A Randomized Trial Comparing the Effect of a Simplified Form of Cardiopulmonary Resuscitation (CPR) Consisting of Only Chest Compressions Compared to CPR With Compressions and Rescue Breaths - the PILOT
Phase: NA
Conditions: Cardiac Arrest, Out of Hospital Cardiac Arrest
Sponsor: Karolinska Institutet

 
 
 
 
 
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MAIN TRIAL PROTOCOL, sept 2022 
 
 
                                             
                                  
 
 
 
 
 
 
 
 
 
A randomized trial comparing the effect of a simplified form of Cardiopulmonary 
resuscitation (CPR) consisting of compressions only compared to CPR with 
compressions and rescue breaths 
 
 
 
 
 
 
 
Version:  
 
 
2.1 
 
Date:  
 
 
2022 09 15 
 
Clinical Trials Identifier:   
NCT02401633 / NCT03981107 
 
 
 
 
 

 
 
 
 
 
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Table of content 
 
LIST OF ABBREVIATIONS ................................................................................................................................. 4 
1. SUMMARY .................................................................................................................................................. 5 
2. TRIAL OVERVIEW ........................................................................................................................................ 6 
2.1. FLOW CHART ................................................................................................................................................... 6 
2.2 PRINCIPAL INVESTIGATORS AND SPONSORS ............................................................................................................. 7 
2.3 TRIAL SITES ...................................................................................................................................................... 7 
2.4. ETHICAL APPROVALS ......................................................................................................................................... 8 
3. INTRODUCTION .......................................................................................................................................... 9 
3.1 BACKGROUND .................................................................................................................................................. 9 
3.2 PRECLINICAL RESULTS AND DATA .......................................................................................................................... 9 
3.3 PREVIOUS PUBLISHED CLINICAL RESULTS ................................................................................................................. 9 
4. OVERALL AIM AND PURPOSE .................................................................................................................... 11 
4.1 PRIMARY OBJECTIVE ........................................................................................................................................ 11 
4.2 SECONDARY OBJECTIVES ................................................................................................................................... 11 
4.3 PICO-QUESTION ............................................................................................................................................. 11 
5. ELIGIBILITY ................................................................................................................................................ 12 
5.1 INCLUSION CRITERIA: ....................................................................................................................................... 12 
5.2 EXCLUSION CRITERIA: ....................................................................................................................................... 12 
5.3: POST RANDOMIZATION EXCLUSION FROM DATA ANALYSIS: ..................................................................................... 12 
6. TRIAL DESIGN ............................................................................................................................................ 13 
6.1 PRINCIPAL STUDY POPULATION AND INTERVENTION ................................................................................................ 13 
6.2 TRIAL PHASES AND INTERVENTION: ..................................................................................................................... 13 
6.2.1. Phase 1 and 2: The work at the dispatch center and CPR by bystander ........................................... 13 
6.2.2. Phase 3: The work and action at EMS arrival ................................................................................... 14 
6.2.3. Phase 4: The work and action during hospital stay and care ........................................................... 14 
6.2.4. Phase 5: Follow-up of survival and neurological function ................................................................ 15 
6.3. BLINDING ..................................................................................................................................................... 15 
6.4. OUTCOME .................................................................................................................................................... 15 
6.4.1 Primary outcome: .............................................................................................................................. 15 
6.4.2 Secondary outcomes: ........................................................................................................................ 15 
6.4.3 Exploratory outcomes: ...................................................................................................................... 15 
7. STUDY PHASES: PRE STUDY RUN-IN PERIOD, PILOT STUDY AND MAIN STUDY ........................................... 16 
7.1. STUDY OVERVIEW: PRE STUDY RUN-IN PERIOD, PILOT AND MAIN STUDIES ............................................................ 16 
7.1.1. Objective pre study RUN-IN period ................................................................................................... 16 
7.1.2. Objective PILOT study ....................................................................................................................... 16 
7.1.2. Objective MAIN study ....................................................................................................................... 16 
7.2. EXPERIENCES FROM THE PRE STUDY RUN-IN PERIOD AND IMPLICATIONS FOR THE PILOT AND MAIN STUDIES. ............... 16 
7.3 SUMMARY OF CHANGES IN PROTOCOL AFTER EXPERIENCES FROM THE PRE STUDY RUN-IN PERIOD AND EFFECTS OF THE 
COVID19 PANDEMIC. ............................................................................................................................................ 17 
8. DATA COLLECTION .................................................................................................................................... 19 
8.1 DATA HANDLING AND RECORD KEEPING ............................................................................................................... 20 
9. ETHICAL CONSIDERATIONS ....................................................................................................................... 21 

 
 
 
 
 
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9.1 INFORMED CONSENT ........................................................................................................................................ 21 
9.2 POTENTIAL RISKS ............................................................................................................................................. 21 
9.3 POTENTIAL BENEFITS ........................................................................................................................................ 22 
10. DATA ANALYTIC AND STATISTICAL ANALYSIS PLAN (SAP) ........................................................................ 23 
10.1 GENERAL STATISTICAL ANALYSIS PLAN ................................................................................................................ 23 
10.2 STATISTICAL HYPOTHESIS FOR NON-INFERIORITY .................................................................................................. 23 
10.2.1 Null hypothesis: ............................................................................................................................... 23 
10.2.2 Alternative hypothesis: .................................................................................................................... 23 
10.3 GENERAL STATISTICAL METHODS ...................................................................................................................... 23 
10.4 ANALYSIS STEP AND STRATEGY OF THE WHOLE STUDY POPULATIONS ........................................................................ 24 
10.5 POWER AND SAMPLE SIZE ESTIMATION .............................................................................................................. 25 
10.7 SUBGROUP ANALYSES .................................................................................................................................... 27 
10.8 RANDOMIZATION .......................................................................................................................................... 27 
11. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ..................................................................... 28 
12. PUBLICATION PLAN AND AUTHOR POLICY .............................................................................................. 28 
13. ENROLMENT AND TIMELINE .................................................................................................................... 28 
14. REFERENCES ............................................................................................................................................ 29 
 
 
 

 
 
 
 
 
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List of abbreviations  
 
AHA 
 
American Heart Association 
ACLS 
 
Advanced Cardiac Life Support 
AED 
 
Automated External Defibrillator 
CO-CPR 
 
Compression-Only CPR 
CPC 
 
Cerebral Performance Category 
CPR 
 
Cardio-Pulmonary-Resuscitation 
CRF 
 
Clinical Report Form 
DC 
 
Dispatch Centre 
DCO 
 
Dispatch Centre Operator 
DSMC 
 
Data Safety Monitoring Committee 
DNR 
 
Do Not Resuscitate 
EMS 
 
Emergency Medical Service 
ER 
 
Emergency Room 
ERC 
 
European Resuscitation Council 
FR 
 
First Responder (fire-fighters or police) 
ICD 
 
Implantable Cardioversion Device 
ITT 
 
Intention to treat 
OHCA 
 
Out of hospital Cardiac Arrest 
PAD 
 
Public Access Defibrillator 
PP 
 
Per Protocol 
PROM 
 
Patient Reported Outcome Measures 
ROSC 
 
Return of Spontaneous Circulation 
RCT 
 
Randomized Controlled Trial 
SCAR 
 
Swedish Cardiac Arrest Register 
S-CPR 
 
Standard CPR 
T-CPR 
 
Telephone-assisted CPR 
VF 
 
Ventricular Fibrillation 
VT 
 
Ventricular Tachycardia 
 
 

 
 
 
 
 
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1. Summary 
 
Title: TANGO2 “A randomized trial comparing the effect of a simplified form of cardiopulmonary 
resuscitation (CPR) consisting of Compression-only, compared to CPR with compressions and rescue 
breaths” 
Background: In 2010, two large prospective, randomized trials showed no significant difference with 
respect to survival between instructions given by emergency medical dispatchers to bystanders 
without previous knowledge of CPR to administer compression-only CPR (CO-CPR) or standard CPR (S-
CPR) in patients with witnessed out-of-hospital cardiac arrests (OHCA).(1, 2) Whether CO-CPR is no 
worse than, or even superior to, S-CPR when performed by bystanders with previous training in CPR 
remains unclear. 
Purpose: To investigate whether bystander CPR (performed by bystanders with prior CPR-training) 
consisting of compressions only (CO-CPR) is non-inferior, or better, than standard CPR (S-CPR) in 
witnessed cases of OHCA. 
Intervention: Cases of witnessed suspected OHCAs, where bystanders have previous knowledge in 
CPR, will be randomized at the dispatch center to instructions to perform either CO-CPR (interventional 
group) or S-CPR (control group) until arrival of the EMS. Upon arrival of the EMS, all patients will receive 
standard advanced cardiac life support (ACLS) in accordance to current guidelines. 
Design: Interventional, prospective, open label, multicenter randomized trial with 1:1 allocation. Since 
CO-CPR is a simplified form of CPR that could lead to a higher incidence of bystander-CPR in itself, a 
non-inferiority design has been chosen. This will be further discussed in part 10, “statistical analysis 
plan”.  
Inclusion criteria:   
- Unconsciousness with no, abnormal or agonal breathing (suspected OHCA) 
- The suspected OHCA is witnessed (seen or heard) 
- Any bystander at the scene has previous training in CPR 
Exclusion criteria: 
- Age 18 or younger 
- Collapse is not witnessed 
- Bystander has never been taught CPR. (These bystanders should be instructed to administer CO-CPR 
in accordance to guidelines) 
- Obvious asphyxia, i.e. drowning, strangulation, hanging 
- Obvious intoxication or drug overdose 
- Pregnancy 
- Trauma 
Primary outcome: 30-day survival 
Secondary outcomes:  Survival to hospital admission, 1-year survival, survival with good neurologic 
outcome at discharge, defined as cerebral performance category (CPC) 1-2, survival with complete 
neurologically outcome defined as CPC 1  
 
 

 
 
 
 
 
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2. Trial overview  
 
2.1. Flow chart 
 
Trial flow-chart and the different phases are presented below in Figure 1.  
For detailed description of Study phases please see Section 6.2 “Trial phases and interventions”. 
Figure 1. Trial overview 
 
 
 
OHCA = Out of Hospital Cardiac Arrest, CO-CPR = Compression Only Cardiopulmonary 
Resuscitation, S-CPR = Standard Cardiopulmonary Resuscitation (Chest compressions and 
rescue breaths 30:2) EMS = Emergency Medical Services, ACLS = Advanced Cardiac Life 
Support 
 

 
 
 
 
 
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2.2 Principal investigators and sponsors 
 
 
Jacob Hollenberg, MD, Professor  
Director, Center for Resuscitation Science, Department of Clinical Science and Education, 
Södersjukhuset, Karolinska Institutet, Sweden 
Department of Cardiology, Södersjukhuset 
SE-118 83 Stockholm, Sweden 
Phone: + 46 70413344 
Mail: Jacob.Hollenberg@ki.se  
 
Gabriel Riva, MD, PhD 
Center for Resuscitation Science, Department of Clinical Science and Education, Södersjukhuset, 
Karolinska Institutet, Sweden Department of Cardiology, Capio S:t Görans Hospital 
Sankt Göransplan 1, SE-112 19 Stockholm, Sweden 
Phone: + 46 70 545 20 86 
Mail: Gabriel.riva@ki.se 
 
2.3 Trial sites  
 
This is a national dispatch study were all dispatch centrals participate. This include all SOS Alarm AB 
dispatch centers as well as the dispatch centers of Sjukvårdens larmcentral 
 
SOS Alarm dispatch centers: 
- Falun 
- Göteborg 
- Halmstad 
- Jönköping 
- Karlstad 
- Luleå 
- Malmö 
- Norrköping 
- Stockholm 
- Sundsvall 
- Västerås 
- Växjö 
- Örebro 
- Östersund 
 
Sjukvårdens larmcentral dispatch centers: 
-  Uppsala 
- Västerås  
- Södermanland 
 

 
 
 
 
 
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2.4. Ethical approvals  
 
The study has obtained ethical approval from the ethical vetting committee in Stockholm;  
Dnr 2014/97-31/2. Main approval 
Dnr 2015/1833-32. Amendment 
Dnr 2019-0489. Amendment 
 
 

 
 
 
 
 
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3. Introduction 
 
3.1 Background 
 
Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of mortality in the industrialized 
world. The etiology for OHCA is heterogeneous but cardiovascular disease remains the most common 
underlying cause. In Sweden, the yearly incidence of EMS treated OHCA is around 5,000 and overall 
survival has remained around 10 % over the last few years.(3) Several factors increase the chance of 
survival and neurological intact survival in OHCA, of which bystander cardio-pulmonary-resuscitation 
(CPR), early defibrillation and high quality post-resuscitation care are among the most important 
ones.(4, 5) Bystander CPR before arrival of the Emergency Medical Service (EMS) is a strong positive 
predictor of survival.(6) During the last decade, the best form of bystander CPR has been debated.(7-
9) To perform rescue breathing is a complex task and bystanders not recently trained in CPR are likely 
to have difficulties in deliver good rescue breaths. Chest compression only CPR (CO-CPR) has been 
advocated as a preferable method in situations where the bystander has no previous knowledge in 
CPR, both because its believed to be equally efficient but also a simplified form of CPR that could lead 
to increased use of bystander-CPR.(10) Furthermore, this more simplified method has already been 
well spread in several parts of the US and Japan.(11, 12) 
3.2 Preclinical results and data  
 
Studies in porcine models show that CO-CPR increases the number of compressions given by the 
bystander per minute and minimizes interruptions in CPR.(13, 14) Therefore, it is believed to maintain 
cerebral and cardiac blood flow over a greater period of time during resuscitation. It is also believed 
that rescue breaths may increase the risk of reflux of gastric content and cause aspiration. Rescue 
breaths increase the intrathoracic pressure and therefore decrease venous return of blood to the right 
ventricle resulting in lower blood flow during compressions.(15) Furthermore, it has been 
demonstrated that hands-off time (i.e. pauses of chest compressions) both prior and after defibrillation 
is associated with worse outcome.(16) On the other hand, compression-only CPR leads to rescuer 
fatigue and poorer compressions.(17) It is also believed that the withdrawal of rescue breaths leads to 
a faster decrease in saturation of arterial blood and therefore is believed to not give crucial oxygen 
delivery to vital organs even though the blood flow to these organs is maintained.(13)  
3.3 Previous published clinical results 
 
Several registry-studies have showed similar or even increased survival rates with a simplified form of 
CPR, consisting of compressions only (CO-CPR), instead of standard CPR consisting of 30 compressions 
and two rescue breaths in non-traumatic/asphyxic OHCA.(10, 18-21) In 2010, two large prospective, 
randomized trials showed no significant difference with respect to survival between instructions given 
by emergency medical dispatchers for CO-CPR and instructions for standard CPR (S-CPR) in patients 
with witnessed OHCA in cases where the bystanders had no previous CPR-training.(1, 2) As a 
consequence, new guidelines recommend telephone-guided CO-CPR for untrained rescuers and 

 
 
 
 
 
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trained bystanders unwilling unable or unwilling to perform rescue breaths.(22, 23) The shift in 
recommendations is also based upon the assumption that a simplified CPR method would increase the 
number of bystanders performing CPR. In an initiative to increase CPR rates the American Heart 
Association has launched public campaigns such as the “hands-only CPR” promoting CO-CPR as an 
option to S-CPR for adult non-asphyxic cardiac arrest.(11) In the 2015 updates of the European 
resuscitation council guidelines it states that the confidence in the equivalence between the two 
methods is not sufficient to change current practice.(24) In Sweden there has been no public 
campaigns promoting CO-CPR. 
Whether CO-CPR leads to a survival rate no worse than, equally effective, or even superior to 
standard CPR in situations where the bystander has previous CPR training however remains unclear. 
This clinical question remains unanswered while millions of people are trained in CPR worldwide 
each year.  
 
 

 
 
 
 
 
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4. Overall aim and purpose 
The overall purpose with this research project is to investigate whether instructions to perform a 
simplified form of CPR consisting of compressions only (CO-CPR) to bystanders with prior CPR-
training is non-inferior, or better than, standard CPR (S-CPR) in witnessed out-of-hospital cardiac 
arrest (OHCA).  
4.1 Primary objective 
To evaluate whether survival to 30 days following instructions to perform CO-CPR is non-inferior 
compared to instructions to perform S-CPR to bystanders with prior CPR training in witnessed OHCA. 
4.2 Secondary objectives 
To evaluate whether there is a difference between CO-CPR and S-CPR in survival to hospital 
admission, neurological favorable survival, defined as survival with cerebral performance category 
(CPC) 1-2, neurologically intact survival defined as CPC 1 and long-term survival, defined as survival to 
one year. To evaluate whether there is a difference between CO-CPR and S-CPR in VT/VF as first 
rhythm and Return of Spontaneous Circulation (ROSC). To compare 30-day survival between CO-CPR 
and S-CPR in pre specified subgroups. 
4.3 PICO-question 
P 
Among adults suffering from non-traumatic witnessed OHCA (P), 
I 
Does instructions to perform CO-CPR performed by trained bystanders (I) 
C 
Compared to instructions to perform S-CPR (C) 
O 
Change 30-day survival (O) 
 
 
 

 
 
 
 
 
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5. Eligibility 
Witnessed cases of adult OHCAs with a non-asphyxic etiology will be the principal study population. 
Patients will be eligible for enrolment if they meet all the following inclusion criteria and none of the 
exclusion criteria. Inclusion and Exclusion criteria are unchanged throughout the different study phases 
(run-in, pilot and main study). 
5.1 Inclusion criteria:  
- Unconsciousness with no, abnormal or agonal breathing (suspected OHCA) 
- The suspected OHCA is witnessed (seen or heard) 
- Any bystander at the scene has previous training in CPR 
  
5.2 Exclusion criteria:  
- Age 18 or younger 
- Collapse is not witnessed 
- Bystander has never been taught CPR. (These bystanders should be instructed to administer CO-CPR 
in accordance to guidelines) 
- Obvious asphyxia, i.e. drowning, strangulation, hanging 
- Obvious intoxication or drug overdose 
- Pregnancy 
- Trauma 
 
5.3: Post randomization exclusion from data analysis: 
- Previous decision that CPR should not be initiated i.e. terminal illness or palliative care 
- No cardiac arrest, other condition (cases where EMS did not start CPR) 
 
 
 

 
 
 
 
 
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6. Trial design 
This is an interventional, prospective, randomized, 1:1 open label, multicenter trial comparing two 
different methods of bystander CPR in witnessed cases of OHCA. Since CO-CPR is a simplified form of 
CPR that could lead to a higher incidence of bystander-CPR by itself a non-inferiority design for the 
primary outcome has been chosen. Superiority testing will also be performed for the purpose of 
demonstrating a possible increase in survival with CO-CPR.  
6.1 Principal study population and intervention 
 
Witnessed cases of OHCAs with a non-asphyxic etiology will be the principal study population. 
According to current guidelines an unresponsive patient with no or agonal breathing is handled as a 
suspected case of OHCA at the dispatch center. These cases are eligible for screening for inclusion. If 
the case is witnessed, any bystander at the scene has previous knowledge in CPR and no exclusion 
criteria are present, the case can be included and randomly assigned to instructions to perform either 
CO-CPR (intervention) or S-CPR (control).  
The intervention arm will consist of instructions from a dispatcher at the dispatch center to the 
bystanders to perform CO-CPR with chest compressions only. 
The control arm will consist the instructions from a dispatcher at the dispatch center to the bystanders 
to perform S-CPR with chest compressions and rescue breaths in a 30:2 ratio. 
 
6.2 Trial phases and intervention:  
6.2.1. Phase 1 and 2: The work at the dispatch center and CPR by bystander 
• 
Identification of cases   
• 
Screening for inclusion and exclusion 
• 
Randomization   
• 
Instructions according to allocation  
Suspected OHCAs identified at the dispatch centre, classified as unconscious with no or agonal 
breathing, are eligible for screening. When a dispatcher suspects a case of OHCA, inclusion criteria and 
exclusion criteria will automatically pop up on their computer screen. The first inclusion criterion is if 
the collapse is witnessed (has been seen or heard). The second inclusion criterion is if any bystander 
on the scene has previous CPR-training. According to current guidelines, the dispatch operator asks 
whether the witness has training in bystander CPR. If not, they are offered instructions on how to 
perform telephone-guided CPR (T-CPR) and the case is not further screened for inclusion in the study. 
If any bystander at the scene has previous CPR-training (any time), or if CPR is already on going, the 
case can be further screened for inclusion in the study. The dispatch operator will mark this on their 
desktop environment. This automatically triggers the appearance of exclusion criteria on the 

 
 
 
 
 
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operator´s desktop: 1) OHCA victim aged 18 or younger? 2) Asphyxia (i.e. drowning, strangulation, 
hanging 3) intoxication, drug overdose? 4) trauma? or 5) pregnancy? 
If any of the exclusion criteria are met, the case is not randomized (and is handled according to 
standard protocol). If no exclusion criteria are present, the case will undergo randomization using a 
Microsoft.NET Random Constructor (Int 32). This will generate a randomized allocation to either 
intervention (CO-CPR) or control (S-CPR). A new pop-up will then appear on the operator’s desktop 
with detailed instructions to the caller in both groups. Simultaneously, the EMS will be dispatched.  
The bystander will, in all cases included and randomized, obtain instructions from the dispatcher to 
provide either CO-CPR or S-CPR until arrival of the EMS.  
 
The instructions from the dispatcher in INTERVENTION arm include:  
- 
An ambulance is dispatched and is on its way to you 
- 
Do CPR with chest compressions only 
- 
Push hard on the chest with a pace of 100/minute without interruptions for rescue 
breathing. 
 
 The Instructions from the dispatcher in the CONTROL arm include: 
- 
An ambulance is dispatched and is on its way to you  
- 
Do CPR with chest compressions and rescue breathing 
- 
Push hard on the chest 30 times and give 2 rescue breaths. The pace of the compressions 
should be 100/minute. 
 
Dispatchers are furthermore instructed to encourage all callers in both groups to stay in connection 
with the callers until arrival of EMS or first responders, instruct callers to put the phone on loudspeaker 
when possible and to ask callers to count aloud while performing chest compressions. Dispatchers 
should try to aim for a compression rate of 100-120/minute and suggest switching CPR-provider every 
2 minutes if multiple rescuers are on the scene. 
6.2.2. Phase 3: The work and action at EMS arrival 
Upon arrival of the EMS (or first responders) the intervention ends. EMS crew will further treat all 
patients with all guidelines (AHA/ERC)(24) recommended standard ACLS, including bag mask 
ventilation, advanced airway management with endotracheal tube or laryngeal mask, oxygen, 
defibrillation and i.v. drugs as well as if ROSC is not achieved (cessation of CPR). 
6.2.3. Phase 4: The work and action during hospital stay and care  
 If the patient is admitted to hospital, patients are treated according to local hospital protocol and 
practice including diagnostic coronary angiography, therapeutic hypothermia (33 or 36 degrees 
Celsius) and intensive care. Hospital practitioners will not know the randomized allocation.  

 
 
 
 
 
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6.2.4. Phase 5: Follow-up of survival and neurological function 
Survival is evaluated for primary endpoint at day 30 through the Swedish cardiac arrest register (SCAR) 
through linkage with the Swedish public population register (folkbokföringsregistret). For the 
secondary outcome of neurologically favorable outcome CPC is obtained through SCAR. In a subset of 
patients (survivors treated at specifically named hospitals), a comprehensive neurological assessment 
using Patient Reported Outcome Measurement (PROM) related follow-up is performed between 30-
90 days. This follow-up is performed by a nurse and/or behavioral therapists blinded to the 
intervention allocation. This comprehensive follow up will not be possible in all sites of the TANGO2 
trial. 
6.3. Blinding  
Because of the inherent logistical problems with blinding of CPR techniques for dispatchers, the trial is 
considered as an “open labeled” trial. Treatment allocation will, however, be blinded in data 
management and at follow-up, for personnel treating the patients at the hospitals and for all 
responsible researchers. Allocation concealment will be preserved. 
 
6.4. Outcome 
6.4.1 Primary outcome: 
- 30-day survival  
6.4.2 Secondary outcomes:  
- Survival to hospital admission 
- 1-year survival 
- Survival with good neurologic outcome at discharge, defined as cerebral performance category 
(CPC) 1-2  
- Survival with complete neurologically outcome defined as CPC 1  
6.4.3 Exploratory outcomes:  
- VT/VF as first rhythm  
- Return of spontaneous circulation (ROSC) 
- Repeated analysis of primary endpoint and all secondary endpoints at 24 months 
 
 
 
 

 
 
 
 
 
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7. Study phases: Pre study RUN-IN period, PILOT study and MAIN 
study 
 
7.1. Study Overview: Pre study RUN-IN period, PILOT and MAIN studies  
The overall study project is conducted in three different phases:   
1) Pre study RUN-IN period, for establishing logistical and technical study procedures (completed) 
2) PILOT STUDY, with focus feasibility, logistics and safety (completed)  
3) MAIN STUDY with focus on 30-day survival (primary end point) and other important clinical 
outcomes (secondary outcomes) 
7.1.1. Objective pre study RUN-IN period 
In order to test the technical inclusion procedures, logistics, feasibility and data collection a pre-study 
RUN-IN period started in Stockholm during 2015.  
7.1.2. Objective PILOT study  
The original aim of the PILOT study was to assess safety and feasibility of the TANGO2 trial, as well as 
intermediate clinical outcomes. The TANGO2 trial started recruitment of patients on January 1st 
2017. All patients from the PILOT study will be included in the MAIN STUDY in a seamless design (for 
details, see section 7.2 and 7.3 below). 
7.1.2. Objective MAIN study  
The aim of the MAIN study is to evaluate whether survival to 30 days following instructions to 
perform CO-CPR is non-inferior compared to instructions to perform S-CPR bystanders in witnessed 
OHCA where the bystander has previous CPR training. Secondary and exploratory objectives include 
the evaluation of neurological favorable survival, ROSC, admission to hospital, long-term survival and 
other clinical outcome variables as well as evaluations of 30-day survival between CO-CPR and S-CPR 
in pre-specified subgroups. The MAIN study will include patients from the PILOT phase in a seamless 
design (for details, see section 7.2 and 7.3 below). 
7.2. Experiences from the pre study RUN-IN period and implications for the 
PILOT and MAIN studies. 
The pre-study RUN-IN period started in Stockholm County in 2015 and analysis were performed 
during 2016. After continuous technological adjustments, the randomization module was integrated 
within the computer aided dispatch system and was found to function well in the end of 2016. 
However, during pre-study RUN-IN period, one major obstacle was identified. Due to unexpected 
technological difficulties and an unanticipated new organization of the dispatch centers in Sweden 
only about 15% of the cardiac arrest calls for patients suffering cardiac arrest in Stockholm were 

 
 
 
 
 
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actually answered by dispatchers in Stockholm; all other calls were transferred to other dispatch 
centers throughout Sweden. This meant that the dispatchers had to consider the geographical site of 
the suspected cardiac arrest and remember if that area was part of the study area. This new 
organization and logistics, were the call could be made in one area and answered and handled at 
another site and county during the pre-study RUN-IN period, resulted in a far slower inclusion rate 
than anticipated and made a correct follow-up of patients unmanageable and unreliable. This made 
it impossible to conduct a PILOT study in Stockholm only. 
As a consequence, a decision was made by the steering committee: 
A) To move the start of the PILOT study forward until completion of the national expansion of the 
study and not to start inclusion of patients into the PILOT study before January 1st 2017. The new 
length of the PILOT study was set to two years to assure sufficient inclusion of patients to assess 
safety in terms of survival to hospital admission. 
B) That the PILOT study seamlessly will move on into the MAIN study in an inferentially seamless 
manner after the PILOT phase inclusion ended on Dec 31 2018. This means that patients from the 
PILOT study will also be included in the MAIN survival study. The outcomes for the PILOT study were 
changed to not interfere with the primary endpoint of the main survival study (see below). Inclusion 
and Exclusion criteria have remained unchanged throughout the whole TANGO2-project.  
7.3 Summary of changes in protocol after experiences from the pre study RUN-
IN period and effects of the Covid19 pandemic.  
Previous changes from original protocol (February 2019): 
- As described above, the start and size of the PILOT-study was modified to include all patients during 
2 years (2017-18).  
- As a consequence of the national expansion, enlargement of the PILOT study as well as the 
seamless design, the primary endpoints of the PILOT study was modified not only to asses feasibility 
but also to include assessment of safety as well as intermediate clinical outcomes until hospital 
admission. 
- The initial secondary endpoint of 30-day survival is not evaluated in the PILOT study. The reason for 
this is to not interfere with the primary endpoint of the MAIN study. 
- Inclusion / Exclusion criteria and intervention/control instructions have remained unchanged since 
the first initial protocol throughout all parts of the TANGO2 project.  
- In Stockholm, first responders are dispatched in parallel to EMS in suspected OHCA. The initial 
protocol included first responders as a part of the trial. However, due to the national expansion of 
the study together with the fact that the information of assigned treatment (CO-CPR or S-CPR) to first 

 
 
 
 
 
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responders during dispatch in the RUN-IN phase was not feasible, the steering committee decided to 
remove first responders from participation in the PILOT study and the MAIN study. 
- The initial protocol stated a randomization procedure through the opening of pre-printed envelopes 
with randomized allocation. This was changed before the start of the pre study RUN-IN period to an 
automated computerized randomization integrated in the dispatchers’ software. 
- For assessment of adherence to protocol a decision was made by the Steering Committee to audit 
all calls during the PILOT study and MAIN study using a standardized template for evaluation of 
dispatcher assisted CPR (cardiac arrest registry to enhance survival – CARES)(25) and that all audit 
evaluators will be blinded to allocation. 
 
Effects of the Covid19 pandemic: 
- Due to the outbreak of the Covid19 Pandemic, the ILCOR and the Swedish Resuscitation Council 
issued temporary guidelines for lay bystander CPR in OHCA, recommending only  looking for signs of 
life and performing chest compressions only.(26, 27) Therefore, this study was put on hold on date: 
12-03-2020.  
- The initial plan was to publish the Pilot-study including years 2017 and 2018. Due to the uncertainty 
during the Covid19-pandemic regarding whether the trial would be able to restart a decision by the 
steering committee was made to postpone the pilot publication.  
- During the pause due to the Covid19-pandemic an independent data monitoring committee 
reviewed all data up until 12-03-2020 (pre-Covid19). Their recommendation was to continue the trial 
without modifications, please see also “11. Interim analysis and data monitoring committee”.  
- When the temporary Covid-19 guidelines were removed the 1 April 2022 the main trail was 
relaunched, and inclusion started in August 2022.  
- A decision was made to include all patients during the period pre-Covid19 in the Pilot-study and the 
dates of the pilot-study were changed accordingly. 
- To assure follow-up all, all EMS records of all calls of suspected OHCA with no matching record in 
SCAR will be reviewed. Please see “8. Data Collection” 
 
 
 
 

 
 
 
 
 
19 
8. Data collection 
From the dispatch organization (SOS-Alarm AB) the following variables will be collected: 
Time of incoming call, time of dispatch of EMS, time of dispatch of first responders when applicable, 
time for screening for inclusion, time of randomization and time of arrival of EMS and first responders. 
Event times are automatically generated and stored in the dispatch organization´s computer system. 
The randomized assignment for each call is stored in a separate data-file generated by the random 
sequence constructor. 
For evaluation of included calls and adherence to protocol all randomized, EMS treated OHCA dispatch 
calls will be audited. All audit evaluators will be blinded to allocation. A standardized template for 
evaluation of dispatcher assisted CPR will be used (cardiac arrest registry to enhance survival – 
CARES).(25) The study specific inclusion criteria will be added as auxiliary variables (supplementary 
app).  
From the Swedish Cardiac Arrest Register the following variables will be collected: 
All EMS units participating in TANGO2 report to the SCAR. For all EMS treated OHCA the following 
variables will be collected from the Swedish Cardiac Arrest Register:  
Date of OHCA, Age, Sex, Location of OHCA, CPR prior to EMS arrival, highest medical educational level 
of CPR provider, first recorded rhythm, defibrillation, airway management and drug administration, 
Return of spontaneous circulation (ROSC) and survival to admission to hospital.  
In calls where there is no matching report in SCAR, ambulance records will be reviewed; if EMS has 
performed CPR or the patient had been defibrillated by an AED the case will be classified as “EMS 
treated” and corresponding variables will be extracted from ambulance records instead.  
The EMS will obtain information on what type of CPR that was provided to the patient before their 
arrival at the scene. This information is obtained by observing on-going CPR at their arrival and asking 
bystanders what type of CPR they provided. EMS crew will also ask bystanders what kind of CPR 
training they have according to a three-leveled division of the bystander’s medical educational level (a 
– off-duty professional caregiver, doctor, nurse; b – CPR-trained layman (including off-duty police and 
fire-fighters); or c – layman with no CPR training). This information is a part of SCAR, but there will be 
emphasis on obtaining this specific data in the TANGO2 trial.Survival is collected for primary endpoint 
at day 30 from SCAR trough linkage with the Swedish public population register 
(folkbokföringsregistret). For the secondary outcome of neurologically favorable outcome CPC is 
obtained through SCAR. In a subset of patients (survivors treated at specifically named hospitals), a 
comprehensive neurological assessment using Patient Reported Outcome Measurement (PROM) 
related follow-up is performed between 30-90 days. This follow-up is performed by a nurse and/or 
behavioral therapists blinded to the intervention allocation. This comprehensive follow up will not be 
possible in all sites of the TANGO2 trial. 

 
 
 
 
 
20 
8.1 Data handling and record keeping 
 
For each call to the dispatch center a unique log number automatically is generated. This log number 
is stored at the dispatch center and used to match calls with EMS records, SCAR reports and hospital 
data. All log numbers and audio-files related to the study will be saved and kept at SOS Alarm, 
Stockholm. A list with all log numbers will be exported to a study specific database at the center for 
resuscitation science. A list of all randomized calls with the randomization allocation for each case will 
be generated by the random sequence constructor and will be exported separately. Finally, data from 
call audit evaluation, SCAR reports and EMS and hospital records will be imported. All data will be 
merged and stored in a specific database at center for resuscitation science. This system fulfills all 
criteria for handling of patient data according to the Swedish legislation on management of personal 
data “GDPR”. In the database, the allocation of each specific case will be blinded during the data 
collection to avoid any bias in reporting or collecting data. Allocation concealment will be preserved. 
In the central database there will be manual crosschecking and completion of missing data through 
EMS and hospital records. 
 
 
 

 
 
 
 
 
21 
9. Ethical considerations 
 
9.1 Informed consent 
This research group has a longstanding experience to perform studies in cardiac arrest patients, like 
the present, within the prehospital setting. In OHCA, the victim is unconscious and therefore 
incapacitated of providing informed consent. OHCA is however also a medical emergency and 
treatment has to be started immediately, making informed consent by a relative or legally authorized 
representative impossible due to practical reasons. As stated by the Helsinki declaration 2008, 
paragraph 30:  
“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 authorized 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 authorized representative.”  
This study has been approved by the ethics committee of Stockholm; Dnr 2014/97-31/2 and reasons 
for involving patients unable to give informed consent have been stated in the research plan.  
9.2 Potential risks 
 
For the individual cardiac arrest patient, rapid actions by bystanders can lead to an increased chance 
of survival. Unless some form of life-support activity is performed before arrival of the EMS, survival 
is dismal. CPR itself rarely leads to damage other than rib fractures. Any pain and discomfort after a 
successful survival is not proportional to the gain of being rescued to life. This pain and discomfort is 
also relatively simple to treat. During CPR, the patient is unconscious and thus experiences no pain. 
The risk of injury associated with CPR is insignificant compared to the potential benefits of 
treatment. Those patients who survive to 30 days after a cardiac arrest often have good quality of life 
with only minor neurological disability. This contradicts the fear that an increased number of cases of 
successful resuscitation lead to a large number of surviving patients with severe disabilities. For the 
helper, however, some discomfort can arise.  Potential risks with this trial are delayed start of CPR 
due to inclusion and randomization. These issues are separately evaluated in the TANGO2 RUN-IN 
and TANGO2 PILOT study. Performing CPR is associated with great emotional stress. It is important to 
be prepared for the reactions that can arise among the lay volunteers. Fear of transmission of 
contagious diseases associated with CPR is greatly exaggerated. Only a few such cases have been 
reported worldwide.  A small but important population of all OHCAs are due to respiratory causes, 

 
 
 
 
 
22 
i.e. drowning, strangulation, hanging or intoxication, some of these involve children. These cases are 
filtered out at the dispatch center and excluded from the study as described in the study protocol. 
We believe that a small group of unclear cases that are not identified by either the witness or by the 
dispatcher at the dispatch center (severe renal failure, pulmonary embolism, hemorrhagic stroke or 
chronic obstructive pulmonary disease) could experience a small risk with this intervention. These 
are very few in numbers and already have a very poor prognosis.  
 
9.3 Potential benefits 
 
Survival after OHCA is very poor, in Sweden ranging between 10-12%.(3) Experimental studies and 
previous randomized trials have shown that successful CPR can be achieved with CO-CPR.(1, 2) 
Rescue breaths are technically difficult and take time from chest compressions. In non-cardiac causes 
of OHCA, rescue breathing might be more important. These cases are therefore excluded prior to 
randomization. CO-CPR could lead to an earlier start of CPR, no interruptions in chest-compressions 
and could therefore be beneficial for a majority of cases. In cases of OHCA immediate, effective chest 
compressions is of absolute necessity to increase the otherwise low chance of survival.  
Today, Sweden has amongst the highest rates of bystander CPR in Europe making a study like this 
possible for the first time. An additional simplification of the CPR-algorithm introducing CO-CPR could 
perhaps increase survival rates in Sweden but has the potential to dramatically increase bystander 
rates throughout Europe and more.  
A simplified method of CPR with shorter CO-CPR courses optimally provided by the Swedish CPR 
council will be more cost-effective in companies, schools and throughout society and could enhance 
the care for this patient group nationally and internationally.  In summary, whether CO-CPR leads to 
a survival rate no worse than, equally effective, or even superior to standard CPR in situations where 
the bystander has previous CPR training remains unclear. This clinical question remains unanswered 
while millions of people are trained in CPR worldwide each year. The potential benefits of this study 
are two-fold in the sense that the results can lead to increased survival rates: 1) simplified CPR might 
be better than traditional CPR b) simplified CPR could lead to more people performing it.  
 
 
 

 
 
 
 
 
23 
10. Data analytic and statistical analysis plan (SAP) 
 
10.1 General statistical analysis plan 
 
This trial is designed to investigate whether CO-CPR is no worse than S-CPR using a non-inferiority 
design. It has also been designed for the possible of a superiority testing. This statistical design has 
been chosen appropriately judged on the presumption that CO-CPR has potential clinical benefit but 
also is easier to perform (and therefore would lead to a higher number of patients receiving the 
treatment). The largest difference in 30-day survival (primary outcome) that is considered clinically 
relevant is 1.0 percentage point (please see also section 9.3). 
Eligibility, allocation, inclusion and exclusion will be displayed in a Consort diagram. Differences in 
proportions between baseline characteristics and outcome will be tested by Fisher exact test. 
Differences in mean or medians between the treatment groups will be tested by either Student’s t-
test or Mann Whitney U test depending on distribution. Normality assumptions will be assessed with 
Kolmogorov Smirnov – test. The estimated between group differences will be presented as 
proportions and 95% confidence intervals (CI), which will be calculated by the asymptotic method 
without continuity correction. P-values below 0,05 will be considered statistically significant. Main 
results will be reported as proportions.  
In addition, comparisons between the treatment groups (CO-CPR vs CPR) with respect to the 
outcomes will be adjusted for background characteristics factors through Binary logistic regression to 
adjust for possible imbalances due to randomization between the treatment groups. The association 
between treatment and primary outcome will be presented as odds ratios and corresponding 95% CI 
intervals. Statisticians at Karolinska Institutet will be responsible for the statistical analysis. 
10.2 Statistical hypothesis for non-inferiority 
 
10.2.1 Null hypothesis: 
The percentage in 30-day survival for those on the standard treatment instruction CPR is better 
(higher) than the percentage for those on instruction CO-CPR by an amount of 1.0-percentage units. 
10.2.2 Alternative hypothesis: 
The percentage in 30-day survival for those on instruction CO-CPR is better than the standard 
treatment instruction CPR or only slightly worse (by no more than 1.0 percentage unit). We will call 
instruction of CO-CPR non-inferior to instruction of S-CPR with respect to 30-day survival if the null 
hypothesis is rejected.  
 
10.3 General statistical methods 

 
 
 
 
 
24 
 
All statistical analyses will be performed using IBM SPSS version 25 and R version 3.3.0 or higher. 
Patient data listings, summary tables and graphical presentations will be provided as applicable. For 
continuous variables, descriptive statistics such as mean, standard deviation, median and range will be 
presented. For discrete variables, counts and percentages will be presented. 
Unless otherwise stated, all statistical tests will be performed at the 5 % two-sided alpha significance 
level. 
 
10.4 Analysis step and strategy of the whole study populations 
 
The target study population is witnessed OHCA of medical origin where any bystander at the scene has 
previous CPR training. All randomized calls of suspected OHCA will be included.  
 
Patient with previous decision that CPR should not be initiated i.e. terminal illness or palliative care 
and cases where EMS did not start CPR for other reasons (sure signs of death, not true OHCA) will be 
excluded from data analysis. The remaining patients will be analyzed in the ITT population.  
Blinded call audit will be used to define type of CPR instructions provided. All randomized EMS treated 
OHCA receiving instructions in accordance with randomized allocation will be treated as the target 
study population treated per protocol (PP1). 
Finally, patients who are randomized but later judged as not fulfilling all criteria for inclusion before 
randomization, as evaluated by call audit (not witnessed, asphyxic, bystanders with no previous CPR 
training), will be removed and remaining patients will be analyzed as PP2. 
Thus, we perform ITT analysis, PP1 and PP2 analysis based on the following patients:  
Intention to treat (ITT) analysis: We define the ITT population as all included and randomized EMS 
treated OHCA patients that not fulfilled any exclusion criteria’s.  
Per protocol 1 (PP1):  We define the PP population as the subset of the ITT population where the 
bystanders received the allocated instructions by the dispatch operator, as defined by the call audit. 
 
Per protocol 2 (PP2):  We define the PP2 population as the subset of the PP1 population where the 
patients fulfilled all inclusion criteria, as defined by call audit.  
 
Please see also Consort Diagram in section 10.5. 
 
The reasoning behind excluding patients after randomization is two-folded:  
First: Dispatchers suspecting OHCA based on initial information in a phone-call do patient inclusion 
and randomization. In this situation there is very limited information and dispatchers are encouraged 
to treat all calls were the patients is not conscious and not breathing normally as suspected OHCA 

 
 
 
 
 
25 
and start CPR instructions. Therefore, patients who do not have a treatable OHCA might be included 
and randomized. These patients can be divided in two categories, either it´s not a true OHCA (the 
patient never suffered an OHCA, for example fainted and thus has a pulse at EMS arrival) or the 
patients is already dead or had a previous decision that CPR should not be initiated. Therefore, EMS 
treated OHCA will serve as the best possible evaluation of treatable OHCA. 
Second: The reason for including all randomized EMS treated OHCA is because at the time of 
randomization the dispatch operator judges the call as meeting all inclusion criteria and no exclusion 
criteria. If call audit or EMS record later reveal that the OHCA was not witnessed, traumatic, caused 
by asphyxia or bystanders without previous CPR training, the initial selection still relied on the 
dispatcher. Therefore, further removal of patients in the PP1 analysis might interfere with the 
interpretation of the study intervention in a real-life setting. A secondary analysis will be performed 
in all patient fulfilling all inclusion (PP2).  
 
10.5 Power and sample size estimation  
 
We estimated that 3260 patients (1630 in each group) would be needed in the primary analysis PP1 to 
have 80% power to show that CO-CPR is non-inferior to standard CPR. This calculation is based on the 
assumptions that the true survival rates after 30 days (primary outcome) in the population for standard 
CPR is 11% compared with 13.1% for CO-CPR, and that alpha (1 tailed) is set at 2.5%.  
 
We defined 1.0 percentage point or less as the largest difference in survival that is clinically acceptable 
(i.e. the non-inferiority level which imply that a difference bigger than this would matter in practise). 
This difference is equivalent to an NNT of 100 (one person of 100 will die among those recommended 
CO-CPR, due to this recommendation). The reason for accepting this difference relies on the 
assumption that CO-CPR is easier to teach and perform, and therefore the treatment can be offered 
to more victims (please see also section 9.3). 
 
In addition, we assumed that 20% will not receive the allocated intervention (e.g. randomized to CO-
CPR but received S-CPR instructions or vice versa). We also assumed that 40% of the included 
patients will be excluded because of exclusion criteria’s not possible to detect at the randomization 
(not OHCA, see section 5.3). Therefore, the recruitment goal was set to 6792 (3260 / (0.8*0.6)) 
randomized cases of suspected out-of-hospital cardiac arrest in order to receive 3260 in the primary 
PP1 analysis. (Please see also Consort Flow Diagram below) 

 
 
 
 
 
26 
 
 

 
 
 
 
 
27 
10.6 Non-Inferiority and Superiority testing 
 
First, the primary analysis will be performed for non-inferiority in the PP1 population. If the primary 
analysis rejects the null hypothesis (i.e. CO-CPR is non-inferior to CPR with respect to the primary or 
some secondary outcomes), the comparisons between the treatment groups will also be done for 
superiority using 95% two sided confidence interval.(28)  Second, the same analysis (first non-
inferiority and then superiority) as above will be done for the ITT and PP2 population.   The non-
inferiority limit 1% will be used for both primary and secondary outcomes. 
 
10.7 Subgroup analyses  
 
Subgroup analyses will be performed for the primary outcome variable using logistic regression models 
with test of treatment-subgroup interaction for each of the predefined subgroup variables. The results 
will be presented as the odds ratio with 95 % confidence interval for each subgroup and the 
corresponding p-value for interaction between treatment and each subgroup variable.  
Subgroups will be analyzed according to the following pre-defined variables:  
• 
Gender 
• 
Age 
• 
Cause of OHCA 
• 
Initial rhythm 
• 
Place of cardiac arrest  
• 
Time to start of CPR 
• 
Time to arrival of EMS 
• 
Neurological severity classification (CPC) 
 
10.8 Randomization  
 
Randomization will be performed by a computerized random generator (Microsoft.NET Random 
Constructor (Int 32)) in a 1:1 allocation ratio. The random generator is integrated in the dispatcher’s 
software and there is no possibility for a dispatcher to see or guess randomization results before 
randomizing, therefore allocation concealment is preserved before randomization. For 
implementation the random generator is programmed so one dispatcher can only randomize a specific 
call one time. The computerized random generator is implemented by SOS-alarm into their software 
“Cord-comp”. 

 
 
 
 
 
28 
11. Interim analysis and data monitoring committee 
The trial will be monitored by an independent Data Safety Monitoring Committee (DSMC) that will 
receive unblinded summaries of data at the two interim analyses scheduled at 750 and 1500 
patients. The DSMC will have mandate to evaluate specific safety concerns), as well as efficacy, with 
the option to either declare sufficient difference in the primary outcome variable, or to recommend 
that the study is continued until 3260 patients have been enrolled. Early stopping for efficacy reasons 
will only be considered if primary outcome differences are seen between the groups according to the 
Pato-Haybittle rule with a p-value ≤0,001. The DSMC will be able to request unblinding of data if they 
find it necessary. The DSMC can initiate analysis at any time they request.  
A Interim analysis was performed by an independent data monitoring committee in early 2022, 
reviewing all data including 30-day survival, after a total of 1250 patients (out of which 696 patients 
were included in the main PP1 population). The recommendation by the data monitoring committee 
was to continue the trial without modification.  
 
12. Publication plan and author policy  
The trial will be analyzed by an independent statistician and the results interpreted by the 
steering group. The principal investigator will prepare the manuscript before the allocation code is 
broken. The final manuscript will be submitted to a peer-reviewed international journal. Authorship 
will be granted using the Vancouver definitions and depending on personal involvement. The author 
list will start with Gabriel Riva and the last name will be Jacob Hollenberg. A separate publication list 
for all authors including the main study, as well as sub studies, has been created. 
 
13. Enrolment and timeline  
 
Q1-2 2014 
 
Application to ethics committee 
 
Q3-4 2014 
 
Preparation 
 
2015-2016  
 
RUN-IN study 
 
2017-2020 
 
PILOT study 
 
2022-2026 
 
MAIN STUDY 
 

 
 
 
 
 
29 
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