Study to Actively Warm Trauma Patients-2 (STAYWARM-2): A Pilot Feasibility Trial of Chemical Versus Passive Warming Blankets in Massively Bleeding Patients
Phase: NA
Conditions: Trauma Injury, Hypothermia, Massive Hemorrhage
Sponsor: Sunnybrook Health Sciences Centre

STAYWARM2 (Version 2.5, 2023-08-21) Page 1 
 
 
 
 
 
 
CONFIDENTIAL DOCUMENT 
 
Clinical Trial Protocol 
 
Title:  
STudy to ActivelY WARM Trauma Patients – 2 (STAYWARM-2): A pilot feasibility 
trial of chemical versus passive warming blankets in massively bleeding patients 
 
Protocol Number:  
v2.5 2023-08-21 
 
 
Principal 
Investigator/ 
Institution: 
Luis Da Luz, MD MSc, Tory Trauma Program, Sunnybrook Health Sciences Centre  
Lowyl Notario, MSc, Integrated Community Program & Tory Trauma Program, Sunnybrook 
Health Sciences Centre 
Co-
Applicant(s)/Ins
titution(s): 
Amie Malkin, MSc, Sunnybrook Research Institute 
Omar Hajjaj BSc, Sunnybrook Research Institute 
Rachel Strauss MPH, Sunnybrook Research Institute 
Jeannie Callum, MD, Hematology, Kingston Health Sciences Centre 
Pablo Perez D’Empaire, Sunnybrook Health Sciences Centre 
Bourke Tillman MD PhD(c), Tory Trauma Program, Sunnybrook Health Sciences Centre 
Dylan Pannell MD PhD, Tory Trauma Program, Sunnybrook Health Sciences Centre 
Corey Freedman, MHS, Tory Trauma Program, Sunnybrook Health Sciences Centre 
Avery Nathens, MD PhD, Tory Trauma Program, Sunnybrook Health Sciences Centre 
Leah Kainer, BSc BScN, Integrated Community Program & Tory Trauma Program, Sunnybrook 
Health Sciences Centre 
Beth Linseman, BScN, Tory Trauma Program, Sunnybrook Health Sciences Centre 
Michelle Wong, BScN, OR and Related Services, Sunnybrook Health Sciences Centre 
Michael Lewis, Tory Trauma Program, Sunnybrook Health Sciences Centre 
Winny Li MD MSc, Tory Trauma Program, Sunnybrook Health Sciences Centre 
Yulia Lin MD, Precision Diagnostics and Therapeutics Program, Sunnybrook Health Sciences 
Centre 
Funding Agency 
Sunnybrook Practice Based Research and Innovation (PBRI) 
Investigational 
Product 
ReadyHeat Blanket 

STAYWARM2 (Version 2.5, 2023-08-21) Page 2 
 
PROTOCOL SIGNATURE PAGE 
I have read this protocol in its entirety and its appendices. I agree to comply with the requirements of 
the study protocol and procedures for data recording/reporting and acknowledge my responsibility for 
the well-being of each research participant, and to ensure that all persons involved in study activities are 
adequately informed about the protocol, the investigational product, and their trial-related duties.  The 
signature below constitutes the agreement to conduct this study in accordance with the REB approved 
protocol, GCP and applicable regulatory requirements, including confidentiality, ethical guidelines and 
regulations regarding the conduct of research in humans. 
 
Qualified Investigator: 
Name: 
(Print) 
Luis Da Luz 
Title & Institution:  
(Print) 
Principal Investigator, Sunnybrook Health Sciences 
Centre 
 
Signature: 
 
Date of signature: 
(yyyy-mmm-dd) 
 
 
 
 
 
 
 
 
 

STAYWARM2 (Version 2.5, 2023-08-21) Page 3 
 
TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE PAGE .............................................................................................................2 
TABLE OF CONTENTS ..........................................................................................................................3 
LIST OF ABBREVIATIONS .....................................................................................................................5 
PROTOCOL SUMMARY .......................................................................................................................6 
1.0 
KEY ROLES AND CONTACT INFORMATION ...............................................................................9 
2.1  
Background ....................................................................................................................... 11 
2.1.1  Hypothermia and Mortality in Trauma ............................................................................. 11 
2.1.2 
Conventional re-warming strategies for in-hospital patients ........................................... 11 
2.1.3 
Chemical warming blankets .............................................................................................. 11 
2.2 
Current Proposal and Rationale ........................................................................................ 11 
2.3 
Study Impact and Benefit ................................................................................................. 12 
3.0 
OBJECTIVES AND SCIENTIFIC AIMS ........................................................................................ 12 
3.1  
Study Objectives ............................................................................................................... 12 
3.2  
Primary feasibility outcome:                                                              ...................................... 12 
1 - Feasibility of enrolling the 74 patients over a span of two years. ............................................ 12 
3.3   
 Secondary Feasibility Outcomes ...................................................................................... 12 
2- Feasibility of applying and keeping the 2 blankets in the trauma bay ...................................... 12 
3- Feasibility of keeping the 2 blankets in the CT scanner suite .................................................... 12 
4- Feasibility of keeping the 2 blankets in the ED .......................................................................... 12 
5- Feasibility of keeping at least one of the blanket in the OR or IR suite (one can be removed for 
procedures and re-applied at the end of the intervention   ............................................. 12 
6- Feasibility of keeping the 2 blankets in PACU (for example one blanket is removed in the OR 
and reapplied at the end of the procedures and kept in PACU before the patient is 
transferred to the ICU) ...................................................................................................... 12 
7- Feasibility of keeping the 2 blankets in the ICU up to 8 hours of until patient achieves 37.5 
degrees Celsius. ................................................................................................................ 12 
 8- Reasons why the blanket was not maintained at each of the next phase of care (CT scanner 
suite, IR suite, OR, ED, ICU)      .......................................................................................... 12 
4.0 
HYPOTHESES ..................................................................................................................... 13 
5.0 
STUDY METHODS ................................................................................................................. 13 
5.1 
Study Design ..................................................................................................................... 13 
5.2 
Study Population ............................................................................................................... 14 
5.2.1  Inclusion Criteria ............................................................................................................... 14 
5.2.2  Exclusion Criteria .............................................................................................................. 14 
5.3 
Study Activities.................................................................................................................. 14 
5.3.1  Patient screening, recruitment, and enrolment ............................................................... 14 
5.3.2  Randomization and stratification ..................................................................................... 15 
5.3.3  Interventions ..................................................................................................................... 15 
5.3.3.1  Investigational Products ................................................................................................... 16 
5.3.3.2  Packaging .......................................................................................................................... 16 
5.3.3.3 Treatment Assignment Procedures .................................................................................. 16 
5.3.3.4 Control arm ....................................................................................................................... 17 
5.3.3.5 Intervention arm ............................................................................................................... 17 
5.3.5.2  Storage and Stability ......................................................................................................... 17 
5.3.5.3  Dispensing of Investigational Product .............................................................................. 17 
5.3.5.4  Return and Destruction of Investigational Product .......................................................... 17 

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5.4 
Study Visits and Assessments ........................................................................................... 17 
5.4.1  Study Visits ........................................................................................................................ 18 
5.4.1.1  Visit 1 ................................................................................................................................. 18 
5.4.1.2  Visit 2 ................................................................................................................................. 18 
5.4.1.3   Visit 3 ................................................................................................................................ 19 
5.6  
Protocol Deviations ........................................................................................................... 19 
6.1 
Primary outcome assessment ........................................................................................... 19 
7.2 
Final Analysis Plan ............................................................................................................. 20 
8.1 
Definitions ......................................................................................................................... 21 
8.1.1 
Adverse Event ................................................................................................................... 21 
8.1.2 
Expected adverse events with Ready-Heat® blankets ...................................................... 21 
8.1.3  Unexpected Adverse Event ............................................................................................... 21 
8.1.5 
Serious Adverse Event (SAE) ............................................................................................. 21 
8.2 
Assessment of an Adverse Event ...................................................................................... 22 
8.2.1 
Relationship (Causality/Relatedness) ............................................................................... 22 
8.2.2 
Expectedness .................................................................................................................... 22 
8.2.3 
Seriousness ....................................................................................................................... 22 
8.2.4 
Severity ............................................................................................................................. 22 
8.2.5 
Adverse Event Recording .................................................................................................. 22 
8.3 
Procedures for Reporting a Serious Adverse Event and Unanticipated Events ............... 23 
8.3.1 
Investigator reporting: Notifying the REB ......................................................................... 23 
8.3.2 
Investigator reporting: Notifying the Sponsor .................................................................. 23 
8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada ................................................. 23 
8.3.4 
Sponsor Reporting of SUADRs: Notifying Sites ................................................................. 23 
8.3.5 
Reporting and Entry Timelines.......................................................................................... 23 
9.0 
Early Termination and Reasons for Withdrawal ............................................................... 24 
9.1 
Data Collection and Follow-up for Withdrawn Participants ............................................. 24 
10.0 
ETHICAL ISSUES .................................................................................................................... 24 
10.1 
Ethical conduct and ethical issues .................................................................................... 24 
10.2 
Informed Consent ............................................................................................................. 24 
11.0 
STUDY ADMINISTRATION ..................................................................................................... 25 
11.1  
Arrangements for day-to-day management of the trial ................................................... 25 
11.2 
Quality Assurance ............................................................................................................. 25 
13.0 
DATA HANDLING AND RECORD KEEPING .............................................................................. 26 
13.1 
Confidentiality ................................................................................................................... 26 
13.2 
Source Documents ............................................................................................................ 26 
13.3 
Data Management Responsibilities .................................................................................. 27 
13.4 
Data Capture ..................................................................................................................... 27 
13.4.1 Case Report Forms ............................................................................................................ 27 
13.5 
Records Retention ............................................................................................................ 27 
13.6 
Clinical Trial Registration .................................................................................................. 27 
14.0 References ............................................................................................................................... 28 
 
 

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LIST OF ABBREVIATIONS 
The following abbreviations describe terms, documents and study personnel used in the conduct of this 
study protocol. 
AE 
Adverse Event 
CTCAE 
Common Terminology Criteria for Adverse Events 
CRF 
Case Report Forms 
DSMB 
Data And Safety Monitoring Board 
ED 
Emergency Department 
FAWB 
Forced Air Warming Blanket 
GCP 
Good Clinical Practice Guidelines 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
INR 
International Normalized Ratio 
MHP 
Mass Hemorrhage Protocol 
MRP 
Most Responsible Provider 
OR 
Operating Room 
PHI 
Personal Health Information  
PHIPA 
Personal Health Information Protection Act Of 2004 
RCT 
Randomized Control Trial 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SHSC 
Sunnybrook Health Sciences Center 
SUADR 
Serious Unexpected Adverse Drug Reactions 
TDL 
Task Delegation Log 
 
 
 

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PROTOCOL SUMMARY 
PRINCIPAL 
INVESTIGATOR 
Luis Da Luz MSc MD 
PROTOCOL TITLE 
STudy to ActivelY WARM Trauma Patients – 2 (STAYWARM-2): A pilot 
feasibility trial of chemical versus passive warming blankets in massively 
bleeding patients 
PROTOCOL NUMBER 
 
PHASE 
I 
INVESTIGATIONAL 
PRODUCT AND 
PLANNED USE 
To evaluate the (1) Feasibility of the Ready-Heat® blanket to increase 
temperature by at least 1⁰C at eight hours from arrival to the trauma bay 
in severely injured trauma patients to whom a massive hemorrhage 
protocol is activated; (2) Feasibility of adherence to the application of the 
Ready-Heat® blanket in patients enrolled in the intervention arm 
throughout the trauma bay resuscitation; (3) Feasibility of adherence to 
body temperature measurement throughout the different phases of care 
(i.e.: TB, ED, CT scanner suite, OR, IR suite, ICU) ; (4) Feasibility of 
maintenance of at least one Ready-Heat® blanket applied throughout the 
different phases of care (i.e.: TB, ED, CT scanner suite, OR, IR suite, ICU) 
STUDY DESIGN 
A phase I, single center, pilot, feasibility, prospective, open-label RCT 
DURATION OF FOLLOW-
UP 
From first application of study product to final study visit = 8 hours 
TREATMENT 
ALLOCATIONS 
Experimental arm: 2 Ready-Heat® 4-panel blankets 
Control arm: standard of care (use of warmed blankets and forced air 
warmed blanket [FAWB]) 
PATIENT POPULATION 
Adults (≥ 16 years old) patients presenting  to Sunnybrook Health 
Sciences Centre (SHSC) as trauma team activations to whom a massive 
hemorrhage protocol is activated  
SETTING 
Single academic Level 1 trauma center 
PLANNED SAMPLE SIZE 
74 patients (37 on each study arm) 
The anticipated duration for this study’s recruitment period is 24 months. 
PATIENT 
INCLUSION/EXCLUSION 
Inclusion criteria: 
● Age ≥ 16 years  
● Requires Massive Hemorrhage Protocol activation (see Table 1) in 
the trauma bay 
● Admission to the trauma bay between 08:00-20:00hrs on 
weekdays 
Exclusion criteria:  
● 
Transferred from another healthcare facility  
● 
Death in the trauma bay prior to randomization 
● 
Arrival to trauma bay with ongoing CPR 
● Patients with penetrating head injury with Glasgow Coma Scale 
of 3 AND loss of brain matter through the wound  

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RANDOMIZATION  
Web-based computerized allocation sequence generated by independent 
statistician 
STUDY OUTCOMES 
Primary outcomes (feasibility):  
(1) Feasibility of performing a pilot pragmatic randomized controlled 
trial (RCT) to evaluate effectiveness of the Ready-Heat® blanket 
to increase temperature by at least 1⁰C at eight hours from time 
of blanket placement in the trauma bay in severely injured 
trauma patients to whom a massive hemorrhage protocol is 
activated 
(2) Feasibility of adherence to the application of the Ready-Heat® 
blanket in patients enrolled in the intervention arm throughout 
the trauma bay resuscitation;  
(3) Feasibility of adherence to body temperature measurement 
throughout the different phases of care (i.e.: TB, ED, CT scanner 
suite, OR, IR suite, ICU) within the first eight hours of blanket 
application. 
(4) Feasibility of maintenance of at least one blanket applied 
throughout the different phases of care (i.e.: TB, ED, CT scanner 
suite, OR, IR suite, ICU) 
Secondary Measures:  
(1) Concurrent warming strategies used (i.e.: fluid warmers, FAWB, etc.) 
within the first eight hours of blanket application  in conjunction with 
or replacement of Ready-Heat® chemical heating blanket;  
(2) Number of units of blood products (plasma, red blood cells, platelets, 
fibrinogen concentrate) transfused within 24 hours of trauma bay 
arrival;  
(3) Coagulation (platelet count, INR, fibrinogen) and perfusion 
parameters (pH, base deficit, serum lactate) measured on arrival, and 
at the next time points collected as per clinician discretion; 
(4) Hemoglobin level measured on arrival, and at the next time points 
collected as per clinician discretion. 
Secondary Safety Measures:  
(1) Number of times blanket is placed directly on the skin;  
(2) Skin redness and/or burns. 
 STATISTICAL ANALYSIS 
The results of this pilot trial will be used to assess the feasibility and 
inform the design of a definitive trial. We will present point estimates of 
feasibility outcomes with 95% confidence intervals.   
 
Demographic and clinical characteristics will be summarized in total and 
by two arms using mean, standard deviation (SD), median (interquartiles) 
and range for continuous variables, and percentages for categorical 

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variables. The Wilcoxon rank-sum test, Chi-square test or Fisher exact 
test will be applied for comparing continuous or categorical variables 
between two arms, as appropriate. The proportion (and 95% confidence 
intervals) of patients with an increased temperature by at least 1⁰C at 8 
hours from arrival to the trauma bay will be calculated and compared 
between two arms using Chi-square or Fisher exact test as appropriate. 
Linear mixed model will be used to search for significant time trends in 
two arms on the hourly body temperature measurements within the first 
eight hours of blanket application. To compare coagulation and perfusion 
parameters measured on arrival and over the first 8 hours, between two 
arms, linear mixed model will also be performed for the repeated 
measurements. P-value < 0.05 will be considered statistically significant. 
 
 
 
 

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1.0 
KEY ROLES AND CONTACT INFORMATION 
Regulatory Sponsor: 
Sunnybrook Research Institute 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
Principal Investigator:   
Luis Da Luz  
Academic Research Organization: 
Sunnybrook Health Sciences Centre 
H115 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
  
 
 
 
 
 
 
 

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Figure 1 Pilot Trial Schema 
 

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2.0 
INTRODUCTION 
This study document is the protocol for a research study involving human participants. This study is to 
be conducted according to Canadian and international standards, and in compliance with the 
International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Participants, 
as well as applicable regulatory and institutional requirements and research policies.  
2.1  
Background 
 
2.1.1  Hypothermia and Mortality in Trauma 
Massively bleeding hypothermic trauma patients have 2.7-fold higher odds of mortality in the first 24 
hours of hospital admission, increased length of stay, and increased need for transfusion.1-7 Hypothermia 
is independently associated with mortality in traumatically injured patients due to its negative 
physiologic effects on hemostasis, cardiorespiratory and renal function.8 Despite this, a retrospective 
quality review at our institution found that approximately 30% of trauma patients will have hypothermia 
despite the treatment provided.9  
2.1.2 
Conventional re-warming strategies for in-hospital patients 
The most common first-line active surface rewarming strategies involve the use of a combination of 
forced air warming blankets (FAWB), and warmed blankets. Unfortunately, these strategies are 
cumbersome and ineffective,10 particularly during the initial hours of admission where multiple transfers 
occur.11 FAWB requires continuous power, which limits portability. In addition, thermally warmed 
blankets require interchange at frequent intervals. 
 
2.1.3 
Chemical warming blankets 
Prehospital, military, and intraoperative studies have suggested chemical warming blankets as a 
pragmatic strategy.8, 12 A recent pilot study (manuscript under review) at our institution demonstrated 
feasibility of using the Ready-Heat® (TechTrade LLC, Orlando, FL, USA) chemical heating blanket in the 
initial phases of hospital care in bleeding trauma patients requiring a mass hemorrhage protocol (MHP). 
In this pilot study, the blanket was applied within a median time of 23 minutes. These chemical blankets 
generate an oxygen-activated exothermic effect in 8-15 minutes, providing warmth over 8 hours (up to 
40 degrees Celsius). These blankets carry the advantage of portability without electricity requirement. 
Furthermore, in conjunction with other strategies, they provide a superior surface rewarming strategy 
for patients at high risk of developing hypothermia. STAYWARM-2 will be the first randomized 
controlled trial performed in-hospital to evaluate a self-warming blanket to address hypothermia in 
massively bleeding trauma patients within the initial hours post hospital arrival.  
2.2 
Current Proposal and Rationale 
We propose a phase I, single centre, pilot, feasibility, prospective, open-label (with blinded outcome 
assessors) RCT. STAYWARM-2 aims to examine the impact of the Ready-Heat® warming blanket on the 
temperature of injured patients receiving a massive transfusion. Current warming strategies increase 
the logistical difficulty of transferring patients (which is frequent during the initial hours of trauma care) 
or must be changed at frequent intervals. Chemical blankets that provide continuous heat address these 
two challenges. This has potential to reduce the overall workload of direct care clinicians, freeing them 
for other patient care duties. Additionally, the intervention may achieve enhanced thermoregulation 
compared to the current strategy (as demonstrated in the prehospital literature), which can provide 
better care and better patient comfort (hypothermia causes patient discomfort15) and avoid the clinical 

STAYWARM2 (Version 2.5, 2023-08-21) Page 12 
 
complications related to hypothermia. Findings from this preliminary study will provide data for a future 
CIHR or military grant to launch a larger randomized controlled trial in the prehospital/in-hospital 
trauma settings, to improve the care of patients at risk of developing hypothermia. 
 
2.3 
Study Impact and Benefit 
The study will provide knowledge on feasibility and efficacy of using the chemical blankets during these 
initial hours of hospital care to further support better management of hypothermia. The new evidence 
generated may be used to inform larger studies (e.g., multicenter trials) in the same setting or in other 
acute care settings, such as the emergency department and in burn units. Finally, the study will 
contribute evidence to be applied in studies in the civilian prehospital setting (e.g., land or air 
Emergency Medical Services) as this setting lacks resources to adequately prevent or treat hypothermia. 
3.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
3.1  
Study Objectives 
1 - To investigate the feasibility of using the Ready-Heat® chemical heating blanket to increase the body 
temperature by at least 1⁰C in severely injured trauma patients with activation of a massive hemorrhage 
protocol (MHP), compared to conventional in-hospital surface rewarming methods (e.g., warmed 
blankets and/or FAWB) for the first eight hours of blanket application on the patient. 
3.2  
Primary feasibility outcome:                                                              
1 - Feasibility of enrolling the 74 patients over a span of two years. 
 
3.3   
 Secondary Feasibility Outcomes 
2- Feasibility of applying and keeping the 2 blankets in the trauma bay 
3- Feasibility of keeping the 2 blankets in the CT scanner suite 
4- Feasibility of keeping the 2 blankets in the ED 
5- Feasibility of keeping at least one of the blanket in the OR or IR suite (one can be removed for 
procedures and re-applied at the end of the intervention   
6- Feasibility of keeping the 2 blankets in PACU (for example one blanket is removed in the OR and 
reapplied at the end of the procedures and kept in PACU before the patient is transferred to the ICU) 
7- Feasibility of keeping the 2 blankets in the ICU up to 8 hours of until patient achieves 37.5 degrees 
Celsius.  
 8- Reasons why the blanket was not maintained at each of the next phase of care (CT scanner suite, IR 
suite, OR, ED, ICU)      
 
3.4  
 Efficacy Outcomes              
9- Increase of temperature from admission up to 8 hours of 1 degree Celsius  
 
3.5 
 Clinical Outcomes 
10- Proportion of adherence to body temperature measurement throughout different phases of care 
(i.e.: ED, CT scanner suite, OR, IR suite, ICU) 
11 -Use of concurrent warming strategies(i.e. fluid warmers, FAWB, etc.) within the first eight hours of 
blanket application in conjunction with, or replacement of, the Ready-Heat® chemical heating blanket 

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12- Number of units of blood products (red blood cells, plasma, platelets, and fibrinogen concentrate) 
transfused within 24 hours post arrival to the trauma bay 
13- Coagulation (platelet count, INR, fibrinogen level) and perfusion parameters (pH, base deficit, serum 
lactate) measured on arrival, and at the next time points collected as per clinician discretion 
14- Hemoglobin level measured on arrival, and at the next time points collected as per clinician 
discretion 
 
3.6 
Safety Outcomes: 
15 - Number of times blanket is placed directly on the patient skin 
16 - Number of times patients developed redness and/or skin burns 
      
4.0 
HYPOTHESES 
We hypothesize that the use of Ready-Heat® blanket will be feasible in this pilot RCT (according to the 
primary outcome measure) in severely injured trauma patients to whom a MHP is activated while in the 
trauma bay.  
5.0 
STUDY METHODS  
5.1 
Study Design 
This will be a pilot, feasibility, prospective, open-label (with blinded outcome assessors) RCT to evaluate 
the feasibility of using two Ready-Heat® half blankets to increase temperature by at least 1⁰C at eight 
hours from arrival to the trauma bay, in severely injured bleeding trauma patients where a MHP is 
activated. A total of 74 participants will be randomized in a 1:1 ratio, to receive the intervention - two 
Ready-Heat® 4-panel half blankets applied indirectly (as per manufacturer’s directions) with two flannel 
blankets placed under them, or the control - two warmed blankets (current standard of care) only. The 
study will take place at Sunnybrook Health Sciences Centre (SHSC). The patient will be screened in the 
trauma bay and enrolled by the TTL. Upon confirming eligibility for the study, a study research 
coordinator/assistant will randomize using a web-based randomization sequence built into REDCap. If 
the patient is randomized to receive the intervention, two Ready-Heat® blankets will be activated by 
opening the seal on the packaging and affixed to the blood product cooler to be given to the trauma 
team in the trauma bay. As this is an open-label trial, only the statistician will remain blinded during the 
final analysis. Enrollment will occur during weekdays between 0800-2000hrs with the aim of assessing 
feasibility of using the blanket when study coordinators are not always available to reinforce 
temperature monitoring, proper blanket placement, and compliance with keeping the blanket on the 
patient over the intervention period. Subjects in the control arm will have two warmed blankets 
obtained from a blanket warmer appliance in the trauma bay and will be applied on the patient by the 
trauma team. Temporary removal of the blanket and partial exposure of the patient may be necessary 
to facilitate clinical procedures. In the intervention arm, two separate four-panel blankets will be used to 
allow for temporary exposure for clinical procedures while still maintaining coverage for the rest of the 
body (i.e., 1 four-panel blanket can be applied to the torso while a fractured femur is reduced). 
Clinicians will be educated to keep the intervention warmer on the patient until 8 hours from time of 
blanket application. If there is a need to remove the intervention prior to the completion of 8 hours, the 
clinical team will document the reason (e.g., adverse reaction, interference with procedure, etc.). In this 
case, clinical teams will be educated to transition to the current standard of care (warmed blankets or 

STAYWARM2 (Version 2.5, 2023-08-21) Page 14 
 
FAWB). If at least one of the two blankets remained until 8 hours post blanket application, clinical teams 
will be instructed to remove them and apply the current standard of care.  
 
 
5.2 
Study Population 
Patients included in this study are severely injured adult trauma patients, admitted to the trauma bay at 
SHSC as trauma team activations (TTA), where a MHP is activated by the TTL or delegate, within the 
period the patient is assessed and managed in the trauma bay.  
 
5.2.1  Inclusion Criteria 
1. Age ≥ 16 years 
2. MHP activated in the trauma bay (see Table 1) 
3. Between 08:00-20:00hrs on weekdays 
 
Table 1 MHP Activation Criteria 
MHP activation criteria 
● Life-threatening bleeding situation requiring mobilization of blood bank, laboratory and clinical 
resources. 
● Anticipated need for at least 4 units of red blood cells immediately and component therapy 
(platelets, plasma, and fibrinogen). 
 
5.2.2  Exclusion Criteria 
1. Transferred from another healthcare facility 
2. Death in the trauma bay prior to randomization 
3. Arrival to trauma bay with ongoing CPR 
4. Patients with penetrating head injury with Glasgow Coma Scale of 3 AND loss of brain matter 
through the wound  
5.3 
Study Activities 
 
5.3.1  Patient screening, recruitment, and enrolment 
 
Recruitment will occur in the trauma bay during weekdays between 08:00-20:00hrs by Staff Trauma 
Team Leaders, with experience in QI initiatives and enrollment of severely bleeding trauma patients in 
clinical trials. Due to the high acuity of the patient condition, who usually needs multiple emergent 
interventions, consent will be obtained retrospectively (delayed consenting process). In addition, by 
seeking the patient’s consent for enrollment during a tenuous point in their care, there is a potential of 
introducing bias, or concerns about coercion into accepting any care related to the initial resuscitation. 
As soon as possible, following the randomization and inclusion, the patient (if able to comprehend) or 
substitute decision maker (SDM), will be approached about the study. They will have their specific 
warming intervention explained, and will have, at that point, the right to request that their data are 
withdrawn from the study.  

STAYWARM2 (Version 2.5, 2023-08-21) Page 15 
 
Study personnel will contact the MRP for permission to approach the patient or ask that they introduce 
the study to the patient. With permission to enter the patient’s circle of care, the research coordinator 
will then approach patients who were randomized and included in the study. The research coordinator 
will introduce the trial, confirm eligibility and conduct the informed consent discussion. This discussion 
will include the rationale for the study, the anticipated risks and benefits of participation, and their 
rights as a study participant (including withdrawal at any time). Capable participants will be offered an 
opportunity to ask questions and consult with their family and/or their physician before making a 
decision to continue  in the study. If the patient is deemed incapable of providing informed consent for 
the study, study personnel will approach the SDM and go over the same process to obtain the consent. 
Patients or SDM will be given an Informed Consent Form to be signed, at this point.  
One signed copy of the informed consent will be placed in the participant’s medical record, another 
copy given to the participant and the original kept in the study file with the research coordinator. If the 
participant does not wish to participate, the reason for declining will be documented.  
Patients will be randomized upon activation of the MHP according to a computer-generated allocation 
sequence using RedCap. If the patient is randomized to receive the intervention, the study research 
coordinator/assistant  will activate the two Ready-Heat® blankets by opening the seal on the packaging. 
A trauma team member will place the blankets on the patient. As this is an open-label trial, only the 
statistician will remain blinded during the final analysis. Enrollment will occur 08:00-20:00hrs on 
weekdays with the aim of assessing feasibility of using the blanket when study coordinators are not 
always available to reinforce temperature monitoring, proper blanket placement, and compliance with 
keeping the blanket on the patient over the intervention period.  
Data will be collected by the research assistants and medical students as the patients are enrolled in the 
trial during weekdays 8 am to 8 pm. REDCap will be used to register the collected variables. 
Research Ethics Board (REB) approval of the protocol and the informed consent form will be obtained. A 
recruitment log of eligible and ineligible patients as well as reasons for non-consent will be kept.  We 
anticipate that this study will take 24 months to complete.  
 
5.3.2  Randomization and stratification 
The patient will be screened in the trauma bay and randomized by the study research 
coordinator/assistant. Patients will be allocated to a treatment group using a secure, concealed, 
computer-generated, web-based (created on REDCap) randomization sequence. Only a non-study 
biostatistician will have access to the randomization sequence within the treatment allocation schedule 
(the study biostatistician will be blinded to treatment allocation for any interim analyses performed). A 
1:1 randomization ratio will be used.  
5.3.3  Interventions 
A schematic representation of the protocol summary is shown in Figure 1.  
 

STAYWARM2 (Version 2.5, 2023-08-21) Page 16 
 
5.3.3.1  Investigational Products 
Ready-Heat® is manufactured by TechTrade LLC13. The manufacturer has confirmed the authorized use 
of this product in Canada, which was a requirement for STAYWARM-1. Further, this product is now 
currently distributed by Canadian vendors for the Canadian marketplace. 
In the attached document from the manufacturer, this device is considered a “Class I medical device”. As 
such, there is no requirement to obtain an investigational testing authorization (ITA) 
 
Adobe Acrobat 
Document
 
The Ready-Heat® product comes in a variety of configurations. The 4-panel blanket is a single-use 
disposable blanket that uses proprietary air-activated warming panels that provide slow continuous and 
consistent warming. Weighing 794 grams, and dimensions of 86cm/122cm, each blanket is stored in an 
oxygen-free poly-bag. Upon opening the package, it gradually heats up to 40°C over a period of 15-20 
minutes, and after reaching peak temperature will remain warm for 10 hours. 
5.3.3.2  Packaging 
Two individually wrapped 4-panel Ready-Heat® blankets will be issued to patients enrolled in the 
intervention arm. The two individual packages, containing one blanket each, will be opened by the study 
research coordinator/assistant upon patient randomization to initiate the air-activated exothermic 
process. 
 
5.3.3.3 Treatment Assignment Procedures 
Once enrolled, patients will be randomized to either the control or intervention arm through the 
randomization procedure described in section 5.3.2.   
 

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5.3.3.4 Control arm 
Patients randomized to the control arm will receive conventional rewarming strategies such as FAWB 
and 2 warmed blankets.  
 
5.3.3.5 Intervention arm 
If the patient is randomized to receive the intervention, the two Ready-Heat® blankets will be activated 
by opening the seal on the packaging and given to the trauma team in the trauma bay. As this is an 
open-label trial, only the statistician will remain blinded during the final analysis. Subjects in the control 
arm will have a warmed blanket obtained from a blanket warmer appliance in the trauma bay. 
Temporary removal of the blanket and partial exposure of the patient may be necessary to facilitate 
clinical procedures. In the intervention arm, two separate Ready-Heat four-panel blankets will be used 
to allow for temporary exposure for clinical procedures while still maintaining coverage for the rest of 
the body. Clinicians will be educated to keep the interventional products until the 8 hours post blanket 
application are completed. If an interventional product becomes soiled before the prescribed 8 hour 
period, a replacement product may be dispensed by contacting the Blood Bank. If there is a need to 
remove the intervention prior to the completion of 8 hours, the clinical team will document the reason 
(e.g., adverse reaction, interference with procedure, etc.). In this case, clinical teams will be educated to 
transition to the current standard of care (warmed blankets, or FAWB). If at least one of the two 
blankets remained until 8 hours post, clinical teams will be instructed to remove them and apply the 
current standard of care.  
 
5.3.5.2  Storage and Stability 
As per manufacturer’s Instructions for Use (IFU) document, the Ready-Heat® blanket may be stored in 
its air-tight protective packaging until ready for use. Upon removing the outer packing, the product will 
reach operating temperature within 15-20 minutes and will remain functional for up to 10 hours. After 
use, the blanket can be disposed of with regular waste as there are no harmful ingredients. The Blood 
Bank will maintain a stock of the Ready-Heat® blankets and stored at room temperature. The study 
product will be dispensed to those randomized to the intervention arm along with the first MHP pack of 
blood products. 
    
5.3.5.3  Dispensing of Investigational Product 
The Ready-Heat® blanket will be provided to randomized patients by  Study research 
coordinator/assistant.An instruction sheet will be provided specifying how to apply the Ready-Heat 
blanket while avoiding direct skin contact. Instructions will be provided to keep the interventional 
products until the 8 hours post blanket application is completed.  
5.3.5.4  Return and Destruction of Investigational Product 
Trauma Team members will be made aware of their responsibility to return any unused investigational 
products in the event the resuscitation is ended before applying the product (i.e.: patient death, 
termination of resuscitation). As per manufacturer’s Instructions for Use (IFU) document, the Ready-
Heat® blanket may be disposed of with regular waste as there are no harmful ingredients. 
5.4 
Study Visits and Assessments   
Study visits will be conducted by research assistants during weekdays to collect data 

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5.4.1  Study Visits 
The following information will be collected during study visits either in person or remotely reviewing 
electronic health records. During weekdays, 8 am to 8 pm, the research assistant will be following the 
patient across the different phases/locations of care and will be collecting data at the same time. 
Research assistants will access all documented data on the next weekday. Visits and specific data 
collection are detailed as follows:  
 
5.4.1.1  Visit 1   
On admission to the trauma bay: Demographics, injury characteristics and surgical management:  
1. Date of injury 
2. Time of injury 
3. Sex 
4. Age 
5. Types of surgical procedures performed in the first 8 hours following hospital arrival 
6. Date of arrival  
7. Time of arrival 
8. Time of randomization 
9. Name of attending TTL and sub-TTL (if applicable) 
10. Initial temperature recorded  
11. Was the blanket placed on the patient? Yes/No 
12. Time that the blanket was placed on the patient, if registered  
13. Reason why blanket was not applied 
14. Blanket applied directly to the patient`s skin? Yes/No  
15. Use of fluid warmers 
16. Use of FAWB 
5.4.1.2  Visit 2  
Within the first eight hours of blanket application:  
1. Location of the patient  
2. Is the blanket kept on the patient? (Yes/No) 
3. If not, what was the reason it was removed? 
4. Temperature recorded, hourly (Yes/No)   
5. If yes, the temperature recorded 
6. Type of temperature measurment 
7. Blanket applied directly to patient`s skin? Yes/No  
8. Use of FAWB  
9. Use of fluid warmers 
At discretion of the clinician, within the first eight hours of blanket application:  
10. Coagulation (platelet count, INR, fibrinogen) 
11. Perfusion parameters (pH, base deficit, serum lactate)  
12. Hemoglobin 

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13. Number of units of red blood cells, plasma, platelets, and fibrinogen concentrate administered 
within the first 8 hours 
5.4.1.3   Visit 3  
At 24 hours post blanket application: 
1. Number of units of red blood cells, plasma, platelets, and fibrinogen concentrate administered 
within the first 24 hours 
2. Type of injury (blunt/penetrating) 
3. Injury Severity Score (ISS) 
4. Frequency of safety events with skin 
 
 
5.6  
Protocol Deviations 
Planned or unplanned deviations may occur on the part of the participant, the investigator, or study 
research team. In resolution to a deviation, corrective/preventative actions are to be developed and 
implemented in a timely manner to avoid subsequent deviations. Protocol deviations will be 
documented and reported as required and assessed where necessary during analysis. If a control or 
study intervention is noted to not be in use, or key data are missing from the health record, a reason for 
noncompliance will be documented. Based on findings from STAYWARM1, reasons for noncompliance 
are hypothesized to arise from patient condition, and lack of familiarity with the study protocol. Several 
educational initiatives will be developed prior to study commencement for trauma team members, to 
avoid protocol deviations during the study period.   
 
6.0 
CRITERIA FOR OUTCOME ASSESSMENT 
6.1 
Primary outcome assessment 
1. Feasibility of Ready-Heat® blanket to increase temperature by at least 1⁰C at eight hours from 
arrival to the trauma bay in massively bleeding trauma patients. 
If the study intervention is unable to increase body temperature by at least 1⁰C in 80% of 
patients at eight hours from arrival, the study as it is currently designed will not be deemed 
feasible. 
 
2. Feasibility of adherence to the application of the Ready-Heat® blanket in patients enrolled in the 
intervention arm throughout the initial trauma bay resuscitation Failure to apply and maintain 
the Ready-Heat® blanket in more than 20% of patients enrolled in the intervention arm 
throughout the initial trauma bay resuscitation, the study will not be deemed feasible. 
 
3. Feasibility of adherence to body temperature measurement throughout different phases of care 
within first eight hours of blanket application. 
Failure to measure body temperature throughout different phases of care (i.e.: ED, CT, OR, IR, 
ICU) within the first eight hours of blanket application  in more than 20% of enrolled patients, 
the study will not be deemed feasible. 
 
7.0  
STATISTICAL ANALYSIS PLAN 
7.1 
Sample Size and Sample Size Justification 

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For the STAYWARM-2 trial, the sample size calculation was based on a compliance rate of 80% to within 
a 95% confidence interval of +/‒ 10%. The sample size obtained was 58 patients (29 per arm) in total to 
estimate a compliance rate of 80% to within a 95% confidence interval of +/‒ 10%. With an anticipated 
20% dropout rate (i.e., withdrawal of consent, exclusion of eligibility, etc), the sample size will be 
inflated to a total of 74 patients, 37 in each arm. If we assumed a 90% confidence interval of +/‒ 10%, 
then we require a sample size of 48 patients (24 per arm) after considering 20% dropout rate. See the 
following outputs for details: 
Confidence Interval of A Proportion 
 
Numeric Results 
 
C.C. 
N 
P0 
 
Confidence 
Sample 
Baseline 
Precision 
Coefficient 
Size 
Proportion 
0.08000 
0.95323 
90 
0.80000 
0.09000 
0.95130 
69 
0.80000 
0.10000 
0.95529 
57 
0.80000 
 
0.08000 
0.90168 
58 
0.80000 
0.09000 
0.90969 
45 
0.80000 
0.10000 
0.90329 
37 
0.80000 
 
Report Definitions 
Precision is the plus and minus value used to create the confidence interval. 
Confidence Coefficient is probability value associated with the confidence interval. 
N is the size of the sample drawn from the population.  
P0 is the estimated baseline proportion. 
 
Summary Statements 
A sample size of 57 produces a 96% confidence interval equal to the sample proportion plus or 
minus 0.10000 when the estimated proportion is 0.80000. 
 
A sample size of 37 produces a 90% confidence interval equal to the sample proportion plus or 
minus 0.10000 when the estimated proportion is 0.80000. 
 
Given that this pilot feasibility trial, a sample size of 58 total patients was deemed appropriate. After 
considering 20% drop out rate, we will aim to enroll 74 patients to determine the feasibility of the trial 
and to provide more accurate estimates of the numbers required for a definitive trial. The trial will 
proceed until there are 74 enrolled patients and at least 58 patients who complete the trial to 13 weeks.  
 
7.2 
Final Analysis Plan 
 
Demographic and clinical characteristics will be summarized in total and by two arms using mean, SD, 
median (interquartiles) and range for continuous variables, and percentages for categorical variables. 
Wilcoxon rank-sum test, Chi-square test or Fisher exact test will be applied for comparing continuous or 
categorical variables between two arms, as appropriate. To investigate the primary objective on the 
feasibility of using the Ready-Heat® chemical heating blanket, the proportion (and 95% CIs) of patients 
with an increased body temperature by at least 1⁰C at 8 hours from arrival to the trauma bay will be 
calculated and compared between two arms using Chi-square or Fisher exact test as appropriate. Line 
graph (with mean and SD) of body temperature over the first 8 hours of blanket application will be 
plotted for two treatment arms. To search for significant time trends in two arms on the hourly body 

STAYWARM2 (Version 2.5, 2023-08-21) Page 21 
 
temperature measurements within first 8 hours of blanket application, linear mixed effects repeated 
model will be performed with both fixed (time in hours, treatment arms, and arms by time interaction) 
and random (patient) effects. To compare treatment effects on the coagulation parameters (platelet 
count, INR, fibrinogen level), perfusion parameters (pH, base deficit, serum lactate), and hemoglobin 
levels measured on arrival and over the first 8 hours, linear mixed effects repeated model will also be 
performed with both fixed and random effects. Skewness and Kurtosis will be tested on the distribution 
of coagulation, perfusion and hemoglobin parameters. Natural logarithm transformation will be applied 
to normalize the distribution if necessary. Descriptive analysis will be summarized in total and by arms 
for safety measurements (i.e., number of units of blood products transfused, number of times blanket is 
placed directly on patient skin, and number of times patients developed redness and/or skin burns). All 
analyses will be conducted using Statistical Analysis Software (SAS version 9.4, Cary, NC) and R package 
(version 4.3.0). P-value < 0.05 will be considered statistically significant.  
8.0  
ASSESSMENT OF SAFETY  
8.1 
Definitions 
8.1.1 
Adverse Event 
 
An Adverse Event (AE) is defined as any new event that may jeopardize the patient which the study 
investigator physician perceives may be directly related to the enrolment in the pilot study or to the 
assigned arm. Adverse events are not study related if they are related primarily to the underlying 
disease. All AEs are to be documented and assessed for relatedness. If related to the study intervention 
and occurring from baseline up to 24 hours (by the final visit), the AE will be recorded on the eCRF and 
coded as per the most recent edition of the Common Terminology Criteria for Adverse Events (CTCAE).  
8.1.2 
Expected adverse events with Ready-Heat® blankets 
 
Prolonged direct skin contact with the Ready-Heat blanket has been known to cause mild burns. The 
manufacturer specifies the need for careful supervision when used with “the elderly….people with 
sensitive skin and those who can’t feel heat or regulate heat”13. Given that some of the enrolled patients 
may be sedated due to clinical condition, the study products will be applied with the express direction to 
avoid direct skin contact. The recommendation will be made to use a standard blanket as an 
intermediary between the skin and the study product. 
     
8.1.3  Unexpected Adverse Event 
An unexpected adverse event is defined as any adverse event that is not identified in section 8.1.2 or in 
nature, severity or frequency in the current Health Canada Product Monograph.  
8.1.5 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) in the study is defined as: 
a) any event that is fatal or immediately life threatening, permanently disabling, severely 
incapacitating, or requires prolonged inpatient hospitalization, or  
b) any event that may jeopardize the patient and requires medical or surgical intervention to 
prevent one of the outcomes listed above, AND 
c) which the attending physician perceives may be directly related to enrolment in the study, or to 
the assigned arm.   

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SAEs will be considered to be study-related if the event follows a reasonable temporal sequence from 
the study intervention and could readily have been produced by the intervention. Adverse events are 
not study related if they are related primarily to the underlying disease. 
8.2 
Assessment of an Adverse Event 
8.2.1 Relationship (Causality/Relatedness) 
The causality assessment is the determination, according to the investigator’s clinical judgment, of the 
existence of a reasonable possibility that the investigational product (IP) caused or contributed to an 
adverse event.  
If the investigator or delegated sub-investigator is unsure about whether or not the study product 
caused or is related to the event, then the event will be handled as “related” to the study product for 
reporting purposes of the trial. If the causality assessment is "unknown but not related” to the study 
product, this should be clearly documented in the source documents.  
8.2.2 
Expectedness 
Events are classified as unforeseen or unexpected if the nature, severity, or frequency is not consistent 
with the risk information set out in Section 9.1.2 or the Product Monograph (PM) or label.     
8.2.3 
Seriousness 
Events are classified as serious if associated with effects threatening the life or physiological functions of 
a participant.  Refer to the definition for “Serious Adverse Events” in section 9.1.5. 
8.2.4 
Severity 
The term "severe" is often used to describe the intensity (severity) of a specific event (e.g. mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is based on 
participant/event outcome or action criteria usually associated with events that pose a threat to a 
participant's life or functioning. The terms “serious” and “severe” are not synonymous. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
To assess the severity of an adverse event the investigators will use the following: 
● the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)  
8.2.5 
Adverse Event Recording 
Investigations into potential adverse events should be done during each contact with a participant.  
Investigations may be done through specific questioning and, as appropriate, by examination.  
Information on all adverse events should be recorded promptly in the source document, and assessed 
by an investigator in a timely manner allowing sufficient time to meet required reporting timelines for 
SAEs and serious unexpected adverse drug reactions (SUADRs) if needed. Adverse event CRFs should be 
completed using source documents by a delegated research team member in a timely manner/within 15 
days of site awareness. All clearly related signs, symptoms, and abnormal diagnostic procedures should 
be recorded in the source document, though should be grouped under one diagnosis. Each diagnosed 

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adverse event should then be categorized in accordance with the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE).  
The following are not considered AEs and therefore do not require recording:  
● Pre-existing diseases or conditions identified and recorded at screening/baseline unless, at the 
discretion of the investigator, the disease or condition worsens in severity or frequency  
● At the discretion of the investigator, events considered likely manifestations of the underlying 
disease or that commonly occur in the study population independent of study drug exposure 
● Elective medical or surgical procedures. 
8.3 
Procedures for Reporting a Serious Adverse Event and Unanticipated Events 
8.3.1 
Investigator reporting: Notifying the REB 
Serious adverse events and unanticipated events should be recorded and reported to the REB in 
accordance with local reporting requirements and timelines.    
8.3.2 
Investigator reporting: Notifying the Sponsor 
The investigator is responsible for reporting SAEs and SUADRs to the sponsor (Sunnybrook Research 
Institute) in accordance with applicable regulations and reporting requirements and timelines.    
Events that are assessed to be serious and unexpected and related or cannot be ruled out as related to 
the investigational product are considered SUADRs. Reporting for SUADRs should include a description 
of the event in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  The minimum information required includes at least one 
identifiable participant, one identifiable reporter, one serious reaction, and one suspect product.  
Additionally, for SAEs and SUADRS, a Suspect Adverse Reaction Report – CIOMS I Form (Appendix B) 
must be completed by the investigator and forwarded to the Sponsor within 24 hours of site awareness.  
Information on other possible causes of the event, such as concomitant medications and illnesses should 
also be provided as soon as is made available. 
8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada 
The regulatory sponsor is responsible for reporting SUADRs to regulatory authorities in accordance with 
local expedited reporting requirements and timelines. In addition, the Sponsor will complete the ADR 
Expedited Reporting Summary Form and submit this form in conjunction with the completed CIOMS 
Form to the appropriate Health Canada directorate.    
8.3.4 
Sponsor Reporting of SUADRs: Notifying Sites 
The regulatory sponsor is responsible for distributing expedited reports of SUADRs to each investigator 
for submission to local Ethics Committees within 15 days of sponsor awareness. 
8.3.5 
Reporting and Entry Timelines 
 Study investigators will report SAEs to the sponsor within the following timelines:   

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● All deaths and immediately life-threatening events, whether related or unrelated, will be 
recorded and reported to the sponsor within 24 hours of site awareness.  
● Serious adverse events other than death and immediately life-threatening events, 
regardless of relationship, will be reported to the sponsor within 72 hours of site awareness.  
Adverse event information will be entered into the CRF in a timely manner and no later than 15 days 
from the time the investigator becomes aware of the event. 
Serious adverse event information will be entered into the CRF in a timely manner/within 72 hours from 
the time the investigator becomes aware of the event. 
9.0 
Early Termination and Reasons for Withdrawal 
While it is not anticipated to cause discomfort, patients may find that they are not able to continue with 
the study product due to the ongoing heat. Patients are permitted to withdraw consent at any time if 
they desire and will not undergo further trial investigations if they do so. Participants withdrawing from 
the study should be contacted by the study research team requesting a final visit and to follow up with 
any unresolved adverse events. Once withdrawn from the study, no further study procedures or 
evaluations should be performed, or additional study data collected.  However, every effort should be 
made to obtain permission to document the reason for withdrawal and to collect participant outcomes, 
such as survival data up to the protocol-described end of participant follow up period, where possible. 
Any data collected prior to the withdrawal of consent may be retained and used by the sponsor. If the 
patient withdraws from the study, the research team will notify the patient’s most responsible 
physician.  
9.1 
Data Collection and Follow-up for Withdrawn Participants 
Patients will be asked to continue with follow-up of body temperature and laboratory tests. It is 
important to continue to follow these patients and capture outcomes that occur once they have 
discontinued study intervention to determine feasibility. Through telephone calls and emails, every 
effort will be made to obtain permission to document the reason participants withdrew consent and to 
continue collecting the body temperature and laboratory values previously mentioned. Patients who 
have had at least one of the blankets applied will be included in the per-protocol analysis.   
10.0 
ETHICAL ISSUES 
10.1 
Ethical conduct and ethical issues 
Approval for patient accrual must be obtained from research ethics board (REB) at SHSC before patient 
recruitment can begin. Any additional correspondence with REB must be maintained by the research 
coordinator/assistant.   
10.2 
Informed Consent 
Due to the clinical condition of the patients during initial presentation, screening and enrollment will be 
at the discretion of the Trauma Team Leader on an urgent basis. When the patient is able to safely 
converse, study personnel will approach the Most Responsible Physician (MRP) for permission to 
approach the patient. With permission, the research coordinator will then approach enrolled patients, g 
to introduce the trial and conduct the informed consent discussion. By being invited into the patient’s 
circle of care with the permission of the MRP, study personnel will Introduce the rationale for the study, 
the anticipated risks and benefits of participation, and their rights as a study participant (including 
withdrawal at any time). Capable participants will be offered an opportunity to ask questions and 

STAYWARM2 (Version 2.5, 2023-08-21) Page 25 
 
consult with their family and/or their physician before final decision. If the patient is deemed medically 
incapable, consent will be obtained from the substitute decision maker (SDM) . One signed copy of the 
informed consent will be placed in the participant’s medical record, another copy given to the 
participant and the original kept in the study file with the research coordinator. If the participant does 
not wish to continue to participate, the reason for declining will be documented and the patient will be 
considered a screening failure (failure to provide informed consent).  
11.0 
STUDY ADMINISTRATION 
This will be a single-site study, conducted at Sunnybrook Health Sciences Centre. The Research 
Coordinators, supervised by the Principal Investigator, will be responsible for trial coordination, site 
training, site start-up/activation, document management, supply management, database development, 
data management and statistical analysis. Study data and patient surveys will be entered and 
maintained on a secure password protected database developed using REDCap 
(www.projectredcap.org) and will be accessible via the Internet for data entry purposes.  
 
11.1  
Arrangements for day-to-day management of the trial 
The research coordinator will be responsible for this aspect of the study, including system checks, 
maintenance, and data back-up. Patient data will be collected as enrollment occurs and entered into the 
electronic case report forms. Data queries will be generated monthly. A bi-weekly status report will 
include an update on the recruitment and status of all randomized patients. Monthly to bi-monthly 
audit and feedback meetings will be held. Protocol violations will be audited and recorded on 
designated Protocol Violation Forms. 
Clinical research coordinators will work with investigators on start-up activities (REB applications; study 
contract; organizing study materials; local in-services). Thereafter, research coordinators will screen, 
consent and enrol patients, complete case report forms, and respond to data queries.    
 
11.2 
Quality Assurance 
Study data will be maintained on a secure password protected database accessible from the world-wide-
web. Quality control will be ensured by oversight by the research coordinator at Sunnybrook Research 
Institute, who will review the electronic data for all participants on a regular basis for completeness and 
consistency.  
 
Quality and completeness of data entry will be reviewed as soon as possible after data entry, within five 
business days of data entry for the first five participants randomized, and within 15 days of data entry 
thereafter. Data queries generated by identification of incomplete or inconsistent data will be raised and 
should be resolved by the study coordinator or PI in a timely manner. Corrections or changes in the data 
management system are tracked with the retention of the original data and the corrected data with the 
date of data entry and submitting personnel.  

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13.0 
DATA HANDLING AND RECORD KEEPING 
13.1 Confidentiality 
Information about study participants will be kept confidential and managed according to the 
requirements of the Personal Health Information Protection Act of 2004 (PHIPA) and the Research Ethics 
Board. PHIPA outlines the rules for the collection, use and disclosure of personal health information.  
The Act requires each participant to consent to the collection, use and access of personal health 
information (PHI), unless consent is waived by the REB. As consent is required, each participant will be 
informed of the following:  
● What PHI will be collected during this study 
● Who will have access to that information and why 
● Who will use or disclose that information 
● The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator may use all 
information collected prior to the revocation of participant authorization. For participants that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the participant is alive) at the end of their scheduled study period. 
13.2 Source Documents 
Source data/documents are original documents, data and records in a clinical study that are necessary 
for the reconstruction and evaluation of the study.  Original documents and data records in this study 
include, but are not limited to: 
● worksheets 
● hospital records  
● medical records 
● memorandum  
● participants’ diaries or evaluation checklists  
● pharmacy dispensing records  
● copies or transcriptions certified after verification as being accurate and complete  
● participant files and records kept at the pharmacy  
● entries entered directly into the source documents 
 
Research coordinators will maintain appropriate medical and research records for this study, in 
addition to regulatory and institutional requirements for the protection of confidentiality of 
participants.  If electronic source data documents are printed it should be signed and dated by the 
investigator to confirm content and filed with other source documents.  
The investigator(s) and research team members listed on the Task Delegation Log (TDL) will have 
access to participant medical records and will collect only the information needed for the study.  
Sponsor delegated monitors, representatives of institutional committees and regulatory authority 
representatives of the country in which the study is being conducted will also have access to examine 
records for the purposes of quality assurance reviews, audits and evaluation of study safety and 
progress. 

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13.3 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study personnel under the 
supervision of the investigator. All source documents and applicable laboratory reports will be reviewed 
as needed and used to ensure that data collected for the purposes of the study are accurate and 
complete. Contemporaneous review of laboratory results and the assessment of clinical significance for 
those results considered out of range will be documented by means of dated signature by the reviewing 
investigator. Study personnel, including data entry team members, should use source documents to 
complete case report forms (CRFs).  
As part of the safety plan for this study, the investigator will review individual study participant records 
to ensure that appropriate mechanisms to protect the safety of study participants are being followed, 
that protocol requirements are being adhered to, and that data is accurate, complete, and secure. 
Participant records include, but are not limited to: consent forms, case report forms, data forms, 
laboratory specimen records, inclusion/exclusion forms, and medical charts. All study data will be 
collected by a member of the study research team and recorded in accordance with applicable 
procedures. 
13.4 Data Capture 
13.4.1 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for this study.  
Electronic/Paper case report forms (eCRFs/pCRFs) will be used to collect data. CRFs will be completed by 
data capture personnel and signed off by the investigator in a timely manner.  Good documentation 
practices will be implemented according to standard operating procedures. All data requested on the 
CRF must be recorded and verifiable by source document.   
13.5 Records Retention 
It is the responsibility of the REB, investigator, and regulatory sponsor to retain study essential 
documents as per local regulatory requirements and GCP Guidelines.   
Study essential documents must be maintained in a secure and confidential manner for participating 
Canadian sites for a period of 15 years. For the purposes of this study, the start date of the retention 
period is the date of the final report of the trial. Exceptions may be made for sites which close 
prematurely, wherein the start date for the retention period will be the date of notification to Health 
Canada of the sites closure. All study records are then to be destroyed according to local and national 
policy and requirements. It is the investigator’s responsibility to request authorization for destruction at 
the completion of the retention period and/or for the sponsor to inform the investigator/institution 
when these documents may be destroyed.  
13.6 Clinical Trial Registration 
In accordance with Health Canada’s Notice “Registration and Disclosure of Clinical Trial Information, 
November 30, 2007”, the investigator will register this study on Clinicaltrials.gov (www.clinicaltrials.gov), 
a publically available registry that conforms to international standards for registries. 
 

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14.0 References 
 
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Hypothermia in massive transfusion: have we been paying enough attention to it? J 
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2. Dirkmann D, Hanke AA, Gorlinger K, Peters J. Hypothermia and acidosis synergistically 
impair coagulation in human whole blood. Anesth Analg. 2008;106(6):1627-32. 
3. Lester ELW, Fox EE, Holcomb JB, Brasel KJ, Bulger EM, Cohen MJ, et al. The impact of 
hypothermia on outcomes in massively transfused patients. J Trauma Acute Care Surg. 
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4. Perlman R, Callum J, Laflamme C, Tien H, Nascimento B, Beckett A, et al. A 
recommended early goal-directed management guideline for the prevention of 
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patients. Crit Care. 2016;20(1):107. 
5. Rajagopalan S, Mascha E, Na J, Sessler DI. The effects of mild perioperative hypothermia 
on blood loss and transfusion requirement. Anesthesiology. 2008;108(1):71-7. 
6. Frank SM, Fleisher LA, Breslow MJ, Higgins MS, Olson KF, Kelly S, et al. Perioperative 
maintenance of normothermia reduces the incidence of morbid cardiac events. A 
randomized clinical trial. JAMA. 1997;277(14):1127-34. 
7. Slotman GJ, Jed EH, Burchard KW. Adverse effects of hypothermia in postoperative 
patients. Am J Surg. 1985;149(4):495-501. 
8. Phillips D, Bowman J, Zafren K. Successful Field Rewarming of a Patient with Apparent 
Moderate Hypothermia Using a Hypothermia Wrap and a Chemical Heat Blanket. 
Wilderness Environ Med. 2019;30(2):199-202. 
9. Bennett BL, Holcomb JB. Battlefield Trauma-Induced Hypothermia: Transitioning the 
Preferred Method of Casualty Rewarming. Wilderness Environ Med. 2017;28(2S):S82-S9. 
10. Oden TN, Doruker NC, Korkmaz FD. Compliance of Health Professionals for Prevention 
of Inadvertent Perioperative Hypothermia in Adult Patients: A Review. AANA J. 
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11. Munday J, Delaforce A, Forbes G, Keogh S. Barriers and enablers to the implementation 
of perioperative hypothermia prevention practices from the perspectives of the 
multidisciplinary team: a qualitative study using the Theoretical Domains Framework. J 
Multidiscip Healthc. 2019;12:395-417. 
12. Torossian A, Van Gerven E, Geertsen K, Horn B, Van de Velde M, Raeder J. Active 
perioperative patient warming using a self-warming blanket (BARRIER EasyWarm) is 
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Clin Anesth. 2016;34:547-54. 
13. TechTrade, LLC (2023). Instructions for Use (IFU): Ready Heat 4 Panel Heated Blanket. 
Orlando, FL.  

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14. Khayyat, H., Callum, J. L., Hill-Strathy, M., Strauss, R., Notario, L., Nathens, A., & da Luz, 
L. (2021). Compliance with the massive hemorrhage protocol in trauma: a retrospective 
quality review. Canadian Journal of Anesthesia, 68(1), 156-158. 
15. Callum, J. L., Yeh, C. H., Petrosoniak, A., McVey, M. J., Cope, S., Thompson, T., ... & 
Pavenski, K. (2019). A regional massive hemorrhage protocol developed through a 
modified Delphi technique. Canadian Medical Association Open Access Journal, 7(3), 
E546-E561. 
 
 

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