Prospective, Interventional Study Evaluating the Feasibility and Safety of the Esophageal Cooling Device in 15 Patients Suffering From Traumatic Brain Injury and Treated With Targeted Temperature Management
Phase: NA
Conditions: Traumatic Brain Injury
Sponsor: Advanced Cooling Therapy, Inc., d/b/a Attune Medical

Protocol № ACT TBI-01   
 
Prospective, interventional study evaluating the feasibility and safety of the 
Esophageal Cooling Device in patients suffering from traumatic brain injury and 
treated with targeted temperature management
Study reference number 
ACT TBI-01 
Sponsor 
Advanced Cooling Therapy, Inc. 
3440 S. Dearborn St. 
#215-S 
Chicago, IL  60616 
Email: info@advancedcoolingtherapy.com 
Phone: +1-312-725-4756 
Fax: +1-888-481-4756 

Protocol No ACT TBI-01 
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Abstract: 
Controlling patient’s body temperature, and in particular, reducing body temperature in a 
treatment referred to as targeted temperature management, has been shown to improve outcomes 
for many conditions, including neonatal hypoxic ischemic encephalopathy, cardiac arrest, and 
traumatic brain injury. However, available modalities for inducing targeted temperature 
management have a number of technical, logistical, and financial barriers. The Esophageal 
Cooling Device is a multi-chambered silicone tube placed in the esophagus that provides a 
highly efficient heat transfer to or from a patient. The Esophageal Cooling Device potentially 
improves the ability to treat patients with targeted temperature management by eliminating the 
risks and complexities of existing methods of inducing targeted temperature management while 
maintaining the functionality of the orogastric tube that it replaces. Initial mathematical and 
animal studies have shown strong support for the efficacy and safety of the Esophageal Cooling 
Device. Placement of a nasogastric or an orogastric tube is a standard of care for unconscious 
patients suffering from conditions typically treated with targeted temperature management. The 
present study will replace the usual orogastric tube with the Esophageal Cooling Device in order 
to evaluate the feasibility and safety of inducing targeted temperature management. 
The aim of this prospective, interventional study is to assess the feasibility and safety of the 
Esophageal Cooling Device in 15 patients from the Ukraine suffering from traumatic brain injury 
who the treating physician is treating with targeted temperature management. Comparison of 
outcomes will be made to historical controls, and analysis will utilize a non-inferiority design. 
The primary outcome is the time to initiation of targeted temperature management, as measured 
from the time a decision is made to begin targeted temperature management, to the time the 
esophageal cooling device is in place.. The secondary endpoints: the feasibility of inducing, 
maintaining, and 
rewarming patients from targeted temperature management using the 
Esophageal Cooling Device (cooling rate, rewarming rate, and the percent of time within goal 
temperature during the goal-temperature maintenance period); evaluation of adverse events 
(including cardiac arrhythmias, severe 
bradycardia, myocardial infarction/re-infarction, 
dysphagia, odynophagia, aspiration pneumonia, non-aspiration pneumonia, reflux, esophageal 
injury, and esophagitis) will be closely monitored during the whole period of targeted temperature 
management 

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Background: 
Current medical practice entails modifying or influencing the temperature of patients for a large 
and growing number of conditions. For example, temperature control (which includes reduction 
of body temperature below normal, maintenance of normal body temperature for the avoidance 
of febrile or hyperthermic states by cooling, and active warming of patients to avoid unintended 
reductions of body temperature) has been shown either preliminarily or definitively to be 
beneficial for: 
• 
patients who remain comatose after resuscitation from cardiac arrest[1-5] 
• 
neonatal hypoxic ischemic encephalopathy[6-10] 
• 
certain subsets of traumatic brain injury[11, 12] 
• 
spinal cord injury[13-15] 
• 
certain subsets of stroke[16-20] 
• 
acute myocardial infarction[21-24] 
• 
traumatic/hemorrhagic cardiac arrest[25] 
• 
surgical operations lasting longer than 1 hour[26-31] 
• 
hepatic encephalopathy[32-34] 
• 
severe heat stroke[35, 36] 
• 
sepsis/septic shock[37] 
Evaluations of temperature management in numerous other conditions are ongoing, including 
conditions such as spontaneous intracerebral hemorrhage, burns, sepsis, adult respiratory distress 
syndrome, acute subdural hematoma, pancreatitis, status epilepticus, necrotizing enterocolitis, 
and for organ preservation prior to donation. A recent search on ClinicalTrials.gov shows almost 
300 open studies evaluating temperature management (hypothermia, normothermia, or targeted 
temperature management) for various clinical conditions. The strength of evidence for improved 
outcomes via modulating temperature of certain conditions (in particular, adults who remain 
comatose after resuscitation from cardiac arrest, neonates suffering from hypoxic ischemic 
encephalopathy, or patients undergoing general surgical procedures longer than one hour in 
duration) is such that it is now considered a standard of care, endorsed by the major resuscitative, 
cardiovascular, neonatal, and/or surgical standards groups (including the American Heart 
Association, the International Liaison Committee on Resuscitation, the European Resuscitation 
Council, the National Institute of Child Health and Human Development, the National Institute 
for Health and Care Excellence, the Centers for Medicare and Medicaid Services via the Surgical 
Care Improvement Project, and the American Society of Anesthesiologists).[38-45] The specific 
term applied to temperature modulation in the case of intentional reductions of body temperature 
to improve outcomes is generally referred to as therapeutic hypothermia (TH) or targeted 
temperature management (TTM). The use of TTM for traumatic brain injury (TBI) has been 
shown in a recent meta-analysis to be beneficial and associated with a significant reduction in 
mortality and a significant reduction in poor outcome.[11] In fact, while further randomized 
controlled studies are ongoing (in particular, the EuroTherm3235 trial), many institutions have 
adopted TH as a standard of care for TBI.[12, 46] 
To date, however, available modalities for inducing TTM have a number of technical, logistical, 
and financial barriers, including difficulties in placement, risks of use (such as needle sticks, 
infections, blood clots, and skin damage), and high cost. The Esophageal Cooling Device is a 
disposable device that potentially improves the effectiveness of TTM while minimizing the risks 

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of other existing methods such as invasive methods.[47] The Esophageal Cooling Device (shown 
in Figure 1 and Figure 2) is a multichambered silicone heat exchanger that is placed in the 
esophagus to provide highly efficient heat transfer to/from a patient while simultaneously 
maintaining access to the stomach to allow gastric suctioning, decompression, and drainage, as 
usually performed in such patients in emergency departments, operating rooms, and intensive 
care units. 
 
 
Figure 1. Photograph of the Esophageal Cooling Device (ECD). 
 
 
The esophagus is in close proximity to blood flow from the heart and great vessels, and the 
Esophageal Cooling Device is designed to take advantage of this heat exchange environment. 
The Esophageal Cooling Device’s ability to decompress the stomach and avoid distention of the 
esophagus away from the device ensures good contact with the esophageal mucosa, and thus 
maximizes heat transfer from the patient. The Esophageal Cooling Device replaces the standard 
orogastric tube which is placed in the target patient population as a routine standard of care, is 
made of standard medical-grade silicone, and is generally similar in size and shape to the 
orogastric tubes currently used. Initial mathematical and animal studies have shown strong 
support for the efficacy and safety of the Esophageal Cooling Device.[47-49] 
 
 
Figure 2. The Esophageal Cooling Device (ECD) shown in place in the esophagus 
(replacing the routine gastric tube placed in the target population as a standard of care), 
and located behind the trachea (containing the endotracheal tube which is placed in the 
trachea routinely to provide ventilation in the target patient population). 

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Study design: 
Prospective, interventional study evaluating the feasibility and safety of the Esophageal Cooling 
Device in 15 patients suffering from traumatic brain injury and treated with targeted temperature 
management. Comparison of outcomes will be made to historical controls, and analysis will 
utilize a non-inferiority design. 
 
 
Primary outcome: 
Time to initiation of targeted temperature management, as measured from the time a decision is 
made to begin targeted temperature management, to the time the esophageal cooling device is in 
place. 
 
 
Secondary outcomes: 
Secondary performance outcomes include the feasibility of inducing, maintaining, and 
rewarming patients from targeted temperature management using the Esophageal Cooling 
Device. Specifically, cooling rate, rewarming rate, and the percent of time during the goal- 
temperature maintenance period within 1°C of goal temperature (typically 33°C, but with some 
centers using anywhere from 32°C to 36°C) will be measured. 
 
Secondary safety outcomes include evaluation of adverse events including the following: cardiac 
arrhythmias, severe bradycardia, myocardial infarction/re-infarction, dysphagia, odynophagia, 
aspiration pneumonia, non-aspiration pneumonia, reflux, esophageal injury, and esophagitis. 
 
 
Specific definitions of adverse events and the methods used to identify and diagnose each during 
the treatment and 30-day follow-up phases are as follows: 
 
• Cardiac arrhythmias - recording of atrial or ventricular arrhythmias during course of 
treatment. 
• Severe bradycardia - heart rate < 30/min and necessitating pacing and cessation of TH. 
• Myocardial infarction - universal definition of myocardial infarction as per the joint 
ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction.[50] 
• Dysphagia - report from patient of difficulty in swallowing for more than 24 hours after 
cessation of device use, diagnosed with a Modified Barium Swallow Study, 
Videofluoroscopic Swallow Study, or patient self-report. 
• Odynophagia - report from patient of pain with swallowing for more than 24 hours after 
cessation of device use, diagnosed by subjective patient sensation. 
• Aspiration pneumonia - demonstration by chest X-ray of evidence of aspiration 
pneumonia, as diagnosed by treating physician, within 24 hours of cessation of device 
use. 

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• Non-aspiration pneumonia - demonstration by chest X-ray of evidence of pneumonia 
within 24 hours of cessation of device use that is diagnosed by the treating physician as 
non-aspiration pneumonia. 
• Reflux - report of symptoms from patient within 3 days of recovery, with diagnosis via 
esophageal pH monitoring or endoscopy. 
• Esophageal injury - evidence of traumatic and/or ischemic esophageal injuries diagnosed 
by gastroenterologist evaluation via esophagogastroduodenoscopy as warranted or 
indicated, and describing the absence of necrosis or not according to the Zargar 
classification used for caustic injuries within  3 days of recovery . 
• Esophagitis - evidence of esophageal inflammation diagnosed by gastroenterologist 
evaluation via esophagogastroduodenoscopy if warranted or indicated, and as defined by 
Savary-Miller and staged from 1 to 4 according to the severity of the disease within 3 
days of recovery. 
 
A serious adverse event (SAE) is defined as any adverse event that: 
• 
Results in death 
• 
Is life threatening 
• 
Requires hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
 
 
 
Patient population: 
Patient population will consist of 15 patients suffering from traumatic brain injury, in whom the 
treating clinician has determined that targeted temperature management will be initiated. 
 
Duration of patient’s participation in the study  
The patient’s duration of the participation should be considered as follows: 
• From signing of consent form by patient’s legal representative and until 30 days if the 
patient has recovered within 30 days from the consent’s signature and is able to sign the 
ICF personally; 
• From signing of consent form by patient’s legal representative and until the patient’s 
recovery  – patient’s ability to sign the consent form (either a full or at least sufficiently 
partial neurologic recovery that allows the patient to awaken, function, understand 
conversation, ability to sign personally); 
• From signing of consent form by patient’s legal representative to patient’s death 
 
Inclusion criteria: 
Adult patients (age 18 years and over) 
 
 
Exclusion criteria: 

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• Patients with known esophageal deformity or evidence of esophageal trauma (for 
example, known esophageal varices, cirrhosis, history of esophagectomy, previous 
swallowing disorders, achalasia, etc.). 
• Patients with known ingestion of acidic or caustic poisons within the prior 24 hours. 
• Patients with less than 40 kg of body mass. 
• Patients known to be pregnant. 
• Terminal disease or “do not resuscitate order” that could lead to early-onset therapeutic 
withdrawal (<48 hours after collapse). 
• Unstable hemodynamic conditions (defined as intractable severe cardiogenic shock or 
ECLS requiring) that could lead to multi-organ failure and early-onset death (<48 hours 
after collapse). 
• Pre-existing severe conductive disorder requiring pacing. 
 
 
Informed consent and ethical considerations: 
Written informed consent will be obtained from each patient’s next of kin or patient’s legal 
representative before inclusion. Surviving patients without severe neurological sequels will 
give their written informed consent. When a patient has recovered, and is able to do so, he/she 
has to sign the informed consent form personally. 
This study will be conducted according to the principles of the Declaration of Helsinki ( as 
amended October 2013) of the World Medical Association. The protocol will be submitted and 
approved by the local Ethics Committee of the institution. 
 
Randomization: 
Randomization: none 
 
Esophageal Cooling Device: 
The placement of the Esophageal Cooling Device will follow standard recommendations as per 
Instructions for Use. The Esophageal Cooling Device will beconnected to the appropriate 
console (Meditherm III, Blanketrol II, or Blanketrol III). 
 
Other treatments: 
Standard treatments for traumatic brain injury will follow local guidelines. Fluid and other 
management is left at the discretion of the attending physician. 
 
Data collection: 
All clinical and biological parameters will be recorded according to the Utstein-style 
recommendations for reporting resuscitation outcomes.[51] Neurologic outcome will be assessed 
according to the Cerebral Performance Category (CPC) score.[52] Initial temperatures will be 
measured via a tympanic or naso-pharyngeal temperature sensors in the prehospital field if 
available, or by other means used as standard of care. Continuous temperature measurement 
(specifically during cooling, maintenance, and rewarming) will be measured by bladder 
temperature sensors or rectal temperature sensors, and arterial temperature monitoring if 
available. Time of ECD placement in a patient will be recorded; the potential side effects (see 
above) will be recorded throughout the entire study.. 

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Study assessments and procedures  
 
Screening on Day 1  
 
This visit includes the primary diagnostic procedures and the verification of the eligibility criteria. 
Subjects are eligible for the study will undergo the following procedures at this visit: 
• Written informed consent (the form will be signed by a patients or legally acceptable 
representative); 
• Previous medical history and co-morbidities; 
• Physical examination including body weight, height and BMI, general appearance, heart, 
lungs, abdomen and extremities examinations; 
• Demographics;  
• Smoking habits; 
• Alcohol consumption;  
• Inclusion/exclusion criteria; 
• Concomitant medications; 
• Pre-hospital data: scene of injury (place of residence/public place/other), witness injury 
(yes/no), time from emergency call to arrival of EMS personnel, estimated time from injury 
to basic life support, estimated time from injury to advanced life support, location patient 
intubated (on scene/in ambulance/in emergency department); 
• First recorded temperature and method of temperature measurement; 
• Glasgow Coma Score; 
• Presence of pupillary and corneal reflex; 
• Any sign of spontaneous breathing/agonal breathing/gasping at admission; 
• Blood gas and FiO2 (pO2, pCO2, BE, pH, lactate); 
• Blood glucose; 
• Troponin; (if obtained) 
• BNP; (if obtained) 
• ECG (normal/STEMI/LBBB/other); 
• Echocardiogram (EF-normal, EF-moderately impaired, EF-severely); (if obtained) 
• Head CT scan (at least the type of injury (subdural, epidural, subarachnoid, etc.) and relevant 
parameters for each (size, midline shift, volume of hematoma, etc.) should be recorded) 
• Surgical interventions (if any) 
 
After screening, subjects eligible for the study participation will undergo the following procedures 
during this time period:  
 
• Temperature will be measured every hour from time point “0” to 39 hours. Time point “0” is 
the time either the patient or patient's legal representative, or close relatives signs the consent 
form. Method of temperature measurement should be recorded for each measurement. Two 
methods should be used for each time point measurement: 1) standard monitored route 
(rectal, Foley, intravascular, etc.); 2) temperature reported from the Blanketrol II 
• Blood glucose and dose of insulin: 0 hr, 4 hr, 16 hr, 28 hr, 36 hr; 
• Lowest and highest heart rate: 0 hr, 4hr, 16 hr, 28 hr, 36 hr; 
• Lowest and highest mean arterial pressure: 0 hr, 4hr, 16 hr, 28 hr, 36 hr; (if arterial pressure 
is measured) 

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• Dose of vasopressor or other inotropic medication: 0 hr, 4hr, 16 hr, 28 hr, 36 hr; 
• PaO2, FiO2 and mean airway pressure (MAP): 0 hr, 4hr, 16 hr, 28 hr, 36 hr;; 
• Anti-shivering therapy administered, type and dose: 0 hr, 4hr, 16 hr, 28 hr, 36 hr; 
• Central venous or mixed venous oxygen saturation: 0 hr, 4hr, 16 hr, 28 hr, 36 hr; (if 
measured) 
• Arterial or venous lactate concentration: 0 hr, 4hr, 16 hr, 28 hr, 36 hr; (if measured) 
• Blood gases (pH, pCO2, pO2, BE): 0 hr, 4hr, 16 hr, 28 hr, 36 hr; (if obtained as part of routine 
care) 
 
 
 After the first 24 hours from the admission of the patient to the hospital Simplified Acute Physiology 
Score (SAPS) III will be measured. 
 
Daily during day 1-7 if ICU stay the following procedures and assessments will be performed and 
recorded in the CRFs: 
• Sequential Organ Failure Assessment (SOFA) scores; 
• GCS scores; 
• Pupillary and corneal reflex check; 
• Highest body temperature; 
• Highest dose and type of vasopressor/inotropic medication; 
• The need for pacing; 
• Intracranial pressure monitor pressures will be recorded (if measured); 
• Recording of a need for mechanical circulatory assistance; 
• Mechanical ventilation (if necessary); 
• Recording od daily net fluid balance; 
• Recording of adverse events; 
 
Daily from day 8 to ICU discharge or day 14 the following records will be made: 
• Patient comatose (yes or no); 
• Mechanical ventilation (yes or no); 
• Renal replacement therapy (yes or no); 
• Presence of pneumonia (aspiration/non-aspiration) and sepsis (yes or no) 
 
CPC should be assessed and recorded daily with the last recording being either at discharge, or at 
the 30 day time point. 
 
Daily from day 1 to day 14 “do not attempt resuscitation order” should be recorded in the CRFs. 
 
Based on investigator’s discretion, the following procedures may be performed if a decision is being 
contemplated for withdrawal of patient care”: 
• Results and time of SSEP, if performed (n20 present bilaterally/n20 present unilaterally/n20 
absent); 
• Results and time of EEG, if performed. 
 
At ICU discharge or 30 days from admission the following procedures will be recorded if performed 
(only CPC and GCS are mandatory): 
• EEG, MRI, CT (if performed) 
• CPC and GCS; 

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• Esophagogastroduodenscopy (if performed) 
 
Throughout the entire study: 
• Concomitant medications; 
• Adverse events 
 
 
Statistical analysis 
Sample size for primary outcome is calculated with an assumption of time to initiate cooling 
being approximately 5 minutes, with standard deviation of 4 minutes for the esophageal cooling 
device, and 20 minutes, with standard deviation of 15 minutes, for alternative devices. A power 
of 80%, and alpha of 5%, yields a sample size of 14 patients (with an equivalent size of historical 
controls). Sample size for secondary outcome is calculated for a non-inferiority test against the 
 
current standard (cooling blankets or evaporative cooling). For the endpoint of percent of time 
over the study period within 1°C of goal temperature (33°C), the treatment effect of the active 
control is large, since non-treatment results in essentially no attainment of goal temperature. An 
estimate of effect of the active comparator (M1) is therefore greater than would be acceptable to 
use as a base for a non-inferiority margin. Consequently, a more restrictive non-inferiority 
margin (M2) is then proposed of 15% (i.e., if the standard maintains goal temperature +/-1°C for 
60% of the time, and the ECD maintains goal temperature +/-1°C for 85% of the time, the lower 
bound of the 95% CI on the difference between percent time at goal temperature between 
standard and test device is greater than 70%).Setting the type I error rate to 5%, for an alpha of 
0.05, and a power of 80%, for a beta of 0.2, yields a sample size estimate of 15 patients in the 
study (with another at least 15 patients coming from historical controls with available 
esophagogastroduodenoscopy evaluation). 
 
Data analysis: as recommended by current FDA guidance documents, both per-protocol (as- 
treated) and intent-to-treat analyses will be performed.[53] Lower 95% confidence limit for 
difference between groups must exclude the non-inferiority margins for primary end point in 
both efficacy and safety. 
 
 
 
Abbreviation 
ACT - Advanced Cooling Therapy  
AE – adverse event 
BNP - brain natriuretic peptide 
ECG - electrocardiogram 
GCS – Glasgow Coma Score 
CPC - Cerebral Performance Category  
CT – computed tomography 
ECD - Esophageal Cooling Device 
ECLS - Extra-Corporeal Life Support 
EEG – electroencephalogram  
LBBB - left bundle branch block 
MAP – mean airway pressure 
MRI - Magnetic Resonance Imaging 

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OTC – over-the-counter 
ROSC - Return of Spontaneous Circulation 
SAE – Serious Adverse Event 
SAPS – Simplified Acute Physiology Score 
SOFA – Sequential Organ Failure Assessment 
SSEP  - Somatosensory evoked potentials 
STEMI - ST-elevated myocardial infarction 
TH - Therapeutic Hypothermia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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