DOuble SEquential External Defibrillation for Refractory Ventricular Fibrillation (DOSEVF) Randomized Controlled Trial
Phase: NA
Conditions: Out-Of-Hospital Cardiac Arrest, Ventricular Fibrillation
Sponsor: Sunnybrook Health Sciences Centre

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Title: DOuble SEquential External Defibrillation for Refractory VF- DOSE VF Randomized Control 
Trial  
Version: 6.2 Dated: June 11 2021 
Principal Investigator: Dr. Sheldon Cheskes, MD, CCFP (EM) FCFP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Title: DOuble SEquential External Defibrillation for Refractory VF- DOSE VF Randomized Control Trial 
Structured Abstract:  
Introduction: Despite significant advances in resuscitation efforts such as cardiopulmonary 
resuscitation (CPR) quality, defibrillation, airway management and antiarrhythmic medications 
given in hopes of promoting the return of an organized rhythm; there are some patients who 
remain in refractory ventricular fibrillation (VF) during out-of-hospital cardiac arrest. Double 
sequential external defibrillation (DSED) and vector change defibrillation (VC) have been 
proposed as a viable option for patients in refractory VF.  
 
Objective: The objective of this study is to compare two novel therapeutic defibrillation 
strategies (DSED and VC) against standard practice for patients remaining in refractory VF 
during out-of-hospital cardiac arrest.   
 
Research Question: Among adult (≥ 18 years) patients presenting in refractory VF or pulseless 
ventricular tachycardia (pVT) during out-of-hospital cardiac arrest, does DSED or VC 
defibrillation (anterior-posterior compared to anterior-lateral pad position) result in greater rates 
of survival to hospital discharge compared to standard defibrillation? 
 
Methods: This will be a three-arm, cluster randomized trial with crossover conducted in six 
regions of Ontario, Canada (Peel, Halton, Toronto, Simcoe, London and Ottawa) over a three 
year period of time. According to randomized cluster assignment, all adult (≥ 18 years) patients 
presenting in refractory VF (defined as patients presenting in VF/pVT and remaining in VF/pVT 
after three consecutive standard defibrillation attempts each separated by 2 minutes of CPR) 
during out-of-hospital cardiac arrest of presumed cardiac etiology will be treated by one of three 
strategies: (1) continued resuscitation using standard defibrillation; (2) resuscitation involving 
DSED; or (3) resuscitation involving VC (change of defibrillation pads from anterior-lateral to 
an anterior-posterior pad position) defibrillation. The primary outcome will be survival to 
hospital discharge. Secondary outcomes will include neurologic outcome at hospital discharge, 
return of spontaneous circulation (ROSC), termination of VF after the first interventional shock, 
termination of VF inclusive of all interventional shocks, and number of defibrillation attempts to 
obtain ROSC. Based on our previous cohort study research and the DOSE VF pilot RCT, we will 
also perform an a priori subgroup analysis comparing rates of survival to hospital discharge for 
those randomized to DSED who receive DSED after three failed successive standard shocks 
(early DSED or first DSED shock is shock 4-6) to those who receive DSED after six failed 
successive standard shocks (late DSED or first DSED shock is shock 7 or later).  
 

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Impact:  A well-designed randomized controlled trial employing a standardized approach to 
alternative defibrillation strategies early in the treatment of refractory VF is urgently required to 
determine if the treatments of VC defibrillation or DSED impact clinical outcomes.  
 
Background:  
 
Out-of-hospital cardiac arrest accounts for over 350,000 unexpected deaths each year in 
the United States and Canada, nearly 100,000 of which are specifically attributable to ventricular 
fibrillation or pulseless ventricular tachycardia (VF/VT).1 VF/VT is considered the most 
treatment-responsive presentation of cardiac arrest and boasts the highest rate of survival. 
However, despite significant advances in resuscitation efforts such as CPR quality, defibrillation, 
airway management, and antiarrhythmic medications given in hopes of promoting the return of 
an organized rhythm, there are some VF patients who remain in persistent or refractory VF. The 
definition of refractory VF varies, but is commonly considered persistent VF without response to 
five standard defibrillation attempts.2   Another common definition for refractory VF is those 
patients for whom VF is not terminated 5 seconds post defibrillatory shock and thereafter remain 
in VF.3 From a pragmatic point of view, this definition would be difficult to apply to current 
cardiac arrest resuscitation practice. Shorter post-shock pauses induce CPR artifact making 
interpretation of VF termination 5 seconds post- shock problematic.  As well, current 
resuscitation require 2 minutes of CPR without a pulse check following defibrillation making the 
determination of VF termination one that would not change clinical practice. It is important to 
note that refractory VF is different than recurrent VF, which is generally defined as VF that 
recurs after successful termination of a VF waveform.4 
Double sequential external defibrillation (DSED) has been studied for decades in the 
electrophysiology lab for patients in both refractory atrial fibrillation and ventricular 

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fibrillation.5-10 Recently, case series and individual case reports have surfaced demonstrating 
conflicting outcomes for patients treated with DSED for refractory VF, both in and outside the 
hospital.11-16 Cabanas et al., were able to demonstrate improved termination of VF employing a 
prehospital protocol with use of DSED but reported no improvement in survival. This was likely 
due to late application of DSED (meant time to first DSED shock was 36.8 minutes, mean 
number of shocks prior to DSED was eight).11 Ross et al., in a retrospective analysis of  50 
DSED cases over a three year time frame, demonstrated no improvement in the primary outcome 
of neurologically intact survival employing DSED, but did not report data regarding the timing 
of the DSED shock nor CPR quality.12 Lybeck et al., and Johnson et al., both described cases of 
early use of DSED with successful outcomes of neurologically intact survival to hospital 
discharge.13,14 Despite growing enthusiasm, particularly in the field of prehospital medicine, 
there is a paucity of evidence to support widespread implementation of this therapy. Further, 
most uses of DSED have been employed as an ad-hoc final effort to convert VF, as opposed to a 
planned early application of this alternative treatment strategy. From a mechanistic viewpoint, it 
is unclear whether the change of vector, timing of the “dual shocks” or the application of 
increased energy is the curative factor for those responding to DSED. Our research group 
evaluated 251 cases of refractory VF (201 standard care, 50 DSED) over a three-year period 
beginning on Jan 1, 2015 in four Canadian EMS agencies currently participating in the DOSE 
VF pilot RCT. Our research demonstrated improved rates of VF termination and ROSC when 
comparing early DSED (shocks 4-8) to similar shocks provided by standard defibrillation. 
Specifically, when early defibrillation attempts were considered (defibrillation attempt 4-8), VF 
termination was higher for those receiving DSED compared to standard defibrillation (29.4% vs. 
17.5%; RR: 1.7; 95% CI: 1.1 to 2.6). Additionally, when early defibrillation attempts were 

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considered (defibrillation attempt 4-8), ROSC was higher for those receiving DSED compared to 
standard defibrillation (15.7% vs. 5.4%; RR: 2.9; 95% CI: 1.4 to 5.9).  
The DOSE-VF Pilot RCT 
Based on our preliminary work, our research group obtained funding from the Laerdal 
Foundation to conduct an internal pilot trial of the DOSE VF protocol 
(https://clinicaltrials.gov/ct2/show/NCT03249948) previously approved by the Sunnybrook 
Health Sciences Center REB. The pilot trial was designed to determine the feasibility of 
conducting a full-scale randomized trial in this population.17,18 The pilot RCT completed on 
September 9, 2019, trained over 2,500 paramedics  in the technique of DSED and vector change 
defibrillation (VC). The pilot took place in four paramedic services in Ontario (Toronto, Peel, 
Halton and Simcoe) with all services actively enrolling patients. All paramedics received in-
person training using a combination of didactic, video and simulated scenarios prior to the study 
launch. All eligible patients with refractory VF (n=152 ) in the participating paramedic services 
have had paramedics successfully apply both VC and DSED. The DOSE-VF Pilot RCT 
demonstrated that the protocol is feasible with 89.5% of patients receiving the treatment they 
were randomized to and 90.2% of patients receiving an intervention shock prior to shock 6 in the 
resuscitation. As well, no safety concerns were noted (no reports of defibrillator damage, skin 
burns, inadvertent shocking of paramedics or bystanders) and was well accepted by paramedics 
in the field. We have as well been able to determine the number of cases occurring in each 
service  during the pilot RCT (varying from 1.4-6.1 cases/month) allowing us to accurately 
calculate the number of patients required to perform an adequately powered definitive RCT. 
Finally, we observed that the rate of VF termination and ROSC were greater in both 

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interventions then standard defibrillation. Specifically, in the standard group, 66.6% of cases 
resulted in VF termination, compared to 82.0% in VC and 76.3% in the DSED group. ROSC was 
achieved in 25.0%, 39.3% and 40.0% of standard, VC and DSED groups, respectively. The 
DOSE-VF pilot RCT has established the feasibility of proceeding with a definitive, adequately 
powered RCT to determine whether employing a standardized approach to alternative 
defibrillation strategies early in the treatment of refractory VF may impact clinical outcomes.             
Objective: The objective of this study is to compare two novel therapeutic defibrillation 
strategies (DSED and VC) against standard practice for patients remaining in refractory VF 
during out-of-hospital cardiac arrest.   
Research Question: Among adult (≥ 18 years) patients presenting in refractory VF or pulseless 
ventricular tachycardia (pVT) during out-of-hospital cardiac arrest, does DSED or VC 
defibrillation (anterior-posterior compared to anterior-lateral pad position) result in greater rates 
of survival to hospital discharge compared to standard defibrillation? 
Population: Adult (≥ 18 years) patients presenting in refractory VF/pVT during out-of-hospital 
cardiac arrest.  Refractory VF will be defined as patients in whom VF/pVT is the presenting 
rhythm and whom remain in VF/pVT after three successive failed defibrillation attempts each 
separated by 2 minutes of CPR.  
Intervention: (1) Resuscitation involving DSED, or (2) Resuscitation involving VC 
defibrillation (anterior-lateral compared to anterior-posterior pad position). 
Comparison: Resuscitation using standard defibrillation (pads in anterior-lateral position 
throughout the resuscitation). 

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Outcomes: The primary outcome will be survival to hospital discharge. Secondary outcomes 
will include neurologic outcome at hospital discharge, ROSC, termination of VF after the first 
interventional shock, termination of VF inclusive of all interventional shocks, and number of 
defibrillation attempts to obtain ROSC. We will also perform an a priori subgroup analysis 
comparing rates of survival to hospital discharge for those randomized to DSED who receive 
DSED after three failed successive standard shocks (early DSED or first DSED shock is shock 4-
6) to those who receive DSED after six failed successive standard shocks (late DSED or first 
DSED shock is shock 7 or later). We will also perform a sensitivity analysis examining the effect 
of time period (pilot study, pre-COVID, during COVID) on our outcomes.  
Inclusion Criteria: ≥18 years of age, non-traumatic cardiac arrest of presumed cardiac etiology, 
with a presenting rhythm of ventricular fibrillation/pVT; with no ROSC or non VF rhythm after 
three consecutive shocks.  
Exclusion Criteria: Traumatic cardiac arrest, patients with pre-existing do not resuscitate 
orders, , patients in recurrent ventricular fibrillation (defined as those with a secondary 
presentation of VF (not the presenting rhythm) or those presenting in VF but did not receive 
three consecutive failed defibrillation attempts). Patient’s whose initial care was provided by 
non-participating EMS agencies or fire services will be excluded.  
Methods: 
 
Study Design and Population 
 
This will be a three-arm, cluster randomized trial with crossover conducted in six regions 
of Ontario, Canada (Peel, Halton, Toronto, Simcoe, London and Ottawa). These six regions were 

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selected because each has its own paramedic service, and all have previously participated in and 
successfully completed prehospital resuscitation trials.19, 20 Two treatment strategies (DSED and 
VC) will be simultaneously assessed against a common control group (standard defibrillation). 
This approach has been chosen to maximize efficiency, allowing comparison of two new 
treatments to usual care in a single three-armed randomized trial.21, 22 
The clusters will be defined by the paramedic service in each of the six regions and each 
cluster will crossover at least twice per year to receive one of three treatment approaches 
(standard care, DSED or VC) for six months. Each service will apply each of the three treatment 
arms twice over the duration of the study The annual prevalence of paramedic treated out-of-
hospital cardiac arrest for these regions is approximately 4,000; of which 800 (20.0%) patients 
will present in VF. Our pilot trial suggests that approximately 180 patients per year will meet the 
study criteria for refractory VF. The study protocol will be approved by each local institutional 
Research Ethics Board and is registered with clinicaltrials.gov. 
(https://clinicaltrials.gov/ct2/show/NCT04080986). 
All adult (≥ 18 years) patients remaining in refractory VF or pVT during out-of-hospital 
cardiac arrest of presumed cardiac etiology will be eligible for inclusion. Patients suffering a 
traumatic cardiac arrest, patients with pre-existing do not resuscitate orders and patients in 
recurrent ventricular fibrillation (defined as secondary presentation of VF or those presenting in 
VF but did not receive three consecutive defibrillation attempts) will be excluded. Patient’s 
whose initial care was provided by non-participating EMS agencies or fire services will be 
excluded.  
Study Protocol: 

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All paramedics treating patients during out-of-hospital cardiac arrest follow a provincial 
protocol for treatment of patients in VF (Appendix 1). Cardiopulmonary resuscitation (CPR) 
will be performed prior to defibrillator pad application. Each rhythm analysis will occur at 
standard two-minute intervals. VF will be determined by paramedic manual defibrillator analysis 
or semi-automatic defibrillator analysis by participating fire services, after which a shock will be 
provided. For all patients, the first three shocks will occur with defibrillation pads placed in the 
anterior-lateral position. Epinephrine and antiarrhythmic medication (amiodarone or lidocaine) 
will be provided as per provincial protocol. For eligible patients remaining in VF after three 
consecutive shocks (following two-minute CPR intervals) that are delivered by paramedics or 
participating fire services (defibrillation shocks provided by bystanders prior to EMS arrival will 
not be counted), all subsequent defibrillations will be randomized to one of the following 
treatment strategies:  
Strategy 1 (Standard Defibrillation): For paramedic services randomized to standard 
defibrillation, all subsequent defibrillation attempts will occur through pads placed in an 
anterior-lateral configuration as noted in Appendix 1.  
Strategy 2 (VC Defibrillation): For paramedic services randomized to VC defibrillation, 
all subsequent shocks will be delivered using anterior-posterior pad placement, as noted in 
Appendix 1. Transfer of pads to the anterior-posterior position from the initial standard anterior-
lateral configuration will occur during the two-minute cycle of CPR following the third shock 
with minimal interruptions in CPR. 
Strategy 3 (DSED): For paramedic services randomized to DSED, paramedics will apply 
a second set of defibrillation pads as soon as possible after the first three shocks (via a second 

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paramedic or fire defibrillator) in the anterior-posterior position, as noted in Appendix 1. 
Application of defibrillation pads for the second defibrillator will occur during the two-minute 
cycle of CPR following the third shock with minimal interruptions in CPR. All subsequent 
defibrillation attempts will be carried out by sequential defibrillation shocks provided by two 
defibrillators. To ensure shocks are not applied at the exact same moment, we will employ a 
short (less than one second) delay to provision of the second defibrillator shock. This will be 
accomplished by a single paramedic pressing the “shock button” on each defibrillator in rapid 
sequence as opposed to simultaneously. Dispatch deployment strategies will be employed by all 
paramedic services participating in the trial to ensure two defibrillators are available for all 
cardiac arrests in the DSED arm of the study. However, in situations when a second defibrillator 
is not available, the treatment will default to standard defibrillation until such time that a second 
defibrillator can be secured.  
Randomization Strategy 
Each cluster (paramedic service) will be randomized to standard defibrillation, 
defibrillation using VC, or DSED (see attached timeline in Appendix 2). All clusters will 
crossover between standard defibrillation, defibrillation using VC or DSED at least twice per 
year (at least six distinct treatment periods). Random assignment of treatment sequence will be 
performed by the coordinating center prior to the start of the study. Specifically, each paramedic 
agency will perform each arm of the study twice during the duration of the trial. Clusters will not 
be informed of their group assignments until necessary to make preparations to start the trial or 
crossover to another study strategy. 
Outcome Measures 

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            The primary outcome will be survival to hospital discharge. Secondary outcomes will 
include neurologic outcome at hospital discharge, ROSC, termination of VF after the first 
interventional shock, termination of VF inclusive of all interventional shocks, and number of 
defibrillation attempts to obtain ROSC.  
Sample Size 
In response to the need for more efficient trial designs that accelerate discovery and 
minimize costs, it has been recommend that researchers consider employing multi-arm trials 
designed for logistical efficiency.21 In a multi-arm trial, several treatments are simultaneously 
assessed against a common control group within a single randomized trial, allowing sizeable 
gains in efficiency. Relative to conducting separate trials for each experimental treatment, a 
multi-arm design has been shown to require a lower total sample size and financial resources 
than separate, sequential two-arm trials.22 
From our internal pilot trial discussed earlier, we observed that across our paramedic 
services, the annual prevalence of paramedic treated out-of-hospital cardiac arrest for these 
regions is approximately 4,000; of which 800 (20.0%) patients will present in VF. Our pilot data 
suggests that approximately 180 patients per year meet the study criteria for refractory VF. 
Holmen et al.24 demonstrated a 30 day survival rate of 28.7% for patients receiving 1-3 shocks, 
declining to 12.4% for those receiving 4-10 shocks, and 4.9% for those receiving greater than 10 
shocks. Based on these findings, we assumed a baseline survival rate of 12% for patients who 
will meet our study criteria. This baseline survival rate will be confirmed by comparing to the 
baseline survival rate of the standard defibrillation arm of the pilot RCT and will be adjusted 
according to this value. 

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We hypothesize that DSED and VC defibrillation earlier in the resuscitation will result in 
survival as high (or higher) as standard defibrillation. We project a minimum absolute increase 
of 8% in survival to hospital discharge when VC or DSED strategies are employed as per our 
protocol, compared to standard care.  
Using these baseline estimates, and assuming a fixed number of paramedic service 
clusters (n=6), we will enroll approximately 20-70 patients per cluster over one year. Data from 
the internal pilot RCT will be included in the final analysis.17 The study design assumes that each 
cluster will cross over twice to receive each of three treatment approaches (standard 
defibrillation, DSED and VC) for approximately six months. We assumed a plausible intra-
cluster correlation (rho) of 0.010 and a plausible inter-period correlation (eta) of between 0.008 
and 0.010 and without multiplicity correction, as has been recommended for exploratory trials 
involving multiple treatment arms.22 ,25 Under these conditions, the trial will have adequate 
power (>80%) with an α level  5%, to detect a minimally important 8% absolute difference in 
survival to hospital discharge with a sample size of 310 patients per arm (total sample size of 930 
patients;  approximately 150 patients from internal pilot RCT and 780 patients from the 
definitive RCT).  
Statistical Analysis and Mock Tables (Appendix 3): 
For this three-arm trial, two treatment strategies (DSED and VC) share a common control 
arm (standard defibrillation). This approach is chosen to maximize efficiency, allowing 
comparison of two new treatments to usual care in a single three-armed trial. The primary 
analysis will compare DSED to standard defibrillation and VC defibrillation to standard 
defibrillation. A secondary analysis will compare DSED to VC defibrillation. We hypothesize 

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that resuscitation involving DSED and resuscitation involving VC defibrillation will have 
superior outcomes compared to resuscitation using standard defibrillation. Because this trial is 
focused on answering the efficacy question for each treatment strategy separately, and the 
interpretation of the results of one comparison have no direct bearing on the interpretation of the 
other. In this situation, no multiplicity adjustment is required.22, 25, 26 
All tests will be 2-sided with p < 0.05 denoting statistical significance. The unit of 
analysis for the comparisons will be the individual patient. All patients will be analyzed 
according to randomized treatment assignment ( intention-to-treat analysis). Based on the DOSE 
VF pilot RCT secondary analyses will be performed based on actual treatment received, 
appropriate randomization performed, and appropriate randomization performed with optimal 
intervention shock timing (shock 4). We will also perform an a priori subgroup analysis 
comparing rates of survival to hospital discharge for those randomized to DSED who receive 
DSED after three failed successive standard shocks (early DSED or first DSED shock is shock 4-
6) to those who receive DSED after six failed successive standard shocks (late DSED or first 
DSED shock is shock 7 or later). Last, we will perform a sensitivity analysis to examine the 
impact of trial phase (pilot study, pre-COVID, and during COVID) on our outcomes. The binary 
primary outcome, survival to hospital discharge, will be compared across the arms of DSED and 
VC defibrillation as an adjusted odds ratio with 95% confidence intervals (CIs) using the 
standard arm as the reference group.27 We will use a generalized linear mixed model (GLMM; 
logit link) with random effects for cluster-period effect, and using fixed-effects for cluster and 
for the period, to account for the effect of period on the outcome, as has been recommended for 
the analysis of cluster crossover trials.28,29 The primary analysis will also adjust for the following 
baseline variables known to impact outcomes after out-of-hospital cardiac arrest: age, sex, 

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bystander witnessed arrest, bystander CPR provided, time to first arrival, public versus private 
location, epinephrine and antiarrhythmic use.30 We will also test for effect modification by trial 
phase, comparing effectiveness in the internal pilot trial and the larger definitive trial. Odds 
ratios with 95% CIs for secondary outcomes will be calculated in a similar manner, where 
appropriate. 
Consent Waiver 
This trial requires timely implementation of the study intervention, and individual patient 
consent will not be feasible prior to randomization. Similar to our previous research, we have 
received a waiver of consent in accordance with the Tri-Council Agreement from the Research 
Ethics Board of Sunnybrook Health Sciences Centre.31-39 We will seek a similar waiver of 
consent from REB providing oversight to the EMS agencies taking part in the study. All enrolled 
patients will receive a letter notifying they were enrolled in the study under waiver of consent. 
Data Collection 
The Sunnybrook Health Sciences Centre in conjunction with the Sunnybrook Osler 
Centre for Prehospital Medicine will oversee data collection, management and data analyses. 
Data sources will include ambulance call reports (ACRs) and electronic defibrillator files that are 
mandatorily recorded and stored for each patient. Paramedic providers in participating regions 
will collect basic demographic information and details about the cardiac arrest, including 
adverse/critical events during transport in addition to other information concerning patient care. 
All services will also capture electronic defibrillator CPR process data, including real-time 
measures of chest compression fraction, compression depth (not available on all defibrillators), 

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compression rate and shock pause duration. These data collection processes were successfully 
implemented and tested in the pilot study. For each case identified as an eligible DOSE VF study 
data (listed below) will be abstracted by a data abstractor hired and trained for the study. Data 
will be abstracted from ACRs and electronic defibrillator files at Sunnybrook Centre for 
Prehospital Medicine, where the data are housed on a secure server. Cases from all agencies will 
be assigned a unique Study ID and all identifiers removed.  Separate lists of ACR identifiers 
corresponding to the unique Study IDs will be maintained in a separate location. 
All data will be handled according to national privacy legislation and its related 
regulations. Data will be entered into a standardized Epi Info 7 data collection form (Epi Info, 
Centers for Disease Control and Prevention, Atlanta, GA.) Data will be checked, validated, 
encrypted, and sent securely to Sunnybrook Health Sciences Centre for analyses. 
Data to be abstracted from Ambulance Call Report and Electronic Defibrillator Files 
(Participating Fire Services or EMS):    
General Characteristics: Study ID, Emergency health service, Fire service if applicable, age, 
sex, weight (approximate), arrest location (public/private), response time, bystander CPR, 
bystander AED, bystander shock, bystander witnessed, highest service level on scene (ALS vs 
BLS). 
General Date/Time Information: Date of Call, call arrival to 911, arrival at scene (wheels stop 
1st vehicle), arrival at patient side, time of first rhythm, second, etc. (all shocks), first shock, 
second shock, etc.(all shocks), depart scene, arrival at hospital. 

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Prehospital Treatment Data: Arrest occurred after EMS arrival (witnessed EMS), AED/Defib 
applied, total shocks delivered, number of each shocks (standard, vector change, DSED), time of 
first ROSC post arrest (ROSC will be defined as the restoration of a spontaneous rhythm noted 
on the defibrillator files with a corresponding palpable pulse noted on the paramedic ambulance 
call report) and termination of VF (defined as the absence of a shockable rhythm 2 minutes after 
each interventional or standard shock). 
CPR quality characteristics: Median CCF during resuscitation, median compression rate during 
resuscitation, median compression depth during resuscitation. 
Specific shock variables (for each shock): Pre-shock pause, post-shock pause, number of 
interventional or standard shocks that resulted in ROSC, rate of re-arrest post-ROSC.  
Variables to be abstracted from a combination of electronic defibrillator files and the ACR 
The data abstractor will use a combination of both electronic defibrillator files and the 
ACR to determine VF termination, time of first ROSC, as well as the number of defibrillatory 
shocks provided to first ROSC. All defibrillator files will be reviewed by two independent 
investigators blinded to the intervention to confirm VF termination as well as the subset of cases 
that meet the criteria for our subgroup analysis. Adjudication by a third investigator blinded to 
the intervention will occur should consensus be required. 
Data linkage to administrative data bases at Cancer Care Ontario CCO: 
 
The primary outcome of survival to hospital discharge will be obtained through linkage 
of our data with the administrative databases at Cancer Care Ontario (CCO). In addition we plan 
on collecting data regarding whether or not a patient had coronary angiography and/or 

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percutaneous coronary intervention (PCI). (ICD-10 codes (PCI): 4802, 4803, 1IJ50, 1IJ54, 
1IJ57GQ and ICD-10 codes (angiography): 4892, 4893, 4894, 4895, 4896, 4897, 4898, 4995, 
4996, 4997, 3IP10). We expect this will occur within six months of the final patient enrolled. 
Patients who are discharged alive or transferred to a receiving hospital in Ontario and 
subsequently discharged alive, health card numbers and other patient information as necessary 
will be linked at CCO with the province-wide hospital discharge abstract database (DAD). 
(Linkage to the CCO administrative database requires use of the Ontario health card number for 
deterministic linking of each subject. Where no match is found, patient names and dates of birth 
will be used to search for corresponding records using probabilistic matching.) 
On the recommendation of the DSMB we have decided to collect data on neurologic outcome as 
a secondary outcome for this study. We will obtain neurologic outcome in two different ways. 
First, we will link patient records with administrative databases at Cancer Care Ontario using the 
same method as we did for our primary outcome of survival to hospital discharge (described 
above). We will link patients to obtain “discharge disposition” from the Discharge Abstract 
Database (DAD) as a surrogate for neurologic status at hospital discharge. This has been done in 
previous cardiac arrest research to represent patient neurologic status. Second, we will obtain 
discharge summaries for patients who survived to hospital discharge by applying to Clinical 
Trials Ontario (CTO) for research ethics board approval to obtain data from participating 
hospitals. Neurologic status at hospital discharge will be obtained from discharge summaries by 
manual data abstraction through use of research assistants or hospital research personnel. 
Trial Organization: 
Coordinating Center     

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This study will be conducted coordinated through Sunnybrook Centre for Prehospital 
Medicine in Toronto who will provide oversight throughout the study including all interactions 
with participating EMS services. Statistical support will be provided through Sunnybrook Health 
Sciences Centre.  
 Steering Committee     
The Executive Steering Committee will consist of a group of key scientific and local 
leaders and will oversee all aspects of the study. An EMS Operations Committee will be 
established and meet on a monthly basis to address the day-to-day operations of the trial.   
Data and Safety Monitoring Board  
Independent oversight of this study will be provided by a data safety monitoring board 
(DSMB) consisting of a biostatistician and two clinical experts, unrelated to the trial. The 
committee will conduct an unblinded interim data safety analysis to assess for lower than 
anticipated rates of survival between the three treatment groups. The committee will meet at one-
year intervals and provide recommendations to the steering committee; however, the 
responsibility for the final decision regarding a DSMB-recommended course of action will rest 
with the steering committee. 
Once 450 patients have been enrolled in the trial (including patients enrolled during the 
internal pilot trial), the DSMB committee will conduct an unblinded interim data analysis and 
will advise if sample size modification if necessary. Sample size modification based on 
unblinded interim results is relatively well understood and is unlikely to introduce bias or raise 
major concerns.40-42 Depending on the estimates of the event rate, they may suggest we maintain 

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the a priori calculated sample size or increase it (but not decrease it). If a sample size increase is 
warranted due to lower than anticipated event rates, REB approval will be sought from each 
participating site.  
During our interim analysis we will also formally examine stopping the trial for harm 
only. The decision to stop for harm will be based on a single interim analysis performed after 
50% recruitment (n=450). We will use a Haybittle-Peto one-sided P value < 0.0005 as evidence 
of harm and criteria to stop the trial. This will not impact the alpha for our final analysis.43 We 
will also monitor adverse events as they occur and take these into consideration during the 
interim analysis. The decision to stop the trial will be based upon recommendations by the 
DSMB in discussion with the trial steering committee.  
Feasibility and Possible Problems    
Recruitment and rates of patients presenting in refractory VF are based on local, 
historical data and the internal pilot RCT. Actual rates of refractory VF in the full trial may be 
higher or lower than projected which may impact the duration of study estimates. Enthusiasm for 
recruitment will be maintained with monthly updates to the paramedics and paramedic services 
through the activities of the EMS operations committee. The assurance of two defibrillators 
being available for all patients randomized to the DSED strategy has the potential to impact 
enrollment in this study arm but will be mitigated by changes in regional dispatch deployment in 
each region to assure two paramedic crews are dispatched to all cardiac arrest calls. Should one 
of the two intervention arms appear to be more successful than standard care, a risk of 
contamination of the study arm may exist for patients randomized to a perceived inferior 
treatment. This will be mitigated by education during the training of all paramedics on the 

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importance of maintaining randomization during the study, stickers applied to each service 
defibrillator labeled to the intervention arm as well as reminders of the importance of 
randomization to the validity of the study while the study is ongoing through continual 
education, individual and service wide paramedic feedback. Previous experience of our services 
in randomized controlled trials will also aid to guard against this occurrence. Defibrillation as 
currently proposed is Health Canada approved for both standard and VC arms of our study. We 
have received input from Health Canada that DSED as proposed in the study protocol is an off 
label use of defibrillation and its use is not within the purview of Health Canada, but does require 
the judgment of the local REB. We have obtained REB approval for the DOSE VF pilot from 
Sunnybrook Health Science Center. 
Ethical and Regulatory Standards  
Good Clinical Practice    
The study will be conducted in accordance with both the Tri-Council Policy Statement44 
and Good Clinical Practice Guidelines.45 
Approval of the Study Protocol  
Before the start of the study, the study protocol and other appropriate documents must be 
submitted to and approved by the local institutional Research Ethics Board and the appropriate 
regulatory authorities in accordance with local legal requirements. Documentation of Ethics 
Committee/REB approvals and confirmation of executed institutional data sharing agreements 
will be required before study randomization and enrollment begin. The study protocol will be 
registered with clinicaltrials.gov. 

21 | P a g e  
 
Maintenance of Records   
The Principal Investigator/Coordinating Centre must maintain all study records, patient 
files and other source data for up to 25 years as per institutional standard operating procedures.  
Confidentiality   
All personal health information will be kept confidential. Direct identifiers (e.g. name, 
date of birth) corresponding to each unique Study ID will be stored separately and securely at 
Sunnybrook Centre for Prehospital Medicine. Data will be de-identified using methods described 
by the Information and Privacy Commissioner of Ontario’s De-identification Guidelines for 
Structured Data. The Principal Investigator agrees to maintain the confidentiality of the study 
protocol.  
Confidentiality Agreement   
All goods, materials, information (oral or written) and unpublished documentation 
provided to the Investigators (or any company acting on their behalf), inclusive of this protocol 
and the patient case report forms are the exclusive property of the Coordinating Centre. They 
may not be given or disclosed by the Investigator or by any person within his authority either in 
part or in totality to any unauthorized person without the prior written formal consent of the 
Coordinating Centre. It is specified that the submission of this protocol and other necessary 
documentation to the Ethics Research Committee is expressly permitted, the Ethics Committee 
members having the same obligation of confidentiality. The Investigator shall consider as 
confidential and shall take all necessary measures to ensure that there is no breach of 

22 | P a g e  
 
confidentiality in respect of all information accumulated, acquired or deduced in the course of 
the trial, other than that information to be disclosed by law.   
 
 
 
 
 
 
Study Team 
Role 
Affiliation 
Dr. Sheldon Cheskes 
PI 
Sunnybrook Centre for 
Prehospital Medicine 
Dr. Richard Verbeek 
Co-I 
Sunnybrook Centre for 
Prehospital Medicine 
Dr. Ian Drennan 
Program Manager 
Sunnybrook Research Institute 
Dr. Shelley McLeod 
Co-I 
Sinai Health System 
Dr. Ruxandra Pinto 
Statistician 
Sunnybrook Health Science 
Centre 
Dr. Linda Turner 
Statistician / Epidemiologist 
Sunnybrook Centre for 
Prehospital Medicine 
Dana Bradshaw 
Data abstractor 
Sunnybrook Centre for 
Prehospital Medicine 
Dr. Michael Feldman 
Co-I 
Sunnybrook Centre for 
Prehospital Medicine 
Dr. Matthew Davis 
Co-I 
London Health Science Centre 

23 | P a g e  
 
Dr. Damon Scales 
Co-I 
Sunnybrook Centre for 
Prehospital Medicine 
 
 
 
 
 
 
 
 
 
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Department of Emergency Medicine 
 
Hospital of the University of Pennsylvania 
 
Benjamin S. Abella, MD MPhil FACEP 
Professor and Vice Chair for Research 
Director, Center for Resuscitation Science 
 
Blockley Hall | 423 Guardian Drive, Room 412 | Philadelphia, PA 19104 | P: 215-279-3452 | F: 215-573-2701 | Benjamin.Abella@pennmedicine.upenn.edu 
Dr. Sheldon Cheskes 
Principal Investigator 
Double Sequential External Defibrillation for Refractory VF – DOSE VF Study 
 
January 28, 2022 
 
Re: Data Safety Monitoring Board Review of Double Sequential External Defibrillation for Refractory Ventricular 
Fibrillation (DOSE VF) Randomized Controlled Trial.  
 
On Friday January 28th 2022, the DSMB met virtually via Zoom to discuss the current status of the DOSE-VF RCT. Prior to 
the meeting, Dr. Sheldon Cheskes circulated a summary report detailing the current status of the DOSE-VF trial, which 
was reviewed by DSMB members Dr. Jim Christenson, Dr. Ben Abella, and Dr. Gerald Lebovic. Steering committee 
members Dr. McLeod, Dr. Verbeek, and Dr. Scales also attended the DSMB meeting to provide context and input 
regarding current challenges. This letter is intended to summarize the discussion from the DSMB meeting. 
 
After a long pause due to the COVID-19 global pandemic, five sites restarted enrolment in September 2020. The sixth 
site, Toronto Paramedic Service, began enrolling patients again in October 2021 (after a 19-month hiatus). Since 
restarting the trial, 132 patients have been enrolled, bringing the total study enrolment to 379 with good balance 
between all arms (DSED 122; Standard 128; Vector Change 129 patients). Despite the continued enrolment of patients, 
Dr. Cheskes presented some concerns regarding the ability of paramedics to continue to enrol patients in the study due 
to the challenges presented by the ongoing COVID-19 pandemic. Some of the major concerns relate to paramedic 
protocol compliance during COVID-19; paramedic staffing concerns and service response times; and the reported 
worldwide decrease in overall survival from cardiac arrest (primary outcome of the study) during COVID-19.  
 
Dr. Cheskes reported an overall decrease in randomization compliance during COVID-19 from 92% (pre-COVID) to 83% 
(during COVID), with compliance dropping in both intervention arms to 73% (down from 83% for vector change and 92% 
for DSED prior to the pandemic) with no significant drop in standard arm compliance. This is concerning as it has the 
potential to bias the trial results towards the null effect. The investigators have followed up with letters, video 
refreshers, sign postage at all stations and other methods in an attempt to keep compliance high, but feedback from 
paramedic services suggests compliance is difficult due to reduced staffing, increased response times, and competing 
priorities associated with COVID-19 protocols on scene and cardiac arrest treatment.  
 
Dr. Cheskes reported a major increase in the number of patients that are receiving initial defibrillation from the fire 
department – from 32% pre-COVID to 39% during COVID (up to 53% in the largest centres - Toronto, Ottawa, and Peel). 
In some cases, patients are receiving multiple shocks (upwards of five) prior to paramedic arrival. This again speaks to 
reduced paramedic staffing levels, increased responses times, and reduced overall protocol compliance – again all 
potentially impacting the study findings. The critical component of the study protocol is to ensure early intervention 
shocks (vector change or DSED) after three failed standard shocks. The current pandemic creates a scenario whereby 
intervention shocks are being delivered at the 6th or later shock, impacting any potential benefit of the intervention 
again biasing the results towards the null effect.  
 
Perhaps most difficult at this time is the impact of paramedic fatigue. Amazingly, Dr. Cheskes and his EMS operations 
committee have been able to maintain paramedic and service interest with this study during COVID-19 when many 
other trials have stopped. The paramedics have continued to enrol to the best of their ability but reduced staffing, 
increased call volume, and pandemic-related job stressors have caused significant burnout and fatigue within paramedic 

services. Each service has spent a minimum of 18 months (except Ottawa Paramedic Service) and up to 3 years enrolling 
patients in the DOSE-VF study. In addition, the pandemic has contributed to an enormous turnover of paramedics in 
many of the participating services. Dr. Cheskes has prepared excellent training videos for all new hires, but without the 
ability to engage in face to face training, there are now a number of paramedics in each service who have had no “hands 
on” training in either of the intervention techniques. While video training is adequate, it cannot replace in-person 
training of all new service hires.  
 
Overall, despite the incredible effort and dedication by all involved, the DSMB recommends the DOSE VF RCT be 
stopped at this time in all sites except for Ottawa Paramedic Service due to the impact of the pandemic on the study 
protocol.  The DSMB unanimously agreed there was no need for an interim analysis and the decision to terminate the 
trial early should be based on the compliance concerns and not the outcomes. For the reasons listed above, it does not 
seem feasible to continue to enrol patients in this study with the same high standard this study was praised for in the 
pre-COVID period. The reduced compliance and paramedic service issues related to the COVID-19 pandemic are likely to 
disproportionately impact the intervention arms, biasing the results towards the null. While there is a concern of the 
trial being under powered by stopping early, it seems unlikely that continued enrolment with reduced compliance would 
help to rectify this concern. The DSMB also discussed the option of pausing the trial again and restarting once COVID-19 
settles down and paramedic staffing issues have resolved, but this does not seem feasible.  
 
The exception to stopping the trial would be the Ottawa Paramedic Service. The DSMB believe all attempts should be 
made to allow this service to continue in the current study arm until they have completed this arm (May 2022) to meet 
the minimum cross over requirements consistent with the trial protocol.  
 
Lastly, the DSMB suggested the PI and the Steering Committee consider altering the patient population analyzed for the 
primary outcome from the a priori intention-to-treat population to a per-protocol population, which is most likely to 
benefit from the intervention. This may eliminate some of the noise that may have entered into the trial during COVID. 
 
Respectfully submitted, 
 
 
 
Benjamin Abella, MD MPhil FACEP 
Professor and Vice Chair for Research 
Department of Emergency Medicine 
Director, Center for Resuscitation Science 
 
 
Jim Christenson MD FRCPC 
Professor, University of British Columbia,  
Department of Emergency Medicine 
Executive Medical Director, BC Emergency Medicine Network 
Co-Director, BC Resuscitation Research Collaborative 
 
 
 
 
Gerald Lebovic, PhD 
Investigator, AHRC, Unity Health Toronto 
Assistant Professor, IHPME, University of Toronto