Core Warming of COVID-19 Patients Undergoing Mechanical Ventilation: a Randomized, Single Center Pilot Study
Phase: NA
Conditions: Covid19
Sponsor: Sharp HealthCare

Version: 3.1 (2022-03-02) 
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Core Warming of COVID-19 Patients Undergoing Mechanical Ventilation: A  
Randomized, Single Center Pilot Study 
Principal Investigator (1) 
David Willms, MD  
Sharp Memorial Hospital  
7901 Frost Street  
San Diego, CA 92123  
(858) 650-5037 
Sub-Investigator (2)   
Ahmed Salem, MD 
Funding Sponsor 
  
Attune Medical 
3440 S. Dearborn St, Suite 215-S 
Chicago, IL 60616 
888-534-4873 
info@attune-medical.com  
Study Device:
  
Attune Medical esophageal heat transfer device - 
ensoETM 
IRB Protocol Number:   
2007901 
IND/IDE
Number
or
clearance: 
FDA
FDA 510(k) Number K172493 
ClinicalTrials.gov Number
NCT04494867 
 
Current version: 3.1 (2022-03-02)  
Previous versions: 1.2 (2020-10-08) 
1.1 (2020-08-12) 
1.0 (2020-04-08)  
2.0 (2021-07-29) 
3.0 (2022-02-10) 

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Table of Contents 
  
  
LIST OF ABBREVIATIONS ............................................................................
4   
STUDY SUMMARY .........................................................................................
5   
1.0 BACKGROUND AND STUDY RATIONALE ............................................
7   
1.1 
INTRODUCTION ...........................................................................................................   
7 
1.2 
BACKGROUND AND RELEVANT LITERATURE ....................................................... 
7 
1.3 
NAME AND DESCRIPTION OF THE CORE WARMING DEVICE ............................ 
9 
1.3.1 
Clinical Data to Date ...................................................................  
9 
2 
STUDY OBJECTIVES .............................................................................
9   
2.1 
PRIMARY OBJECTIVES ..............................................................................................   
10 
2.2 
SECONDARY OBJECTIVES .......................................................................................   
10 
3 
INVESTIGATIONAL PLAN ......................................................................
10   
3.1 
GENERAL DESIGN ......................................................................................................   
10 
3.1.1 
Screening Phase ........................................................................
10 
3.1.2 
Study Intervention Phase ...........................................................
10 
3.1.3 
Follow Up (Day 30) .....................................................................  
11 
3.1.4 
Allocation to Interventional Group ..............................................  
11 
3.2
STUDY ENDPOINTS .................................................................................................... 
11
3.2.1
Primary Study Endpoints............................................................
11
3.2.2 
Secondary Study Endpoints .......................................................  
11 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION .............
11   
4.1 
INCLUSION CRITERIA .................................................................................................   
11 
4.2 
EXCLUSION CRITERIA ............................................................................................... 
12 
4.3 
SUBJECT RECRUITMENT .......................................................................................... 
12 
4.4 
DURATION OF STUDY PARTICIPATION ...................................................................   
12 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES ...........................................................   
12 
5 
STUDY INTERVENTION .........................................................................
12   
5.1 
INTERVENTION REGIMEN..........................................................................................   
12 
5.2 
BLINDING ..................................................................................................................... 
13 
5.3 
DEVICE ACCOUNTABILITY ........................................................................................   
13 
6 
SCHEDULE OF PROCEDURES AND DATA EXTRACTION .................
13   
6.1 
PRE-SCREENING .......................................................................................................   
13 
6.2 
STUDY VISITS & DATA COLLECTION ..................................................................... 
13 
6.2.1 
Screening, Enrollment, and Randomization ...............................  
13 
6.2.2 
Post-placement ..........................................................................
14 
6.2.3 
Post treatment ............................................................................  
15 
6.3 
RESCUE THERAPY .....................................................................................................   
15 
6.4 
UNSCHEDULED VISITS ..............................................................................................   
15 
6.5 
SUBJECT WITHDRAWAL ............................................................................................   
15 
 

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6.5.1 
Data Collection and Follow-up for Withdrawn Subjects ....................... 
7 
STATISTICAL PLAN ........................................................................................ 
PRIMARY ENDPOINT ........................................................................................................................... 
7.1 
SECONDARY ENDPOINTS ..................................................................................................... 
7.2 
SAMPLE SIZE AND POWER DETERMINATION ................................................................... 
7.3 
STATISTICAL METHODS ........................................................................................................ 
16 
15 
16 
16 
16 
16 
7.3.1 
Efficacy Analysis .................................................................................   
16 
7.3.2 
Interim Safety Analysis ........................................................................   
16 
7.4 
SUBJECT POPULATION(S) FOR ANALYSIS ........................................................................   
16 
8 
SAFETY AND ADVERSE EVENTS .................................................................. 
17 
  
8.1 
DEFINITIONS ............................................................................................................................   
17 
8.1.1
Adverse Event.....................................................................................
17
8.1.2 
Serious Adverse Event ........................................................................   
17 
8.1.3
Unanticipated Problems Involving Risk to Subjects or Others.............
17
8.1.4
Preexisting Condition ..........................................................................
18
8.1.5 
General Physical Examination Findings ..............................................   
18 
8.1.6 
Post-study Adverse Event ...................................................................   
18 
8.1.7
Hospitalization, Prolonged Hospitalization or Surgery.........................
18
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................   
19 
8.3 
CLASSIFICATION OF ADVERSE EVENTS ............................................................................   
19 
8.4 
ADVERSE EVENT REPORTING PERIOD .............................................................................   
20 
8.5 
EXPEDITED REPORTING OF EVENTS .................................................................................   
20 
8.5.1 
Follow-up report ..................................................................................   
20 
8.5.2 
Sponsor reporting: Notifying the Funding Sponsor ..............................   
20 
8.6 
UNBLINDING PROCEDURES .................................................................................................   
21 
8.7 
DATA AND SAFETY MONITORING .......................................................................................   
21 
9 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING 
  .. 21 
  
9.1 
CONFIDENTIALITY ..................................................................................................................   
21 
9.2 
DATA COLLECTION AND MANAGEMENT ............................................................................   
21 
9.3 
RECORDS RETENTION ..........................................................................................................   
22 
10 STUDY MONITORING, AUDITING, AND INSPECTING .................................... 
22 
  
10.1 STUDY MONITORING PLAN ..................................................................................................   
22 
10.2 AUDITING AND INSPECTING .................................................................................................   
22 
11 ETHICAL CONSIDERATIONS ......................................................................... 
22 
  
11.1 RISKS ........................................................................................................................................   
23 
11.2 BENEFITS .................................................................................................................................   
24 
11.3 RISK BENEFIT ASSESSMENT ...............................................................................................   
24 
11.4 INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .........................................   
24 
12 STUDY FINANCES ............................................................................................. 
24 
  
12.1 FUNDING SOURCE .................................................................................................................   
24 

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12.2 CONFLICT OF INTEREST .......................................................................................................   
24 
 
12.3 PARTICIPANT STIPENDS OR PAYMENTS ................................................................................................... 24 
13 PUBLICATION PLAN ......................................................................................... 24 
14 REFERENCES ................................................................................................... 24 
List of Abbreviations 
AE: Adverse event 
ARDS: Acute Respiratory Distress Syndrome 
COVID-19: Coronavirus disease 2019 
EMR: Electronic Medical Record 
ICU: Intensive Care Unit 
SAE: Serious adverse event 
SARS-CoV-2: Etiology of coronavirus disease 2019 
SOC: Standard of care 
SOFA Score: Sequential Organ Failure Assessment Score 
 

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Study Summary 
Title 
Core Warming of COVID-19 Patients Undergoing Mechanical 
Ventilation: a randomized, single center pilot study 
Short Title 
COVID Core Warming 
IRB Number 
Pending 
Phase 
Pilot Study 
Methodology 
Randomized, single center pilot study 
Study Duration 
Approximately 3-5 months 
Study Center 
Sharp Memorial Hospital 
Objectives 
Primary:
 
Determine the change in PaO2/FiO2 ratio at 0, 24, 48, 
and 72 hours after implementation of core warming of 
ventilated patients, and compare this change to 
patients undergoing standard care. 
Secondary:
 
Determine the change in viral load measured in 
nasopharyngeal swab by Cycle Threshold at 0, 24, 48, 
and 72 hours after implementation of core warming of 
ventilated patients, and compare this change to 
patients undergoing standard care. 
 
Measure the impact of core warming on duration 
of mechanical ventilation. 
 
Determine impact of core warming on patient mortality. 
Number of 
Participants 
22 
Length of 
Participation 
72 hour intervention phase; 30 day follow up 
 

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Inclusion Criteria 
1. Patients above the age of 18 years old. 
2. Patients with the diagnosis of COVID-19 requiring 
mechanical ventilation. 
3. Patient maximum baseline temperature (within previous 
12 hours) < 38.3°C. 
4. Patients must have surrogate or legally authorized 
representative able to understand and critically review 
the informed consent form. 
Exclusion Criteria 
1. Patients without surrogate or legally authorized 
representative able to provide informed consent. 
2. Patients with contraindication to core warming using 
an esophageal core warming device. 
3. Patients known to be pregnant. 
4. Patients with <40 kg of body mass. 
5. Patients with DNR status. 
6. Patients with acute stroke, post-cardiac arrest, or 
multiple sclerosis. 
Investigational 
Device 
Attune Medical esophageal heat transfer device – ensoETM. 
Used as indicated for patient temperature management. 
Duration of 
administration 
72 hours 
Reference therapy 
Standard temperature management as routine at study site 
Statistical 
Methodology 
A total of 11 patients for each group will be required to yield 
the necessary pilot data regarding the feasibility and effect of 
core warming on viral load and ventilation requirements. 
Safety Evaluations 
Standard adverse event monitoring (device is in widespread 
use for patient warming and cooling). 
Data and Safety 
Monitoring Plan 
The PI and research team will be responsible for data and safety 
monitoring. 
 

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This study will be conducted in full accordance with all applicable study site research policies and 
procedures and all applicable federal and state laws and regulations. 
1.0 Background and Study Rationale 
1.1 
Introduction 
Traditionally, fever has been treated because its metabolic costs were felt to outweigh its potential 
physiologic benefit in an already stressed host.[1] However, increasing data suggest that fever may be 
a protective adaptive response that should be allowed to run its course under most circumstances.[2, 
3] Although one randomized controlled trial using physical cooling of mechanically ventilated patients 
with septic shock found a reduction in vasopressor dose and reduced early mortality when treating 
fever,[4] a growing number of studies have found either no clinically important benefit, or harms, in 
treating fever of infectious origin. 
1.2 
Background and Relevant Literature 
Studies have found that higher early fever is associated with a lower risk of death among patients with 
an ICU admission diagnosis of infection [5, 6] and that fever may enhance immune-cell function,[7, 8] 
inhibit pathogen growth,[9-11] and increase the activity of antimicrobial drugs.[12] Fever potentially 
benefits infected patients via multiple mechanisms; in vitro and animal studies have shown that elevated 
temperatures augment immune function, increase production of protective heat shock proteins, directly 
inhibit microorganism growth, reduce viral replication, and enhance antibiotic effectiveness.[3, 13] More 
rapid recoveries are observed from chickenpox,[14] malaria,[15] and rhinovirus [16] infections with 
avoidance of antipyretic medication, and many innate and adaptive immunological processes are 
accelerated by fever.[17-19] The UK National Institute for Health and Care Excellence (NICE) 
recommend not using antipyretic agents “with the sole aim of reducing body temperature in children 
with fever.”[17, 20] As recently as the 1910’s, the “malaria fever cure” (inducing fever to treat a range 
of conditions, an approach known as “pyrotherapy”) was widespread, with the originator of the idea 
receiving the Nobel Prize in Medicine or Physiology in 1927.[21, 22] 
A randomized control trial published in 2005 evaluating the impact of antipyretic therapy on outcomes 
in critically ill patients had to be terminated at the interim analysis as there were seven deaths in the 
aggressive group and only one death in the permissive group.[23] Another randomized controlled trial 
in critically ill patients (without neurotrauma or severe hypoxia) failed to support the treatment of fever; 
no significant differences in ICU and hospital length of stay, or mortality between those receiving 
external cooling for temperature ≥38.5 ℃ vs. no antipyretic treatment was found.[24] A prospective 
controlled trial randomized 700 patients with fever of known or suspected infectious etiology to receive 
either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of 
fever, cessation of antimicrobial therapy, or death.[25] The primary outcome, ICU-free days until day 
28, was not decreased in the treatment arm, and secondary outcomes (28 and 90-day mortality, ICU 
and hospital length of stay) were also not significantly different between groups.[25] 
A systematic review and trial sequential analysis of randomized controlled trials found a total of 6 
randomized controlled trials including 819 patients.[26] Overall, there was no beneficial effect of 
antipyretic therapy on mortality risk in patients with established sepsis (OR: 1.02, 95% CI: 
  

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0.50–2.05), and the review failed to identify any beneficial effect of antipyretic therapy on ICU patients 
with established diagnosis of sepsis.[26] Another systematic review and meta-analysis of randomised 
controlled trials investigating treatments administered to febrile patients found fifteen studies reporting 
results from 13 trials, and found that active temperature management neither increased nor decreased 
mortality risk, ICU, or hospital length of stay in critically ill adults.[27] A meta-analysis examining the 
impact of antipyretic therapy on mortality in critically ill septic adults found 8 randomized studies (1,507 
patients) and 8 observational studies (17,432 patients).[28] Antipyretic therapy did not reduce 28-
day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77–1.13; I2 = 0.0%) or 
observational studies (odds ratio, 0.90; 95% CI, 0.54–1.51; I2 = 76.1%), and the authors concluded that 
antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with 
sepsis.[28] 
A retrospective cohort study evaluated 1,264 patients requiring mechanical ventilation initiated in the ED 
with subsequent admission to an intensive care unit.[29] The authors found that high fever (≥39.5°C) was 
associated with increased risk for mortality in mechanically ventilated patients; however, in patients with 
sepsis, moderate fever (38.3°C-39.4°C) was protective, and antipyretic medication was not associated 
with changes in outcome.[29] An open, parallel-group pilot randomized clinical trial (the FEVER pilot trial) 
enrolled 87 pediatric intensive care unit patients who were randomly assigned to permissive (antipyretic 
interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on 
respiratory support.[17] Length of stay, duration of organ support and mortality were similar between 
groups, and no pre-specified serious adverse events occurred.[17] Finally, a pilot study of external 
warming of septic patients (ClinicalTrials.gov Identifier: NCT02706275) has recently been completed, 
with initial analysis of results appearing promising (manuscript in preparation). 
Temperature has been suggested to influence the virulence of an earlier discovered coronavirus, SARS 
CoV, [30] and most isolates of human rhinovirus, the common cold virus, replicate more robustly at the 
cool temperatures found in the nasal cavity (33–35 °C) than at core body (lung) temperature (37 °C).[31] 
Rhinovirus replicates preferentially at cooler nasal cavity temperature due, in part, to a less efficient 
antiviral defense response of infected cells at cool temperature, raising the possibility that inhaling cool air 
might diminish resistance to respiratory virus infections by lowering the temperature of potential host cells 
lining the nasal cavity.[31] Influenza 
B virus viral hemagglutinin exhibits higher expression at 33°C (a temperature required for membrane 
fusion), indicating pronounced adaptation to the mildly acidic pH and cooler temperature of human 
upper airways.[32] Specifically, protein expression of influenza B virus viral hemagglutinin proved to be 
temperature dependent, with expression highest at 33°C and gradually decreasing at higher 
temperatures.[32] On the other hand, avian influenza A viruses, adapted to the temperature of the avian 
enteric tract (40°C), show restricted growth at cooler temperatures (∼32°C).[32] 
More recently, simulations of the receptor binding domain (RBD) of SARS-CoV-2 found that it is more 
flexible than SARS CoV, especially near the binding site, suggesting that the RBD will have a higher 
entropy penalty upon binding angiotensin-converting enzyme II (ACE2) compared to the RBD of SARS-
CoV.[33] Consequently, SARS-CoV-2 may be more temperature-sensitive in terms of human infection 
than SARS-CoV.[33] 
  

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Hyperthermia induced by directly heating the body (as opposed to fever induced by introducing bacterial 
extracts or other foreign substances) is normally limited to 41.8 to 42°C when used to kill tumor cells in 
cancer treatment, with minimal adverse effects.[34-37] Furthermore, hyperthermia and elevated 
temperature have been found to have positive impacts on the immune system. Cells have been found 
to exhibit increased levels of heat-shock proteins, specifically HSP70 [38] and HSP90, [39] which are 
directly related to and/or cause antigen presentation and cross‐presentation, activation of macrophages 
and lymphocytes, and activation and maturation of dendritic cells,[40] all of which are essential antiviral 
immune responses. Notably, fever has often abated by the time a COVID-19 patient requires 
mechanical ventilation.[41] 
The aim of this study is to determine the effect of active core warming patients diagnosed with COVID-
19 and undergoing mechanical ventilation. We hypothesize that active core warming will reduce the 
severity of acute respiratory distress syndrome, reduce the duration of mechanical ventilation, and 
improve survival compared to standard of care. 
1.3 
Name and Description of the Core Warming Device 
Core warming will be performed using an esophageal heat transfer device (ensoETM, Attune Medical, 
Chicago, IL) This device is an FDA cleared device, and is a multi-lumen silicone tube placed in the 
esophagus for the purpose of cooling or warming a patient while simultaneously allowing gastric 
decompression and drainage. Modulation and control of the patient’s temperature is achieved by 
connecting the device to an external heat exchanger. Two lumens connect to the external heat 
exchanger, while a third central lumen provides stomach access for connection to a fluid collection 
device with low intermittent suction for gastric decompression. Distilled water circulates within the device 
just like a water blanket. The device can be placed by most providers in the operating room, emergency 
room, or intensive care unit. It is a single-use, disposable, non-implantable device with an intended 
duration of use of 72 hours or less. For this study, the device will be used during mechanical ventilation 
of patients with diagnosed COVID-19, under the intended indication of patient temperature management 
as detailed in the product instructions for use. 
1.3.1 Clinical Data to Date 
Core warming and cooling has been used safely in thousands of patients for temperature control, making 
it the ideal approach to use for this study. Core cooling or warming using an esophageal heat transfer 
device is used for a range of temperature management purposes, including post-cardiac arrest 
therapeutic hypothermia [42-45], warming of burn patients [46], warming general surgical patients,[47] 
cooling traumatic brain injury,[48] cooling heat stroke,[49] and the treatment of central fever.[50, 51] 
2 
Study Objectives 
The purpose of the proposed pilot study is to determine if core warming improves respiratory physiology 
of mechanically ventilated patients with COVID-19, allowing earlier weaning from ventilation, and 
greater overall survival. 
  

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2.1 
Primary Objectives 
1. Determine the change in PaO2/FiO2 ratio at 0, 24, 48, and 72 hours after implementation of core 
warming of ventilated patients, and compare this change to patients undergoing standard care. 
2.2 
Secondary Objectives 
1. Determine the change in viral load measured in nasopharyngeal swab by Cycle Threshold at 0, 
24, 48, and 72 hours after implementation of core warming of ventilated patients, and compare 
this change to patients undergoing standard care. 
2. Measure the impact of core warming on duration of mechanical ventilation. 
3. Determine impact of core warming on patient mortality. 
3 
Investigational Plan 
3.1 
General Design 
This is a small scale pilot study to evaluate if core warming improves respiratory physiology of 
mechanically ventilated patients with COVID-19, allowing earlier weaning from ventilation, and greater 
overall survival. This prospective, randomized study will include 22 patients diagnosed with COVID-19, 
and undergoing mechanical ventilation for the treatment of respiratory failure. Patients will be randomized 
in a 1:1 fashion with 11 patients (Group A) randomized to undergo core warming, and the other 11 patients 
(Group B) serving as the control group who will not have the ensoETM device used. Patients randomized 
to Group A will have core warming initiated in the ICU or other clinical environment in which they are being 
treated after enrollment and provision of informed consent from appropriate surrogate or legally authorized 
representative. 
3.1.1 Screening Phase 
Subjects will be recruited from the ICU or other clinical environment in which they are being treated 
(Emergency Department, step-down unit, etc.). Patients will be identified by the PI or other study 
investigators/coordinators as available. All patients without a DNR order with a diagnosis of COVID-19 
and meeting inclusion criteria will be eligible for screening for any exclusion criteria. Written informed 
consent for the research study will be obtained from patient’s surrogate or legally authorized representative 
prior to enrollment. 
3.1.2 Study Intervention Phase 
Participants who have a signed research study consent form (via surrogate or legally authorized 
representative) will be randomized in a 1:1 fashion to core warming with the study device (ensoETM) or to 
standard of care (standard temperature management and treatment). The device will be used as indicated 
(for warming). Patient temperature measurement will be collected for both the core warming and standard 
of care arms during the study period (72 hours). 
Core warming will be performed using standard technique per instructions for use for the esophageal 
heat transfer device. The esophageal heat transfer device will be set to 42°C temperature after initial 
placement, and maintained at 42°C for the duration of treatment. It is expected that patient temperature 
will increase from baseline by 1°C to 2°C, but due to ongoing 
  

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heat loss from the patient, the expected maximum patient temperature is below 39°C. The time course 
of illness of COVID-19 is such that most patients no longer have fever by the time of mechanical 
ventilation.[41] If patient temperature increases above this range and reaches 39.8°C, the device will 
be set to an operating temperature of 40°C, thereby preventing any further increase in patient 
temperature (ambient heat loss precludes patient from reaching device operating temperature). 
Monitoring and Evaluation 
All patients will have usual standard of care labs, vital signs, and imaging for patients undergoing 
mechanical ventilation in the ICU. Specific parameters to be measured include PaO2 at regular intervals 
appropriate for patients undergoing mechanical ventilation, and FiO2 at the time of obtaining blood 
gases for PaO2 measurement, to allow calculation of P/F ratio. 
3.1.3 Follow Up (Day 30) 
Follow up data will be collected at 30 days following initiation of study treatment. 
3.1.4 Allocation to Interventional Group 
The randomization algorithm will be built into the electronic data capture system, Redcap, which will be 
used to collect data in the study. Once the randomization form is entered into the system and saved, 
the back end algorithm will run and a participant will be assigned an arm corresponding to either study 
device (Group A – Core warming) or standard of care (Group B – Control). Patients will undergo 
randomization after being enrolled into the study and prior to the placement of the core warming device. 
Randomization will be performed in a 1:1 fashion and maintained on the limited access, encrypted, 
Redcap database. 
3.2 
Study Endpoints 
The purpose of the proposed pilot study is to determine if core warming reduces the severity of acute 
respiratory distress syndrome as measured by PaO2/FiO2 ratio 72 hours after initiation. 
3.2.1 Primary Study Endpoints 
The primary endpoint of this study will be: 
1. PaO2/FiO2 ratio at 0, 24, 48, and 72 hours after initiation of core warming 
3.2.2 Secondary Study Endpoints 
1. Viral load measured in nasopharyngeal swab by Cycle Threshold at 0, 24, 48, and 72 hours after 
initiation of core warming 
2. Duration of mechanical ventilation 
3. Mortality 
4 
Study Population and Duration of Participation 
All patients will have a diagnosis of COVID-19 requiring mechanical ventilation. Duration of intervention 
will be 72 hours. Follow-up will be to 30 days. 
4.1 
Inclusion Criteria 
1. Patients above the age of 18 years old. 
2. Patients with a diagnosis of COVID-19 on mechanical ventilation. 
3. Patient maximum baseline temperature (within previous 12 hours) < 38.3°C. 
  

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4. Patients must have a surrogate or legally authorized representative able to understand and 
critically review the informed consent form. 
4.2 
Exclusion Criteria 
1. Patients without surrogate or legally authorized representative able to provide informed 
consent. 
2. Patients with contraindication to core warming using an esophageal core warming device. 
3. Patients known to be pregnant. 
4. Patients with <40 kg of body mass. 
5. Patients with DNR status. 
6. Patients with acute stroke, post-cardiac arrest, or multiple sclerosis. 
4.3 
Subject Recruitment 
Subjects will be recruited from the ICU or other clinical environment in which they are being treated 
(Emergency Department, step-down unit, etc.). Patients will be identified by the PI or other study 
investigators/coordinators as available. All patients without a DNR order with a diagnosis of COVID-19 
and meeting inclusion criteria will be eligible for screening for any exclusion criteria. The study team 
will pre-screen the potential subject’s EMR, to assess all other inclusion/exclusion criteria, prior to 
approaching the patient and/or their surrogate / legally authorized representative about study 
participation. Written informed consent for the research study will be obtained from patient’s surrogate 
or legally authorized representative prior to enrollment. If a patient enrolled in the study gains the 
capacity to consent for him/herself while the study is in progress, the patient will be approached by a 
study team member and the consent document will be presented directly to the patient. All questions 
the patient might have will be answered. The patient will be given the opportunity to either withdraw 
from the study or sign the consent form. The patient will be informed that his or her decision to withdraw 
from the study will not affect his or her medical care 
4.4 
Duration of Study Participation 
Participants will be involved for approximately 30 days, including screening, treatment, and follow-up. 
After consent, patient participation in the intervention phase will last 72 hours for active treatment. The 
follow up for determination of outcome and duration of mechanical ventilation will occur at 1-month post-
treatment. Additional data will be collected via chart review. 
4.5 
Total Number of Subjects and Sites 
Recruitment will end when 22 participants are randomized. 
5 
Study Intervention 
5.1 
Intervention Regimen 
Patients who are randomized to core warming will have the esophageal heat transfer device placed in 
the ICU or other treatment area where patient is undergoing mechanical ventilation. The device will 
remain in place until the study is completed (72 hours). The device will be set to 42°C for the duration 
of the study period, with the exception of any elevations in patient temperature as described in section 
3 above. 
  

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5.2 Blinding 
Due to the nature of this study, the physicians will not be blinded to the randomization assignment, 
however participants will be blinded. Once a subject is randomized, the research team will receive 
the randomization assignment (core warming or standard of care) and proceed with the procedures 
per the assignment. 
5.3 
Device Accountability 
Core warming device accountability logs will be kept on file, will be completed on a regular basis, and 
will include product number, date of use, participant ID code, device damaged/destroyed and date of 
damage/destruction (including return date if applicable). 
6 
Schedule of Procedures and Data Extraction 
Study Phase 
Screening 
Randomization/  
Intervention Phase 
Follow up 
Study Days
Day -1to 0 
Day 0 
Day 1-2 
Day 30 
Informed Consent
X
Review Inclusion/Exclusion Criteria
X
Demographics
X
Medical History/Interim History*
X
X
Physical Examination*
X
X
X
Vital Signs: Temperature, BP, HR, RR*
X
X
X
X
Height and Weight
X
Pregnancy Test
X
Clinical Labs
X
X
X
Respiratory tract viral load
X
X
Ventilator settings
X
X
X
SOFA score
X
X
X
Clinical Imaging (per routine)
X
X
X
Prior/Concomitant Medications
X
X
Randomization
X
Temperature monitoring
X
X
PaO2, FiO2, parameter recording
X
X
Adverse Event / Unanticipated 
Problems
Assessment
  
X 
X 
X 
* Interim medical history, physical exam, and vitals will be collected via chart review from routine 
clinical care. 
6.1 Pre-Screening 
Patients will be screened within 24 hours prior to the Baseline/Randomization timepoint to determine 
potential eligibility. 
6.2 
Study Visits & Data Collection 
6.2.1 Screening, Enrollment, and Randomization 
Study personnel will assess each subject against each inclusion and each exclusion criterion and 
the Investigator will determine the subject’s eligibility for study participation. The principal 

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investigator or documented members of the research team will discuss the underlying rationale for 
the study, the procedures to be followed, the potential benefits and risks, and other issues mandated 
by the consent process with the surrogate or legally authorized representative. The participant’s 
surrogate or legally authorized representative will be asked if they would like to participate, and if 
so, this will be documented using the study ICF. Determining the eligibility for each participant will 
require information generated during the course of routine clinical care as dictated by their attending 
physicians. Selected testing data will be collected in order to characterize the type, cause and 
severity of the patient’s need for mechanical ventilation and the treatments received prior to 
enrollment. The data will include information from the evaluations listed below. 
Once the Investigator has reviewed and signed the eligibility checklist, the research staff will enter 
the participant’s information into the RedCap system to obtain the randomization assignment. 
Data collection: 
 Inclusion/Exclusion criteria review 
 Study Informed Consent 
 Collect Demographics (including sex/gender, race, ethnicity, and age via date of birth) 
 Medical Record Review (including any history of disease, social history, physical exam 
findings and physicians notes) 
 Review of Concurrent Medications 
 Physical Exam 
 Vital Signs: temperature, blood pressure, heart rate, respiration rate, height and weight 
 Routine Clinical Labs/Phlebotomy such as a complete blood count (CBC) and chemistry 
profiles, along with most recent arterial blood gas for determination of PaO2, if collected as 
routine care. 
 Specific labs recorded include: sodium, potassium, creatinine, hematocrit, white blood cell 
count, and CRP, if collected as routine care. 
 Lower respiratory tract (tracheal aspirate, sputum) viral load (cycle threshold) 
 SOFA score 
 Ventilator settings 
 Pregnancy test for women of childbearing potential 
 Randomization 
 Adverse Event/Unanticipated Problem assessment and recording 
6.2.2 Post-placement 
As part of routine monitoring, participants will have regularly obtained parameters (labs, vital signs, 
ventilator settings) recorded, as well as viral load at start and end of treatment. 
 
Interim medical history review 
 
Physical Exam 
 
Vital Signs: temperature, blood pressure, heart rate, respiration rate, height and weight 
  

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 
Routine Clinical Labs/Phlebotomy such as a complete blood count (CBC) and chemistry 
profiles, along with most recent arterial blood gas for determination of PaO2, if collected 
as routine care. 
 
Specific labs recorded include: sodium, potassium, creatinine, hematocrit, white blood cell 
count, and CRP, if collected as routine care. 
 
Lower respiratory tract (tracheal aspirate, sputum) viral load (cycle threshold) 
 
Ventilator settings 
 
Adverse Event/Unanticipated Problem assessment and recording 
6.2.3 Post treatment 
Participant’s clinical status and outcome will be reviewed 30 days after study completion. 
The following procedures will be collected: 
 
Interim medical history review /concomitant medications 
 
Physical Exam & Vital Signs 
 
Adverse Event/Unanticipated Problem assessment and recording 
 6.3 
Rescue Therapy 
The core warming device will be removed and replaced if at any time there is evidence of a potential 
device malfunction. The device can be easily removed and replaced during treatment if needed. 
Should evidence of continued malfunction occur after replacement of the study device, the device 
will be removed, allowing the patient to undergo the standard of care with respect to temperature 
monitoring and control. 
 6.4 
Unscheduled Visits 
The research team will assess for the occurrence of any adverse event(s)/unanticipated problem(s) 
should a patient present for any unscheduled visit after discharge, up through 30 days following the 
study. 
 6.5 
Subject Withdrawal 
Subjects may withdraw from the study at any time without impact to their care. They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to study 
procedures or visit schedules, AEs, or should it become clinically necessary to deviate from the study 
protocol during the course of the study. The Investigator may also withdraw subjects who violate the 
study plan, or to protect the subject for reasons of safety or for administrative reasons. It will be 
documented whether or not each subject completes the clinical study. We will attempt to have one 
final visit or contact to follow up regarding adverse events for participants who withdraw prior to the 
30 day follow up visit. 
6.5.1 Data Collection and Follow-up for Withdrawn Subjects 
We will attempt to have one final visit or contact to follow up regarding adverse events for 
participants who withdraw prior to the 30 day follow up visit. During this contact they will be asked 
for permission to have the study team look into their survival status via their electronic medical 
records and publicly available means. 

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7 
Statistical Plan  
Primary Endpoint 
The primary endpoint of this study will be the change in PaO2/FiO2 ratio at 0, 24, 48, and 72 hours 
after implementation of core warming of ventilated patients. This endpoint will be compared between 
patients receiving core warming and those randomized to undergo standard care (standard 
temperature management, with or without antipyretics as needed). 
7.1 
Secondary Endpoints 
Secondary endpoints include: 
1. Viral load measured in nasopharyngeal swab by Cycle Threshold at 0, 24, 48, and 72 hours 
after initiation of core warming 
2. Duration of mechanical ventilation 
3. Patient mortality 
7.2 
Sample Size and Power Determination 
Based on a prior study in patients with sepsis, a maximum temperature of 38.3°C to 39.4°C was 
associated with survival (aHR 0.61 [95% CI, 0.39-0.99]).[29] However, the effect of warming specific 
to COVID-19 patients remains uncertain, and as such, we are unable to accurately perform a power 
calculation for this pilot study. We believe that a total of 10 patients for each group will be required to 
yield the necessary pilot data to make an appropriate conclusion regarding the potential utility of core 
warming in reducing viral shedding, improving pulmonary physiology, reducing mechanical ventilation 
duration, and increasing patient survival. It is anticipated that data from this pilot study can be used 
for planning future larger studies. 
7.3 
Statistical Methods 
We will utilize standard measures to report outcomes and measure differences between groups. 
Specifically, we will use descriptive statistics, including mean (standard deviation) and median 
(interquartile range). Normality will be assessed using histograms and the Kolmogorov–Smirnov 
test. Categorical variables will be compared using the chi-squared test or Fisher exact test. 
Continuous variables will be compared using the independent samples t or Mann–Whitney U test. 
7.3.1 Efficacy Analysis 
This is a pilot study to determine the potential role of core warming during COVID-19 treatment.. 
7.3.2 Interim Safety Analysis 
All subjects entered into the study and randomized at the baseline timepoint will have detailed 
information collected on adverse events for the overall study safety analysis. An interim safety 
analysis will be performed after the first 10 subjects are enrolled in the trial. At this time the safety 
and tolerability of the study device will be assessed and if deemed safe and appropriate, enrollment 
will continue to 22 subjects. 
7.4 
Subject Population(s) for Analysis 
All patients enrolled, randomized to a study arm, and completed in the study will be included for 
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8 
Safety and Adverse Events 
8.1 
Definitions 
8.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
For FDA regulated studies the FDA defines an adverse event as the following: 
Unanticipated adverse device effect is any serious adverse effect on health or safety, any life-
threatening problem or death caused by, or associated with a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the application; or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
8.1.2 Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that 
is: 
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance. They may jeopardize the subject, and may require intervention to prevent 
one of the other serious outcomes noted above. For example, drug overdose or abuse, a seizure 
that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in an 
emergency department would typically be considered serious. 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events. 
8.1.3 Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 

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 Unexpected in nature, severity, or frequency (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
 Related or possibly related to participation in the research (i.e. possibly related means there 
is a reasonable possibility that the incident experience, or outcome may have been caused 
by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
8.1.4 Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition should 
be recorded as an adverse event if the frequency, intensity, or the character of the condition worsens 
during the study period. 
8.1.5 General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. At 
the end of the study, any new clinically significant findings/abnormalities that meet the definition of 
an adverse event must also be recorded and documented as an adverse event. 
8.1.6 Post-study Adverse Event 
All unresolved adverse events considered probably or definitely related should be followed by the 
investigator until the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained. At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study. 
8.1.7 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented 
and reported as a serious adverse event unless specifically instructed otherwise in this protocol. 
Any condition responsible for additional surgery should be documented as an adverse event if the 
condition meets the criteria for an adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition. Surgery should not be reported as an outcome of an adverse event 
if the purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
  

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 8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event case report form 
(CRF). All clearly related signs, symptoms, and clinically significant abnormal diagnostic procedures 
results should be recorded in the source document, though should be grouped under one diagnosis. 
All adverse events occurring during the study period (consent through 30 day follow up) will be 
recorded. The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study intervention or participation is not the cause. Serious adverse 
events that are still ongoing at the end of the study period will be followed up to determine the final 
outcome. Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study intervention or study participation will be recorded and reported 
immediately. 
 8.3 
Classification of Adverse Events 
Severity  
 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention is not indicated. 
 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; limiting to age-
appropriate instrumental activities of daily living (ADL; instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc.). 
 Grade 3: severe or medically significant but not immediately life threatening; hospitalization 
or prolongation of hospitalization is indicated; disabling; limiting to self-care ADL (self-care 
ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
 Grade 4: life-threatening consequences; urgent intervention is indicated. 
 Grade 5: death due to an AE. 
Relatedness  
1) Definite: the AE is clearly related to the research procedures 
2) Probably: the AE is likely related to the research procedures 
3) Possible: the AE may be related to the research procedures 
4) Unlikely: the AE is doubtfully related to the research procedures 
5) Unrelated: the AE is clearly not related to the research procedures 
Expectedness   
AEs must be assessed as to whether they were expected to occur or were unexpected, meaning 
not anticipated based on current knowledge found in the protocol, investigator brochure, product 
insert, or label. 
Expected: an AE known to be associated with the intervention or condition under study. 
  

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OHRP defines an unexpected AE as any AE occurring in one or more subjects participating in a 
research protocol, the nature, severity, or frequency of which is not consistent with either: 
1) the known or foreseeable risk of AEs associated with the procedures involved in the 
research that are described in a) the protocol-related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and b) other relevant sources of information, 
such as product labeling and package inserts; or 
2) the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the AE and the subject’s predisposing risk factor profile for the AE. 
 8.4 
Adverse Event Reporting Period 
For this study period during which adverse events must be reported is defined as the period from 
the initiation of any study procedures (consent) to the end of the study follow-up (1-Month follow up 
visit/Visit3). Adverse events that do not require expedited reporting (see section 9.5 below) will be 
reported in summary to the IRB at continuing review. 
 8.5 
Expedited Reporting of Events 
Any study-related unanticipated problem posing risk to subjects or others, and any type of 
unanticipated serious adverse event or unanticipated adverse device effect, will be reported to the 
IRB in accordance with the institutional and FDA requirements. Investigators will use the appropriate 
SAE/UP CRF to record events and a line item will also be added to the AE log CRF. 
The minimum necessary information to be provided at the time of the initial expedited event report 
includes: 
 
Study identifier 
• Current status 
 
Study Center 
• Whether 
study 
intervention 
was 
 
Subject number 
discontinued 
 
A description of the event 
• The reason why the event is classified as 
 
Date of onset 
serious 
 Investigator assessment of the association 
between the event and study intervention 
8.5.1 Follow-up report 
If an SAE, UP or Unanticipated Adverse Device Effect has not resolved at the time of the initial 
report and new information arises that changes the investigator’s assessment of the event, a follow-
up report including all relevant new or reassessed information (e.g., concomitant medication, 
medical history) should be submitted to the IRB. The investigator is responsible for ensuring that all 
events are followed until either resolved or stable. 
8.5.2 Sponsor reporting: Notifying the Funding Sponsor 
Electronic notification of any adverse events related to the use of the core warming device will be 
sent to the funding sponsor as determined by the principal investigator and study team. 
  

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8.6 Unblinding Procedures 
The study team will not be blinded to the randomization assignment. The study team will be 
instructed to maintain blinding for participants unless a participant has a clinical need to know their 
randomization assignment. The decision to unblind will be at the discretion of the study PIs and only 
if unblinding would change clinical care. Unblinding for safety reasons will be recorded in study 
records and it will be reported to the IRB and the funding sponsor at the time of continuing review. 
8.7 
Data and Safety Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study. The Principal 
Investigator and designated members of the study team will be responsible for monitoring subject 
safety and applicable reporting to the IRB and study sponsor. This safety monitoring will include 
careful assessment of eligibility and detailed assessment and appropriate reporting of adverse events 
as noted above. Data collected on the study will be reviewed after 10 people are enrolled in the study. 
Another data review will occur at 22 patients enrolled. 
9 
Study Administration, Data Handling and Record Keeping  
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization. For 
subjects 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 subject is alive) at the end of their scheduled 
study period. 
9.2 
Data Collection and Management 
Data will be collected by trained research staff using source documents and CRFs. Source and 
CRFs will be entered into a RedCap data management system. Participants will be assigned a 
Participant ID “PID” for use on CRF data collection for entry into the data management system to 
protect and ensure confidentiality. 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and 
  

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records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial. 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the CRF 
is left blank because the procedure was not done or the question was not asked, write “N/D”. If the 
item is not applicable to the individual case, write “N/A”. All entries should be printed legibly in black 
ink. If any entry error has been made, to correct such an error, draw a single straight line through 
the incorrect entry and enter the correct data above it. All such changes must be initialed and dated. 
DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain entries, print 
the clarification above the item, then initial and date it. The study data will be stored indefinitely. A 
de-identified data set may be shared with the funding sponsor. 
9.3 
Records Retention 
Study records, including administrative and participant related source and CRFs, will be retained for 
7 years after the completion of the research (often marked by a final progress report). 
10 Study Monitoring, Auditing, and Inspecting  
10.1 Study Monitoring Plan 
The investigator and research team will allocate adequate time for such monitoring activities. The 
Investigator will also ensure that the monitor or other compliance or quality assurance reviewer is 
given access to all the above noted study-related documents and study related facilities (e.g. ICU), 
and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.). The investigator will ensure the capability for inspections of applicable study-related 
facilities. Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies and 
procedures. This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the funding sponsor before commencement 
of this study if required. The formal consent of a subject, using the IRB-approved consent form, must 
be obtained before that subject undergoes any study procedure. The consent form must be signed 
by the subject or legally acceptable surrogate or legally authorized representative, and the 
appropriately delegated research staff obtaining the consent. 
  

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11.1 Risks 
Risks of the study procedures are described below: 
Core warming risks: Placement of the core warming device, similar to any device in the esophagus, 
can result in or exacerbate esophageal tissue damage, particularly in patients with known 
esophageal deformity or evidence of esophageal trauma. These risks are similar to those who 
receive the standard of care orogastric or nasogastric tubes inserted into the esophagus during 
routine clinical care of ICU patients. 
There is also a risk that placement of the core warming device may result in movement of the tongue 
to the side, which can persist after removal; however, it is unclear whether this tongue deviation is 
caused by the endotracheal tube used during mechanical ventilation or if it is part of the disease 
progression of COVID-19 infection. Tongue deviation is one of the known sequelae of infection with 
SARS-CoV-2, better known as COVID-19.[53][54][55] Electromyography of the muscles innervated 
by the pharyngeal, superior laryngeal, and recurrent laryngeal branches of the vagus nerve, and by 
the accessory and hypoglossal nerves, have shown asymmetric patterns of acute or chronic 
neurogenic damage, or both.[54] Whether these findings reflect the direct (viral) or indirect (immune-
mediated) effect of SARS-CoV-2 remains to be established.[54] 
Loss of Confidentiality Risks: There is the potential for loss of confidentiality during data collection. 
Temperature modulation risks: Warming critically ill septic patients has been previously 
investigated, with no unforeseen risks identified. Whole-body hyperthermia (to core body 
temperatures > 39.0°C) has been tested in sedated patients undergoing colorectal surgery, as well 
as in oncological patients in combination with radiotherapy and/or chemotherapy.[52] Patients in 
these studies suffered no serious hyperthermia-related side effects despite being warmed to 
temperatures much higher than targeted in this study. 
Potential adverse effects of external warming/body temperature elevation include: 
(1) Vasodilation of arteriovenous shunts in the skin resulting in decreased blood pressure and an 
increase in vasopressor dose 
(2) Elevated heart rate 
(3) Increased respiratory rate 
(4) Increased metabolic rate 
(5) Patient discomfort 
(6) Sweating 
(7) Worsened long-term neurological function in patients with acute stroke or post-cardiac arrest 
(8) Exacerbation of multiple sclerosis symptoms 
This study will only enroll COVID-19 patients, and will exclude any with acute stroke, post-cardiac 
arrest, or multiple sclerosis. 
  

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11.2 Benefits 
There are no known direct benefits to the participants in this study. There may be a benefit to core 
warming of patients with COVID-19. The knowledge gained by participation in this study may 
benefit society as a whole in the future and potentially lead to additional studies. 
11.3 Risk Benefit Assessment 
The risks of participating in the study are outweighed by the potential benefits of participating in the 
study. 
11.4 Informed Consent Process/ HIPAA Authorization 
Participants’ surrogate or legally authorized representative will be provided an IRB approved 
consent form describing this study and providing sufficient information to make an informed 
decision about their participation in this study. A verbal review of the consent form will take place 
with the participant and delegated personnel. This consent form will include HIPAA authorization 
language which will also be reviewed with the participant. The formal consent of a subject, using 
the IRB-approved consent form, will be obtained before that subject undergoes any study 
procedure. The consent form must be signed by the subject or legally acceptable surrogate or 
legally authorized representative, and the investigator-designated research professional obtaining 
the consent. The participant will be consented in a private clinical space and will be given ample 
time to ask questions and have questions answered. As the majority of the procedures that will 
occur are standard of care, we will clearly discuss what the research part of the day and days after 
will include. The voluntary nature of the study will be reviewed and participants will be told that 
should they choose not to consent, their clinical care will not be effected. 
12 Study Finances  
12.1 Funding Source 
Pending 
12.2 Conflict of Interest 
All Investigators will follow the institution’s policies on Conflicts of Interest related to research. 
12.3 Participant Stipends or Payments 
Participants will not receive payment. 
13 Publication Plan 
Investigators will follow all applicable policies and guidelines relating to publishing study results. 
The research team will share materials planned for publication to the Funding Sponsor according 
to the terms of the Clinical Trial Agreement. 
14 References 
1. 
Mohr NM, Doerschug KC: Point: Should antipyretic therapy be given routinely to febrile 
patients in septic shock? Yes. Chest 2013, 144(4):1096-1098. 
  

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2. 
Ray JJ, Schulman CI: Fever: suppress or let it ride? Journal of thoracic disease 2015, 
7(12):E633-E636. 
3. 
Drewry AM, Hotchkiss RS: Counterpoint: Should antipyretic therapy be given routinely 
to febrile patients in septic shock? No. Chest 2013, 144(4):1098-1101. 
4. 
Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, Dellamonica J, Bouadma 
L, Cook F, Beji O et al: Fever control using external cooling in septic shock: a randomized 
controlled trial. Am J Respir Crit Care Med 2012, 185(10):1088-1095. 
5. 
Saxena M, Young P, Pilcher D, Bailey M, Harrison D, Bellomo R, Finfer S, Beasley R, Hyam 
J, Menon D et al: Early temperature and mortality in critically ill patients with acute 
neurological diseases: trauma and stroke differ from infection. Intensive Care Med 
2015, 41(5):823-832. 
6. 
Young PJ, Saxena M, Beasley R, Bellomo R, Bailey M, Pilcher D, Finfer S, Harrison D, 
Myburgh J, Rowan K: Early peak temperature and mortality in critically ill patients with 
or without infection. Intensive Care Med 2012. 
7. 
Berman JD, Neva FA: Effect of temperature on multiplication of Leishmania 
amastigotes within human monocyte-derived macrophages in vitro. Am J Trop Med 
Hyg 1981, 30(2):318-321. 
8. 
Mace TA, Zhong L, Kilpatrick C, Zynda E, Lee C-T, Capitano M, Minderman H, Repasky EA: 
Differentiation of CD8+ T cells into effector cells is enhanced by physiological range 
hyperthermia. Journal of Leukocyte Biology 2011, 90(5):951-962. 
9. 
Chu CM, Tian SF, Ren GF, Zhang YM, Zhang LX, Liu GQ: Occurrence of temperature-
sensitive influenza A viruses in nature. J Virol 1982, 41(2):353-359. 
10. 
Moench LM: A Study of the Heat Sensitivity of the Meningoeoecus in Vitro within the 
Range of Therapeutic Temperatures. Journal of Laboratory and Clinical Medicine 1937, 
22:665-676. 
11. 
Small PM, Tauber MG, Hackbarth CJ, Sande MA: Influence of body temperature on 
bacterial growth rates in experimental pneumococcal meningitis in rabbits. Infection 
and immunity 1986, 52(2):484-487. 
12. 
Mackowiak PA, Ruderman AE, Martin RM, Many WJ, Smith JW, Luby JP: Effects of 
physiologic variations in temperature on the rate of antibiotic-induced bacterial 
killing. American journal of clinical pathology 1981, 76(1):57-62. 
13. 
Launey Y, Nesseler N, Mallédant Y, Seguin P: Clinical review: fever in septic ICU 
patients--friend or foe? Critical care (London, England) 2011, 15(3):222-222. 
14. 
Doran TF, De Angelis C, Baumgardner RA, Mellits ED: Acetaminophen: more harm than 
good for chickenpox? J Pediatr 1989, 114(6):1045-1048. 
15. 
Brandts CH, Ndjave M, Graninger W, Kremsner PG: Effect of paracetamol on parasite 
clearance time in Plasmodium falciparum malaria. Lancet 1997, 350(9079):704-709. 
16. 
Stanley ED, Jackson GG, Panusarn C, Rubenis M, Dirda V: Increased virus shedding with 
aspirin treatment of rhinovirus infection. Jama 1975, 231(12):1248-1251. 
17. 
Peters MJ, Woolfall K, Khan I, Deja E, Mouncey PR, Wulff J, Mason A, Agbeko RS, Draper 
ES, Fenn B et al: Permissive versus restrictive temperature thresholds in critically ill 
children with fever and infection: a multicentre randomized clinical pilot trial. Critical 
care (London, England) 2019, 23(1):69-69. 
18. 
Evans SS, Repasky EA, Fisher DT: Fever and the thermal regulation of immunity: the 
immune system feels the heat. Nature reviews Immunology 2015, 15(6):335-349. 

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19. 
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