with 10% per minute from collapse to first defibrillation4, 5. Hence, 
efforts to decrease time to first defibrillation are crucial.  In many cases, the time from recognition 
of cardiac arrest to arrival of Emergency Medical Services (EMS) is long 7, leaving bystanders in a 
critical position to increase survival by bystander cardiopulmonary resuscitation (CPR) and rapid 
defibrillation by a nearby Automated External Defibrillator (AED). AEDs have shown to increase 
survival markedly after OHCA and are safe and effective to use by laypersons. Strategies of placing 
publicly available AEDs in high-risk areas in the community have evolved, providing the opportunity 
of defibrillation before the arrival of the EMS 8-12. For optimal survival benefit AEDs need to be used 
within minutes of the event and, thus, be close to the victim, easily locatable, and accessible to 
bystanders. Several studies have shown a significant increase in OHCA survival when AEDs are 
placed in public locations where the criteria mentioned above are met like airports8, on aeroplanes9, 
10, and in casinos11, with reported survival rates as high as 49% to 75%8-11. These findings have led 
to a more widespread AED deployment in public locations with a positive effect on OHCA survival12-
15. In accordance, several countries have implemented national public-access defibrillation 
programs with AED deployment in public high-risk areas of OHCA13, 15-17, in agreement with current 
international guidelines recommendations18, 19. 

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1.2. Initiatives within Denmark 
In Denmark, various initiatives have been undertaken to increase survival after OHCA. In 2007, the Danish 
AED network was established, and in 2010 it was integrated with the EMS system so dispatchers can guide 
bystanders to the nearest AED. Since 2011, emergency medical dispatchers have followed a standardized 
protocol guiding bystanders to perform CPR and retrieve the nearest AED when cardiac arrest is suspected. 
Since 2012 the AED network has been made available through a mobile application (app) showing the nearest 
accessible AED. Resuscitation training has been mandatory in elementary schools since 2005 and when 
acquiring drivers licenses since 2006. From 2001-2012 defibrillation rates for OHCA in public increased from 
1.2 to 15.3%. Disappointingly defibrillation rates for residential areas remained unchanged at 1.3% in the 
same period.6 Since 2017 EMS dispatchers have been able to alert citizen first responders through a mobile 
application (app) based alert system called HeartRunner when they suspect an OHCA. Citizens can voluntarily 
sign up as citizen first responders. There are no requirements for prior training in CPR or AED use; 
nevertheless, the majority of citizen responders have undergone training. Citizen first responders are either 
guided to collect an AED and bring it to the scene of the OHCA or to go straight to the scene and perform 
CPR. The effect on survival and defibrillation rate from this intervention is currently under investigation, and 
no results have yet been published. Dispatcher also have the option of connecting to the scene of the OHCA 
through one of the bystanders smart phones. This way, the dispatcher can  reassess the diagnosis and guide 
CPR. 
1.3. Residential areas 
The vast majority of all cardiac arrests (65-80%) occur in residential areas20-22, where on-site AEDs are rarely 
available20, 23, and where the chance of successful resuscitation is only achieved in 2-4% of cases3, 23, 24. 
Patients in non-public places are therefore primarily assisted by dispatched first-responders (police or 
firefighters bringing an AED) or the EMS system. Furthermore, only a few attempts have been made with 
public access defibrillation in residential areas, and the results have been disappointing 14, 25, 26. The most 
extensive study to date is the Home use of AED trial with 7,001 patients with previous anterior wall 
myocardial infarctions who were not candidates for an implantable cardioverter-defibrillator. The patients 
were randomly assigned to receive either standard care or standard care plus a home AED 25. Disappointingly, 
access to a home AED did not significantly improve overall survival, mainly because the rate of OHCA was 
less than 1% per year (corresponding to the chance of AED use not exceeding 1% per year even if an AED was 
used in every event).  

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Whereas the home AED strategy only provides the opportunity to treat those in the immediate household, 
placing AEDs outside people’s homes in selected high-risk residential areas provides the opportunity to use 
an AED in treating any one of many persons at risk. Residential areas need early first-responder activation to 
benefit optimally from AEDs. Such a responder needs to be closer to the cardiac arrest patient than 
traditional first responders (police or firefighters) and/or EMS and must be alerted to act.  
One solution implemented in several regional dispatch centres in Europe including Denmark, is an app-based 
alert system27. In the case of a suspected OHCA, the dispatcher manually activates the alert process, and a 
software program then automatically identifies nearby available citizen responders and AEDs. The app alerts 
citizen first responders and directs them to the OHCA or to retrieve an AED and bring it to the OHCA. The aim 
is for the citizen responders to perform CPR and defibrillate before EMS arrival. Such systems, based in either 
apps or text messages, have been tested and implemented in several regional dispatch centres in Europe 28, 
29. Experiences from Holland showed that by activating  citizen first responders, it was possible to shorten 
the time from OHCA to first defibrillation significantly and importantly, that among citizen responders 
activated by a text message alert 87.5% were used in residential areas.27 
1.4. Research Hypothesis 
Strategic deployment of public access AEDs and training of residents to be citizen responders is superior to 
standard care after OHCA regarding the proportion of OHCA patients defibrillated by bystanders.  
1.5. Study Objectives 
To determine if strategic deployment of public access AEDs, training residents in CPR and AED use and 
recruiting them as citizen responders in high-risk residential areas is superior to “standard care” with the 
primary endpoint being bystander defibrillation.  
1.6. Trial Design 
The Cardiac Arrest in Residential Areas with Mobile First Responder Activation (CARAMBA) trial is a 
prospective cluster-randomized superiority trial that will compare the proportion of bystander defibrillation 
between geographically defined intervention and control areas. Twenty-six residential areas will be pair-
matched and allocated 1:1 to intervention or control. In the interventional areas, AEDs will be strategically 
deployed, and residents will undergo training in CPR and AED use. Further, in the case of suspected OHCA, 
registered citizens will be activated to respond through the HeartRunner app system. The intervention will 
serve as a supplement to standard care, and the control area will receive existing standard care from 
emergency medical services in the case of suspected OHCA. 

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2 Methods: Participants, Interventions, and Outcomes 
2.1 Study Setting 
The study will take place in residential areas within the metropolitan area of Copenhagen, covering 
approximately 355.7 km2 and with a resident population of ≈ 1,2 million. A total of twenty-six areas have 
been selected for the trial. Each area has between 600-5000 inhabitants, ranging from 0.04-0.77 km2 and 
each area had between 2-7 cardiac arrests per year. The mean OHCA incidence rate in the twenty-six selected 
residential areas is 194 OHCA/100,000 inhabitants, CI(184;285). In comparison, the incidence rate for the 
Capital Region of Copenhagen is 83 OHCA/100,000 inhabitants. The areas are characterized by high rise 
buildings, high living density, low socio-economic status, and high incidence of cardiac arrest. The areas 
primarily consist of public housing and housing cooperatives. 
2.1.1 Identifying research areas 
The clusters have been selected based on criteria of: 
• 
High living density of people above 60 years of age24. 
• 
The presence of shared social infrastructures such as volunteer organizations, resident cafés, or 
sports associations. This criterion was prioritized in order to facilitate the implementation of the 
intervention taking advantage of existing social structures.  
• 
At least one historic cardiac arrest per area per year.  
Procedure for identification of clusters: 
1. To identify the relevant study areas which fulfilled the criteria of high density of persons > 60 years of age, 
we used data on age and living density in 100x100 meter grid cells covering all of Denmark. Using the 
Geographic Information Systems program, QGIS, and maps of Denmark from the Agency of Data Supply and 
Efficiency, the number of persons above 60 years of age was mapped as a gradient. 
2. To identify residential areas with a high risk of OHCA, we mapped all historic cardiac arrests from the 
Capital Region of Copenhagen from 2016-2018 as well as cardiac arrest from the Copenhagen Municipality 
from 1994-2015.  
To identify housing units of an appropriate size with shared social infrastructures and to exclude nursing 
homes, every area with a high density of persons above 60 and a high incidence of OHCAs was evaluated 
using google search and google maps. When a nursing home was identified inside the relevant areas, the 

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nursing home coordinates were fenced off through the GIS program, thus excluding the appropriate 
geographical location from the study.  
2.2 Eligibility Criteria 
2.2.1Inclusion criteria 
All EMS-treated OHCAs, except those describe in the exclusion criteria, within the twenty-six clusters will be 
included in the trial. The cases are included, no matter how many citizen responders are within 1800 meters 
or their response to the alarm. 
2.2.2 Exclusion criteria 
The following OHCAs will not be included in the analysis: 
• 
Not true OHCA (suspected, but not verified) 
• 
EMS-witnessed  
• 
Not witnessed by a bystander 
• 
Due to trauma, intoxication, or suicide 
• 
Not treated by the EMS due to ethical reasons or apparent signs of death 
• 
Under the age of 8 
• 
In nursing homes or health care facilities  
These cases will be accounted for but not included in the analysis of the outcome. 
2.3 Interventions 
The intervention will consist of three parts; strategically deployed AEDs, training residents in CPR and AED 
use, and recruiting residents as citizen first responders. 
2.3.1 Strategically placed AEDs 
AEDs will be deployed visibly and with 24/7 accessibility so that all residents will have a maximum of 1.5-
minute walking distance to and AED. A total of 74 AEDs will be deployed in cabinets, and appropriate signage 
will be installed. All AEDs will be registered with the national AED network and thus linked to the emergency 
dispatch center. 
2. CPR and AED training 
Training will consist of 30-minute hands-on training courses in groups of 5-10 participants each, following 
recommendations from de the Danish Resuscitation Council. Residents in the intervention areas will be 
invited to participate in CPR and AED training. Approximately twice a year, 2-4 courses will be conducted in 
each area. We will evaluate on an ongoing basis whether there is a basis for organizing more training 

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depending on interests from the residents and the housing associations. The goal is to train as many as 
possible.  
As standard practice in intervention studies, a board of residents from the study areas will conduct meetings 
to discuss the intervention, recruitment, and unforeseen challenges as they appear, in order to ensure 
successful implementation of the intervention30. The discussion will follow the theory of change, which is 
currently under development for the project. The theory of change describes every step necessary for the 
intervention to succeed and every assumption made. It serves as a means to identify challenges and explain 
the findings of the study. It is a dynamic tool that will be developed on an ongoing basis during the 
implementation, recruitment, and trial phase31. 
2.4 Study procedure 
For control areas, the following standard procedure will take place: 
• 
For all 1-1-2 calls with suspected OHCA to the emergency dispatch center will activate a two-tiered 
response consisting of dispatch of an ambulance with an emergency medical technician, a physician-
staffed mobile emergency care unit, and citizen first responders through the Heart Runner app.  
• 
The medical dispatcher offers telephone assisted CPR to bystanders. Furthermore, if more than two 
bystanders are present and an AED is accessible within 1½ minute travel distance (depending on the 
type of terrain), then one bystander is guided to localize and retrieve the AED. 
 
For intervention areas, the following procedure will take place: 
• 
Standard care, as described above for control areas. 
• 
Strategical deployment of AEDs with 24:7 availability and 1½ minute walking distance to every 
residence within the area. The AEDs will be registered with the AED network and thus linked to the 
emergency dispatch center. 
• 
The emergency dispatch center will retrieve data from used AEDs.  
• 
For each interventional area, all residents will be invited to participate in a course in CPR and AED 
use regularly. At each course, the participants will be informed about the citizen responders and the 
possibility to volunteer so they can be activated through the HeartRunner app in case of a nearby 
OHCA. 
• 
Campaign material regarding the HeartRunner app will be mailbox distributed, posted in social media 
groups, and/or printed in residents magazines as appropriate for each area.  

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2.4.1 Procedure for activation of citizen responders 
For the CARAMBA Trial, the Heart Runner system will be activated in every case of suspected OHCA in both 
intervention and control areas. The location of the incoming emergency call will be compared to the 
geographical mapping of mobile phones connected to the Heart Runner app. The app sends out new locations 
whenever a citizen responder changes positions according to the “significant change of location service”32. 
The latest updated position is stored as coordinates and used to identify citizen responders nearby a cardiac 
arrest. If a position is over 72 hours old, the heart runner is considered inactive and not included. The 
HeartRunner software will identify all citizen responders (mobile phones) within a radius of 1800 meters 
(configurable) from the suspected cardiac arrest. Up to 20 heart runners (configurable) closest to the site of 
cardiac arrest will receive an alarm on their smartphone requesting whether they can respond. When the 
citizen responders accept the alarm, they will send out a new, updated, position and the software will confirm 
that the updated position is within 5,000 meters. If the heart runner is >5,000 meters of the cardiac arrest, 
the heart runner will be informed they are now too far from the cardiac arrest and their help will therefore 
not be required. The system will then recruit the remaining heart runners to either go directly to the site of 
arrest and begin CPR or to fetch a publicly accessible AED. An algorithm will be used to instruct citizen 
responders who accept an alarm. Starting from the first citizen responder accepting the alarm, the first four 
citizen responders will be instructed to fetch the nearest accessible AEDs and then go to the cardiac arrest 
location. The fifth citizen responder is instructed to go directly to the cardiac arrest location and perform 
CPR. This algorithm is performed up to 4 times, depending on how many first citizen responders that are 
close to the cardiac arrest. If a citizen responder aborts the alarm, the assignment (AED or CPR) is relocated 
to the next citizen responder accepting the alarm. If there are no publicly available AEDs close to the cardiac 
arrest, all citizen responders who accept the alarm will be directed to start CPR. The software includes the 
total distance from the citizen responder to the AED and then to the cardiac arrest to select the 20 nearest 
heart runners. The location of cardiac arrest is displayed on a map through the Heart Runner app including 
the address of the cardiac arrest. A map showing the route from the citizen responder’s location to the 
location of the cardiac arrest is also provided. The Heart Runner app is linked to the Danish AED-Network and 
only takes accessible AEDs into account, at the time of alarm.  
2.5. Outcomes 
The primary outcome is bystander defibrillation, and the secondary outcome is 30-day survival. Both 
outcomes are based on OHCA witnessed by a bystander. 
Exploratory outcomes are  
• 
Time from OHCA collapse to first defibrillation (either AED or manual defibrillator) 

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• 
Proportion of OHCA patients achieving return of spontaneous circulation (ROSC) at hospital 
admission 
• 
Whether surviving patients after admission return to their home or a nursing home.  
• 
Whether surviving patients who were in work prior to the OHCA return to their occupation or not. 
• 
Diagnosed with cerebral injurie 
2.6. Participant Timeline 
The trial will have a phase of implementation of the intervention of an estimated 12 months and started in 
June 2020. Due to the coronavirus pandemic the implementation process has been longer than expected and 
ended in December 2021. The data collection in each pair of clusters will start as soon as the intervention 
cluster has completed CPR training and AEDs have been deployed and registered with the AED network. 
Given that the implementation phase will occur sequentially among clusters, data collection will start for 
some clusters during the implementation phase. The trial is planned to run for 5 years after data collection 
begins.   
Participant timeline  
2020 
2021 
2022 
2023-2026 
2027 
Jan-
Jun 
Jul-
Dec 
Jan-
Jun 
Jul-
Dec 
Jan-
Jun 
Jul-
Dec 
  
Jan-
Jun 
Jul-
Dec 
Pair-matching and randomization 
  
  
  
  
  
  
  
  
  
  
  
Recruitment of residential areas 
  
  
  
  
  
  
  
  
  
  
  
Deployment of AEDs 
  
  
  
  
  
  
  
  
  
CPR and AED training 
  
  
  
  
  
  
  
  
  
  
  
Data collection 
  
  
  
  
  
  
  
  
  
  
  
Analysis and results submission 
  
  
  
  
  
  
  
  
  
  
  
 
2.7. Sample Size 
From 2016-2018, 1 out of 186 OHCAs within the study areas received bystander defibrillation. This mounds 
to a defibrillation rate of 0.5 (0.01;3.0) %. Based on data from the Danish Cardiac Arrest Registry, the total 
number of historic OHCAs per year in the selected areas is 79. For this study, we will strive to improve the 
proportion of patients receiving bystander defibrillation from 1 to 12%, based on prior evidence and assessed 
clinical relevance33.  
2.7.1. Clustering effect 
In contrast to individual randomized trials, OHCAs within residential areas are not independent in cluster-
randomized trials. OHCAs within each residential area (i.e. cluster) are more alike as compared to OHCAs in 
different clusters. In order to conduct the power calculation, the Intra Cluster Coefficient (ICC) was taken into 
account34, 35. Since there have been no prior trials of this kind, existing literature does not provide possible 
examples of ICCs. It is also not feasible to conduct a pilot study due to the rarity of the disease. When ICC is 
unknown, it is customary to assume the value of 0.05-0.10. 
It is possible to calculate ICC based on data of historic cardiac arrests within the research areas. For this trial, 
ICC has been calculated for age using cardiac arrest data 1994-2018 and for rates of bystander defibrillation 

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and OHCA witnessed by a bystander using data from 2016-2018. The ICC for age is 0.026 (0.0001;0.086). The 
ICC for defibrillation rates is <0 and for witnessed status is 0.001. A negative ICC can be interpreted as close 
to zero, meaning that members within a cluster are not more alike than members between clusters. The data 
suggest that the ICC for this trial might be low, but with the wide confidence interval, it is important to remain 
conservative when estimating the sample size. ICC has been calculated in R using the ICC-package for 
continuous data and the ICCbin-package for binary data36, 37.  
Power calculations were done to estimate the trial duration since the number of clusters (i.e. residential 
areas) was known. With the desired power of 80% and a significance level of 5%, power calculations were 
conducted with varying ICCs and effect sizes to determine a conservative estimation of the sample size.  
Obs 
Number of 
clusters  
intraclass 
correlation 
Number of 
individuals in 
a cluster  
Effect size 
(standardiseret 
difference) power 
1 
13 
0.05 
5 
1% til 15% 
0.84 
2 
13 
0.05 
10 
1% til 10% 
0.81 
3 
13 
0.05 
10 
1% til 12% 
0.90 
4 
13 
0.05 
10 
1% til 15% 
0.97 
5 
13 
0.10 
5 
1% til 15% 
0.79 
6 
13 
0.10 
10 
1% til 12% 
0.81 
 
Tabel 1: Powercalculation using varying ICC, cluster sizes, and effect size.  
To make a conservative estimation of the ICC, option no. 6 was chosen. That corresponds with a sample size 
of 130 witnessed OHCAs in each arm, which would result in a study duration of 5 years. This calculation does 
not take into account that an OHCA must have occurred in each cluster. For the statistical analysis, a strategy 
has been chosen that can account for cluster with no events. A study duration of 5 years is anticipated to 
achieve the desired number of cases.  
2.7.2. Varying cluster sizes 
It is recommended to take variable cluster sizes into account when the coefficient of variability (CV) being 
the variance of mean cluster size is greater than 0.23.35, 38 
CV = standard deviationcluster size/meancluster size, 
In this study, the CV of the expected cluster sizes is 0.5. Pair matching can account for varying cluster sizes. 
After pair-matching, CV is replaced with variances of cluster means within the pairs. CVpairs range from 0.00 
to 0.24, allowing us not to take varying cluster sizes into account when conducting power calculations.34, 38  
2.8. Recruitment 
For this trial to succeed, it will be important to ensure it is anchored in the intervention areas. We plan to use 
the existing structures of social, sports, or cultural activities already present in the areas. Through this 

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method, the goal is to reach members of the communities that are socially well connected and resourceful. 
Each of the selected residential areas has a website or a Facebook group and by searching the sites, one key 
informant for each intervention area will be identified. This informant will help get an overview of the 
community and the subgroups and ensure contact. The different subgroups within the areas must be 
included in the CPR training in order to ensure broad support and engagement within the community.  
The administrative personnel of each housing unit will register the AEDs at the AED network and look after 
the AEDs. All AEDs have a service agreement and the administrative personnel can contact them in case of 
any malfunction, vandalism, or the AED has been in use.  The service agreement also ensures that all AEDs 
are checked once a year to ensure they are functioning and available at the AED network.  
3. Methods: Assignment of Interventions 
3.1. Pair-matching 
Pair-matching of research areas has been conducted to balance baseline characteristics. Optimal pair-
matching increases power in CRTs and makes covariate adjustment during data analysis more effective34, 39. 
Variables for the pair-matching are chosen based on their association with the outcomes and availability 
data. The variables included are age, number of inhabitants, and AED/km2. To conduct the pairing, distances 
matrixes were created for every included variable. The distance matrixes create the distances of the chosen 
variables for every possible pair. The age variable has been weighed in order to gain balanced pairings. Some 
of the areas are located close to each other. In order to prevent contamination between the areas, they will 
be linked during randomization and will both be either intervention or control. For that reason, they cannot 
become a pair, which has been defined in the matrix. Using the pre-selected twenty-six areas, the trial has 
276 possible pairs. The distance matrixes are used to create 13 pairs with the minimum absolute sum of 
distances creating the best possible matches. The R-package “designmatch” has been used to conduct the 
above described pair-matching.40 The function nmatch does nonbipartite matching by several variables. 
Afterward, the quality of the matching has been checked by reviewing the pairs manually.  
3.2. Allocation 
Within each pair, the areas are randomized to either intervention or control. To limit contamination between 
areas, areas with less than 1000 meters apart have been linked, meaning that they both become either 
control or intervention areas. In total six areas have been linked two and two. Each pair have been 
randomized using an R-program that accounts for the linked areas. Since all areas will receive the same 
standard emergency medical care, the dispatcher continues, as usual, not knowing whether the OHCA is in 
an interventional area, observational area, or outside the study sites.  

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3.3. Blinding 
Due to the nature of the study, treatment allocation is not blinded to rescuers or patients.  The steering 
committee will, during the study, receive information on total numbers of arrests and overall success of 
providing defibrillation.  The steering committee will not receive information on whether defibrillation took 
place in areas allocated to intervention or no intervention.  Only the safety committee will have access to all 
information. 
4. Methods: Data Collection, Management, and Analysis 
4.1. The study sites and data collection area 
The study sites consist of one major housing 
association and have a varying size from 0.05 
to 0.77 km2. Since we expect that the 
residents will act not only within their own 
housing association but also in the 
surrounding area, the inclusion of cases will 
occur from the data collection area. The 
data collection area consists of the study site 
and a buffer zone surrounding the study site 
(map 1). The buffer zone does vary from 
area to area. It can consist of one family 
houses or high-rise buildings but most often 
it is a combination of the two. Non-
residential areas such as shopping centers and train stations has been excluded from the buffer zone. This 
design has the benefit of supporting the study with a higher amount of cases, which is needed to produce 
significant results within a reasonable time frame. The buffer should be big enough to achieve enough cases 
but small enough so that all cases can be expected to benefit from the intervention. A buffer distance of 250 
meters achieves enough cases and results in an average distance from the center of the study site to the 
outer edge of the buffer zone of approx. 500 meters, which is an appropriate distance for a citizen responder. 
Within the study site and buffer zone, elderly homes have been excluded (map 1). Further, parts of the buffer 
zone that are cut off by impassible structures such as train railway tracks or highways are excluded (map 1).  
4.2 Data Collection and Management 
During the trial, data on cardiac arrest within the areas will be collected through the existing data collection 
system, the Danish Cardiac Arrest Registry, which records all OHCAs in Denmark3, 41. The Danish Cardiac Arrest 
Registry has existed since 2001 and has previously been described in detail. The National Cardiac Arrest 
Map 1: data collection area consists of both the study sites and the buffer 
zone. Railway tracks become the boundary on the east side of the buffer 
zone. The hole in the middle of the study site represents an elderly home 
that has been excluded from the data collection area. 

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Registry follows the Utstein template for reporting cardiac arrest.42 The following information is collected 
through the Danish Cardiac Arrest Registry: witnessed status, location of arrest, first recorded rhythm, 
whether bystander performed CPR and/or defibrillation, EMS CPR and/or defibrillation, whether the arrest 
was EMS treated, time of EMS first shock, return of spontaneous circulation, time to return of spontaneous 
circulation, patient status at hospital admission (terminated at the scene, ongoing CPR, return of 
spontaneous circulation but comatose or Glasgow Coma Scale >8, alive). Each case is validated through 
patient charts to validate the cardiac arrests and exclude misclassified cases.  
Data on 30-day survival will be retrieved through Statistics Denmark. Data on neurological status will be 
retrieved from patient journals. Data on socioeconomic factors will retrieved through Statistics Denmark. 
Through the exact location of arrest, it will be possible to identify OHCAs in the study area. 
Personal data will be treated with the usual secrecy in compliance with current regulations and legislation in 
the Capital Region of Copenhagen, Denmark. Personal Identifier numbers such as social security numbers 
and all other data that may lead to the identification of subjects included in the study will be coded and keys 
for decoding will only be accessible to key persons in the project. 
Data will be stored on a dedicated and secure server at the Emergency Medical Services Copenhagen, Capital 
Region of Denmark. Only a few people in the research group have access to data logging and a code to access 
data. Data will be stored for ten years after the closing of the study. 
4.2. Statistical Methods 
Eligibility, allocation, inclusion, and exclusion are 
displayed in a trial diagram (Figure 1).  
The primary outcome is bystander defibrillation, and 
the secondary outcome is 30-day survival. 
The statistical analysis for this trial will be conducted 
as a stratified (matched) logistic regression with an 
exact score test of intervention will be used. The data 
structure is multilevel with 3 levels being pairs, areas 
(clusters) nested within pairs and intervention group, 
and finally, cardiac arrests (figure 2). Data will be 
aggregated at area level, as number of OHCA and 
number of outcome events. In the stratified logistic regression, number of outcome events out of number of 
Figure 1 Trial diagram 

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OHCA within area is an event/trial outcome. Pair of areas is the strata variable. Intervention is a fixed. An 
exact score test of the effect of intervention on the outcome will be used. 
For the primary outcome, we will conduct the above described stratified logistic regression with an exact 
score test of intervention. The event/trial outcome is number of primary events out of number of OHCA. 
The secondary outcome will be analyzed using the same statistical procedure as described for the primary 
outcome. The event/trial outcome is number of secondary events out of number of OHCA. 
An assumption for the analysis is independent observations. It is assumed that the observations are 
independent as we expect no relation between OHCA cases. Aggregation of data at area level and using a 
stratified analysis account for the hierarchical data structure.  
 
 
 
5. Safety Monitoring board 
For the course of the study, a safety committee with statistical and clinical insight will be appointed.  This 
committee functions independent of the steering committee and will be the only body receiving all 
information during the conduct of the study.  Thus, the steering committee will follow the overall 
development of the study and be provided overall numbers of cardiac arrests and defibrillations.  The Safety 
Monitoring Board will receive all information available including the areas randomized to intervention. 

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During the course of the study, the steering committee will oversee the general conduct of the trial and 
provide the safety committee will information.  The safety committee will restrict information to the steering 
committee only to recommend the continuation of the study or discontinuation. 
6. Financing and Insurance 
The study is financed by an unrestricted research grant from TrygFonden. Further, Zoll provided 100 AEDs 
and funding for AED cabinets purchase and deployment. Provision of this support is provided with contracts 
signed by TrygFonden and Zoll respectively, the principal investigator and the head of the Emergency Medical 
Services in Copenhagen. This is an investigator-initiated trial and Danish patients are in general covered by 
rules that ensure coverage of patients when exposed to adverse events during the course of treatment. 
All AEDs and cabinets has been insured through the insurance company Tryg. 
 
7. Ethics and Dissemination 
7.1. Ethical considerations 
7.1.2. Scientific aspects 
In Denmark, survival following OHCA at home is 6.5% and the rate of defibrillation is 1,7%41 but 7 out of 10 
may survive if defibrillated by an AED within the first minutes after collapse.11 The AED registry in the Capital 
Region of Denmark currently holds nearly 6000 AEDs3, 6, 43. Bystander defibrillation is not only crucial for 
survival but also survival with a favourable neurologic outcome and the chance of returning to work.44, 45 By 
deploying AEDs strategically within the areas and ensuring the presence of well-trained citizen first 
responders the proportion of patients who receive bystander of defibrillation and survival may increase. 
Given this background, we find that the risks involved with the study are justified by a good chance of 
improving outcomes. 
7.1.3. Legal aspects 
The ethical committee in the Capital Region of Denmark has evaluated the project and found that it is not 
notifiable to the ethical committee in the Capital Region of Denmark and that the project can be initiated 
without approval from the ethical committee (Journal nr.: 19037170). This decision was based on the design 
of the study which randomizes residential areas to intervention with AED deployment and training in CPR 
and AED use vs. control with standard care.  
The study is registered by the Danish Data Protection Agency via The Capital Region of Denmark (journal nr.: 
2012-58-0004, VD-2018-28, I-Suite nr.: 6222). The study is also registered by the Danish law regarding the 
handling of personal data for patients will be adhered to. The study has also been registered with the Danish 

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Patient Safety Authority (3-3013-2721/1). 
 
7.1.4. Information regarding the intervention during the study 
This study performs intervention in selected areas and no intervention in other areas.  The intervention is 
provided on top of all currently provided treatment and no area is therefore deprived of treatment that could 
have been expected.  In the areas of intervention efforts are performed to disseminate knowledge of the 
intervention and to train local people.  No information is provided in areas without intervention.  The 
intervention adds a greater likelihood of bystander defibrillation which is part of standard treatment.  
Therefore, patients subjected to treatment in intervention areas are not provided further information and 
not requested to consent. 
Citizen first responders: To complete the registration through the HeartRunner app, all volunteer citizens 
must sign the terms of agreement. These include not to disclose any details about suspected cardiac arrests 
that could lead to the identiﬁcation of individual patients. Heart runners also sign a confidentiality agreement 
ensuring personal information about the patient or resuscitation attempt or patient is not to be disclosed. 
Heart runners also agree to being geographically located when they are logged on to the app, including 
before receiving alarms and to be contacted by the research team. Heart runners can erase their user 
information in the app at any given time. Data is stored in accordance with Danish data legislation. 
7.2. Declarations of interests 
The principal investigators have previously received grants from TrygFonden to perform epidemiological 
studies of out-of-hospital cardiac arrest. The investigators are otherwise independent of TrygFonden.  
Zoll Medical Corporation has donated AEDs and funding for cabinets and deployment. Zoll Medical 
Corporation does not influence the study design, data collection, data analysis, or article writing in any way.  
7.3. Access to data 
Data for this study are derived from the Danish Cardiac Arrest Registry and the HeartRunner Mission Survey. 
Further sources of data are those collected in register via the research environment in Statistics Denmark.  
A single statistician has access to the study code during the trial and can provide listings and calculations for 
the Safety Monitoring Board. When the study closes as scheduled, or prematurely, the code is made available 
to further study staff. 
Personal data will be treated with the usual secrecy in compliance with current regulations and legislation in 
the Capital Region of Copenhagen, Denmark. Personal Identifier numbers such as social security numbers 

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and all other data that may lead to the identification of subjects included in the study will be coded, and keys 
for decoding will only be accessible to key persons in the project. 
Data will be stored on a dedicated and secure server at the Emergency Medical Services Copenhagen, Capital 
Region of Denmark. Only a few people in the research group have access to data logging and a code to access 
data. Data will be stored for 10 years after the closing of the study. 
7.4. Dissemination policy 
Regardless of the result of the study the main result will be published in an international peer-reviewed 
journal and presented at relevant congresses. The protocol will be made publicly available as the study starts 
and will be registered as required for proper publication. 
8. Trial organization  
8.1. Principal investigator 
Fredrik Folke, MD, PhD, Associate Professor 
Herlev and Gentofte Hospital, Department of Cardiology, 
Copenhagen University Hospital, 
Kildegårdsvej 28, 2900 Hellerup and 
Head of Research, Emergency Medical Services Copenhagen, 
Telegrafvej 5, opgang 2, 3.sal 
2750 Ballerup 
Fredrik.Folke@Regionh.dk 
0045-28182978 
8.3. Co-principal Investigator 
Carolina Malta Hansen, MD, PhD 
Postdoctoral Researcher, Emergency Medical Services Copenhagen 
Carolina.malta.hansen.01@regionh.dk 
8.2. Executive scientific steering committee: 
Professor Christian Torp-Pedersen, Department of Clinical Investigation and Cardiology, North Zealand 
Hospital, Denmark 
Professor Annette Kjær Ersbøll, Department of Population Health and Morbidity, National Institute of Public 
Health, Denmark 
Dr. Jesper Kjærgaard, Department of Cardiology, Rigshospitalet, Denmark 
Professor Christian Hassager, Department of Cardiology, Rigshospitalet, Denmark 

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Professor Gunnar Gislason, Herlev and Gentofte Hospital, Hellerup, Denmark and the Danish Heart 
Foundation, Denmark 
Dr. Freddy Lippert, Emergency Medical Services Copenhagen, Ballerup, Denmark 
Professor Tine Tjørnhøj-Thomsen, National Institute of Public Health, University of Southern Denmark, 
Copenhagen, Denmark 
Dr. Carolina Malta Hansen, Emergency Medical Services Copenhagen, Ballerup, and Herlev and Gentofte 
Hospital, Division of Cardiology, Capital Region of Denmark, Denmark.  
Dr. Anne Juul Jørgensen, Emergency Medical Services Copenhagen, Ballerup, Denmark 
Assistant Professor Fredrik Folke, Emergency Medical Services Copenhagen and Herlev and Gentofte 
Hospital, Hellerup, Denmark (chair) 
The steering committee is responsible for study conduct. All decisions regarding management of the study 
will be made by the steering committee. During the study the steering committee will remain blinded to 
study outcome, but the committee will be continuously informed of study progress. This ensures that the 
steering committee has sufficient information to handle any problems with study progress. The steering 
committee will regularly be provided with updates by the Safety Committee and Monitoring Board. These 
updates are restricted to a recommendation to either continue or discontinue the study. No further 
information can be given by the Safety Committee and Monitoring Board during the course of the study. 
 
 

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10. References 
1. 
Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, 
Mann H, Dickersin K, Berlin JA, Doré CJ, Parulekar WR, Summerskill WS, Groves T, Schulz KF, Sox HC, 
Rockhold FW, Rennie D and Moher D. SPIRIT 2013 statement: defining standard protocol items for clinical 
trials. Annals of internal medicine. 2013;158:200-7. 
2. 
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, 
Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, 
Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, 
Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, 
Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C 
and Stroke Statistics S. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart 
Association. Circulation. 2016;133:e38-e360. 
3. 
Wissenberg M, Lippert FK, Folke F, Weeke P, Hansen CM, Christensen EF, Jans H, Hansen PA, 
Lang-Jensen T, Olesen JB, Lindhardsen J, Fosbol EL, Nielsen SL, Gislason GH, Kober L and Torp-Pedersen C. 
Association of national initiatives to improve cardiac arrest management with rates of bystander 
intervention and patient survival after out-of-hospital cardiac arrest. Jama. 2013;310:1377-84. 
4. 
Valenzuela TD, Roe DJ, Cretin S, Spaite DW and Larsen MP. Estimating effectiveness of 
cardiac arrest interventions: a logistic regression survival model. Circulation. 1997;96:3308-13. 
5. 
Larsen MP, Eisenberg MS, Cummins RO and Hallstrom AP. Predicting survival from out-of-
hospital cardiac arrest: a graphic model. Annals of emergency medicine. 1993;22:1652-8. 
6. 
Hansen SM, Hansen CM, Folke F, Rajan S, Kragholm K, Ejlskov L, Gislason G, Kober L, Gerds 
TA, Hjortshoj S, Lippert F, Torp-Pedersen C and Wissenberg M. Bystander Defibrillation for Out-of-Hospital 
Cardiac Arrest in Public vs Residential Locations. JAMA Cardiol. 2017;2:507-514. 
7. 
Sasson C, Rogers MA, Dahl J and Kellermann AL. Predictors of survival from out-of-hospital 
cardiac arrest: a systematic review and meta-analysis. Circulation Cardiovascular quality and outcomes. 
2010;3:63-81. 
8. 
Caffrey SL, Willoughby PJ, Pepe PE and Becker LB. Public use of automated external 
defibrillators. N Engl J Med. 2002;347:1242-7. 
9. 
O'Rourke MF, Donaldson E and Geddes JS. An airline cardiac arrest program. Circulation. 
1997;96:2849-53. 
10. 
Page RL, Joglar JA, Kowal RC, Zagrodzky JD, Nelson LL, Ramaswamy K, Barbera SJ, Hamdan 
MH and McKenas DK. Use of automated external defibrillators by a U.S. airline. N Engl J Med. 
2000;343:1210-6. 
11. 
Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW and Hardman RG. Outcomes of rapid 
defibrillation by security officers after cardiac arrest in casinos. N Engl J Med. 2000;343:1206-9. 
12. 
Nielsen AM, Folke F, Lippert FK and Rasmussen LS. Use and benefits of public access 
defibrillation in a nation-wide network. Resuscitation. 2013;84:430-4. 
13. 
Kitamura T, Iwami T, Kawamura T, Nagao K, Tanaka H and Hiraide A. Nationwide public-
access defibrillation in Japan. N Engl J Med. 2010;362:994-1004. 
14. 
Hallstrom AP, Ornato JP, Weisfeldt M, Travers A, Christenson J, McBurnie MA, Zalenski R, 
Becker LB, Schron EB and Proschan M. Public-access defibrillation and survival after out-of-hospital cardiac 
arrest. N Engl J Med. 2004;351:637-46. 
15. 
Davies CS, Colquhoun MC, Boyle R and Chamberlain DA. A national programme for on-site 
defibrillation by lay people in selected high risk areas: initial results. Heart. 2005;91:1299-302. 
16. 
Colquhoun MC, Chamberlain DA, Newcombe RG, Harris R, Harris S, Peel K, Davies CS and 
Boyle R. A national scheme for public access defibrillation in England and Wales: early results. 
Resuscitation. 2008;78:275-80. 

The CARAMBA Trial 
 
January 8th 2022 
NCT ID: 04446585 
22 
17. 
Fleischhackl R, Roessler B, Domanovits H, Singer F, Fleischhackl S, Foitik G, Czech G, 
Mittlboeck M, Malzer R, Eisenburger P and Hoerauf K. Results from Austria's nationwide public access 
defibrillation (ANPAD) programme collected over 2 years. Resuscitation. 2008;77:195-200. 
18. 
Link MS, Atkins DL, Passman RS, Halperin HR, Samson RA, White RD, Cudnik MT, Berg MD, 
Kudenchuk PJ and Kerber RE. Part 6: electrical therapies: automated external defibrillators, defibrillation, 
cardioversion, and pacing: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation 
and Emergency Cardiovascular Care. Circulation. 2010;122:S706-19. 
19. 
Koster RW, Baubin MA, Bossaert LL, Caballero A, Cassan P, Castren M, Granja C, Handley AJ, 
Monsieurs KG, Perkins GD, Raffay V and Sandroni C. European Resuscitation Council Guidelines for 
Resuscitation 2010 Section 2. Adult basic life support and use of automated external defibrillators. 
Resuscitation. 2010;81:1277-92. 
20. 
Eisenberg MS and Mengert TJ. Cardiac resuscitation. N Engl J Med. 2001;344:1304-13. 
21. 
Pell JP, Sirel JM, Marsden AK, Ford I, Walker NL and Cobbe SM. Potential impact of public 
access defibrillators on survival after out of hospital cardiopulmonary arrest: retrospective cohort study. 
BMJ. 2002;325:515. 
22. 
Folke F, Lippert FK, Nielsen SL, Gislason GH, Hansen ML, Schramm TK, Sorensen R, Fosbol EL, 
Andersen SS, Rasmussen S, Kober L and Torp-Pedersen C. Location of cardiac arrest in a city center: 
strategic placement of automated external defibrillators in public locations. Circulation. 2009;120:510-7. 
23. 
Norris RM. Circumstances of out of hospital cardiac arrest in patients with ischaemic heart 
disease. Heart. 2005;91:1537-40. 
24. 
Folke F, Gislason GH, Lippert FK, Nielsen SL, Weeke P, Hansen ML, Fosbol EL, Andersen SS, 
Rasmussen S, Schramm TK, Kober L and Torp-Pedersen C. Differences between out-of-hospital cardiac 
arrest in residential and public locations and implications for public-access defibrillation. Circulation. 
2010;122:623-30. 
25. 
Bardy GH, Lee KL, Mark DB, Poole JE, Toff WD, Tonkin AM, Smith W, Dorian P, Packer DL, 
White RD, Longstreth WT, Jr., Anderson J, Johnson G, Bischoff E, Yallop JJ, McNulty S, Ray LD, Clapp-
Channing NE, Rosenberg Y and Schron EB. Home Use of Automated External Defibrillators for Sudden 
Cardiac Arrest. N Engl J Med. 2008. 
26. 
Eisenberg MS, Moore J, Cummins RO, Andresen E, Litwin PE, Hallstrom AP and Hearne T. Use 
of the automatic external defibrillator in homes of survivors of out-of-hospital ventricular fibrillation. Am J 
Cardiol. 1989;63:443-6. 
27. 
Zijlstra JA, Stieglis R, Riedijk F, Smeekes M, van der Worp WE and Koster RW. Local lay 
rescuers with AEDs, alerted by text messages, contribute to early defibrillation in a Dutch out-of-hospital 
cardiac arrest dispatch system. Resuscitation. 2014;85:1444-9. 
28. 
Berglund E, Claesson A, Nordberg P, Djarv T, Lundgren P, Folke F, Forsberg S, Riva G and 
Ringh M. A smartphone application for dispatch of lay responders to out-of-hospital cardiac arrests. 
Resuscitation. 2018;126:160-165. 
29. 
Caputo ML, Muschietti S, Burkart R, Benvenuti C, Conte G, Regoli F, Mauri R, Klersy C, 
Moccetti T and Auricchio A. Lay persons alerted by mobile application system initiate earlier cardio-
pulmonary resuscitation: A comparison with SMS-based system notification. Resuscitation. 2017;114:73-78. 
30. 
Andersson N. Community-led trials: Intervention co-design in a cluster randomised 
controlled trial. BMC public health. 2017;17:397. 
31. 
Breuer E, Lee L, De Silva M and Lund C. Using theory of change to design and evaluate public 
health interventions: a systematic review. Implementation science : IS. 2016;11:63. 
32.
 
https://developer.apple.com/documentation/corelocation/getting_the_user_s_location/usi
ng_the_significant_change_location_service. 
33. 
Rajan S, Wissenberg M, Folke F, Hansen SM, Gerds TA, Kragholm K, Hansen CM, Karlsson L, 
Lippert FK, Kober L, Gislason GH and Torp-Pedersen C. Association of Bystander Cardiopulmonary 

The CARAMBA Trial 
 
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NCT ID: 04446585 
23 
Resuscitation and Survival According to Ambulance Response Times After Out-of-Hospital Cardiac Arrest. 
Circulation. 2016;134:2095-2104. 
34. 
Crespi CM. Improved Designs for Cluster Randomized Trials. Annu Rev Public Health. 
2016;37:1-16. 
35. 
Xu X, Zhu H and Ahn C. Sample size considerations for stratified cluster randomization design 
with binary outcomes and varying cluster size. Stat Med. 2019. 
36. 
Facilitates Clustered Binary Data Generation, and Estimation of 
Intracluster Correlation Coefficient (ICC) for Binary Data [computer program]. R-packages version 1.1.1; 
2017. 
37. 
Facilitating Estimation of the Intraclass Correlation 
Coefficient [computer program]. R-package version 2.3.0; 2015. 
38. 
Rutterford C, Copas A and Eldridge S. Methods for sample size determination in cluster 
randomized trials. Int J Epidemiol. 2015;44:1051-67. 
39. 
Greevy R, Lu B, Silber JH and Rosenbaum P. Optimal multivariate matching before 
randomization. Biostatistics (Oxford, England). 2004;5:263-75. 
40. 
deignmatch: Matched Samples that are Balanced and Representative by Design [computer 
program]. R package version 0.3.1.; 2018. 
41. 
S. M. Hansen KBR, M. Wissenberg, R. N. Mortensen, F. Folke, F. K. Lippert, P. Berlac, S. 
Mikkelsen, P. A. Hansen, P. S. Nielsen, O. M. Hendriksen, C. Torp-Pedersen. Dansk Hjertestopsregister 2016. 
2016. 
42. 
Perkins GD, Jacobs IG, Nadkarni VM, Berg RA, Bhanji F, Biarent D, Bossaert LL, Brett SJ, 
Chamberlain D, de Caen AR, Deakin CD, Finn JC, Grasner JT, Hazinski MF, Iwami T, Koster RW, Lim SH, Huei-
Ming Ma M, McNally BF, Morley PT, Morrison LJ, Monsieurs KG, Montgomery W, Nichol G, Okada K, Eng 
Hock Ong M, Travers AH, Nolan JP and Utstein C. Cardiac Arrest and Cardiopulmonary Resuscitation 
Outcome Reports: Update of the Utstein Resuscitation Registry Templates for Out-of-Hospital Cardiac 
Arrest: A Statement for Healthcare Professionals From a Task Force of the International Liaison Committee 
on Resuscitation (American Heart Association, European Resuscitation Council, Australian and New Zealand 
Council on Resuscitation, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, 
Resuscitation Council of Southern Africa, Resuscitation Council of Asia); and the American Heart Association 
Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, 
Perioperative and Resuscitation. Circulation. 2015;132:1286-300. 
43. 
Karlsson L, Malta Hansen C, Wissenberg M, Moller Hansen S, Lippert FK, Rajan S, Kragholm K, 
Moller SG, Bach Sondergaard K, Gislason GH, Torp-Pedersen C and Folke F. Automated external defibrillator 
accessibility is crucial for bystander defibrillation and survival: A registry-based study. Resuscitation. 
2019;136:30-37. 
44. 
Kragholm K, Wissenberg M, Mortensen RN, Hansen SM, Malta Hansen C, Thorsteinsson K, 
Rajan S, Lippert F, Folke F, Gislason G, Kober L, Fonager K, Jensen SE, Gerds TA, Torp-Pedersen C and 
Rasmussen BS. Bystander Efforts and 1-Year Outcomes in Out-of-Hospital Cardiac Arrest. N Engl J Med. 
2017;376:1737-1747. 
45. 
Kragholm K, Wissenberg M, Mortensen RN, Fonager K, Jensen SE, Rajan S, Lippert FK, 
Christensen EF, Hansen PA, Lang-Jensen T, Hendriksen OM, Kober L, Gislason G, Torp-Pedersen C and 
Rasmussen BS. Return to Work in Out-of-Hospital Cardiac Arrest Survivors: A Nationwide Register-Based 
Follow-Up Study. Circulation. 2015;131:1682-90.