Transnasal Induction of Normothermia in Febrile Stroke Patients
Phase: NA
Conditions: Stroke, Ischemic, Stroke Hemorrhagic, Fever, Seizures, Metabolic Encephalopathy
Sponsor: CoolTech LLC

 
PROTOCOL PAGE 1 of 57 
 
Transnasal Induction of Normothermia in NCCU Fever 
Patients  
 
Contents 
 
 
Protocol Number: 
P-224011-0003 
Protocol Version: 
D 
Sponsor: 
CoolTech 
40 East Cross Street 
Baltimore, MD 21230 
Sponsor Contact: 
Casey Hannan 
410.646.8522 o 
203.685.6352 c 
channan@cooltechcorp.com  
Product Designer / Developer  
Contact: 
Key Technologies, Inc. 
Baltimore, MD  
Will DeMore, Project Manager 
410-385-0200  
wdemore@keytechinc.com  
Product Manufacturer 
(Disposables) Contact: 
Engineered Medical Systems (EMS)  
2055 Executive Drive 
Indianapolis, IN 46241 
Jeff Quinn, General Manager(317) 246-5500 
jquinn@engmedsys.com 
Monitor: 
Paul Manberg, PhD 
Corolla ClinReg Consulting  
854 Parkland Place 
Glen Allen, VA 23059 
508-878-0297 
pmanberg@gmail.com  
Lead Investigator: 
Neeraj Badjatia, MD, MSc 
Chief of Neurocritical Care, Program in Trauma 
Professor of Neurology 
University of Maryland School of Medicine 
22 S. Greene Street, G7K19 
Baltimore MD 21201 
410.328.4515 
nbadjatia@umm.edu  

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1.0 
Summary of Study Plan ......................................................................... 6 
2.0 
Literature review: Background and Rationale ................................. 14 
2.1 
Neurogenic Fever .............................................................................................. 14 
2.2 
Principles of the COOLSTAT Technology ..................................................... 14 
2.3 
Study Rationale .................................................................................................. 16 
3.0 
Description of the COOLSTAT Device ............................................ 16 
3.1 
Device Description ............................................................................................ 16 
3.2 
Control System ................................................................................................... 18 
4.0 
Indication for Use and Contraindications ........................................ 19 
4.1 
Indication for Use .............................................................................................. 19 
4.2 
Contraindications .............................................................................................. 19 
5.0 
Risk/Benefit Analysis ........................................................................... 19 
5.1 
Analysis of Risks to Subjects and Potential Benefits .................................... 19 
5.1.1 
Risks Associated with Use of the Device ............................................................... 20 
5.1.2 
Risks Associated with Denying Standard of Care ................................................ 25 
5.2 
Manner in Which Risks will be Minimized ................................................... 25 
5.3 
Justification for the Investigation .................................................................... 27 
5.4 
Description of Patient Population ................................................................... 27 
5.5 
Alternative to this Treatment ........................................................................... 27 
5.5.1 
Advantages of COOLSTAT Compared to Predicate Technologies .................... 28 
5.5.2 
Risks and Disadvantages of COOLSTAT Compared to Predicate Technologies
 
28 
6.0 
Study Design .......................................................................................... 29 
6.1 
Definitions .......................................................................................................... 29 
6.2 
Purpose and Objectives .................................................................................... 29 
6.3 
Primary Efficacy Endpoint and Success Criteria .......................................... 29 
6.4 
Safety Outcomes ................................................................................................ 29 
6.5 
Investigational Duration and Follow-up ........................................................ 30 
6.6 
Sample size calculations ................................................................................... 30 
6.7 
Number of Investigational Sites and Locations ............................................ 31 

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6.8 
Methods to Reduce Bias and Conduct of the Investigation ........................ 31 
6.9 
Intracranial Pressure Monitoring .................................................................... 31 
6.10 
Transition from 8-hour Cooling to 24-hour Cooling .................................... 31 
7.0 
Subject Recruitment and Enrollment ................................................ 32 
7.1 
Patient Recruitment ........................................................................................... 32 
7.2 
Point of Enrollment and Therapy Initiation Defined ................................... 32 
8.0 
Study Inclusion and Exclusion Criteria ............................................ 34 
8.1 
Inclusion Criteria ............................................................................................... 34 
8.2 
Exclusion Criteria .............................................................................................. 34 
9.0 
Sequence of Investigational Assessments and Procedures .......... 35 
9.1 
Study Team Member Activities to Assess Eligibility for Cooling .............. 35 
9.2 
Phase 0 – Monitoring Before Cooling ............................................................. 36 
9.3 
Phase 1 – Active Cooling Phase ....................................................................... 37 
9.4 
Phase 2 – Post-Therapy Monitoring Phase .................................................... 40 
9.5 
Phase 3 – Post-Cooling Follow-up .................................................................. 40 
9.6 
Tasks during Cooling ........................................................................................ 40 
9.7 
Anti-Shivering Regimen ................................................................................... 41 
9.8 
Turning Off and Clean-up ................................................................................ 41 
9.9 
Subject Study Completion ................................................................................ 42 
10.0 
Adverse Events, Warning, and Precautions .................................. 42 
10.1 
Adverse Event Definitions ............................................................................... 43 
10.2 
Unanticipated Adverse Device Effect (Event) ............................................... 43 
10.3 
Actions in Response to Adverse Events ......................................................... 44 
10.4 
Anticipated Adverse Events ............................................................................ 44 
    10.5         Serious Adverse Events……………………….…………………………….45 
10.6 
Technical Device Failures ................................................................................. 45 
10.7 
Warnings ............................................................................................................. 45 
10.8 
Precautions ......................................................................................................... 45 
10.9 
Follow-up of Unresolved Events ..................................................................... 46 

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11.0 
Investigational Medical Devices ..................................................... 46 
11.1 
Description of Investigational Medical Devices ............................................ 46 
11.2 
Product Packaging and Labelling ................................................................... 46 
11.2.1 
Device Operating Instructions ................................................................................. 46 
11.2.2 
Device Package Labels .............................................................................................. 46 
11.2.3 
Disposable Package Labels ....................................................................................... 47 
11.3 
Required Experience and Training ................................................................. 47 
11.4 
Storage and Handling ....................................................................................... 47 
11.5 
Accountability of Investigational Medical Devices ...................................... 47 
12.0 
Data Collection and Management .................................................. 48 
12.1 
Case Report Forms ............................................................................................ 48 
12.2 
Review and Query of Completed CRFs ......................................................... 48 
12.3 
Retention of Records and Documentation ..................................................... 49 
12.4 
Data Management ............................................................................................. 49 
12.5 
Collection of Medical History Data for Patient ............................................. 49 
12.6 
Collection of Data by Device ............................................................................ 50 
12.7 
Collection of Manual Data ................................................................................ 51 
13.0 
Statistical Analysis Plan .................................................................... 51 
13.1 
Primary Performance Outcome Analysis ...................................................... 52 
13.2 
Secondary Performance Outcome Analysis .................................................. 53 
13.3 
Safety Assessment ............................................................................................. 53 
13.3.1 
Nasal Examination .................................................................................................... 53 
13.3.2 
Adverse Events .......................................................................................................... 53 
14.0 
Study Management and Responsibilities ..................................... 53 
14.1 
Informed Consent .............................................................................................. 54 
14.2 
Withdrawal of Subjects ..................................................................................... 54 
14.3 
Urgent Change in Therapy ............................................................................... 54 
14.4 
Investigator Responsibilities ............................................................................ 54 
14.5 
Study Monitoring and Data Safety Review Boards ...................................... 55 
14.6 
Institutional Review Board ............................................................................... 56 

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14.7 
Cost to the Subjects ............................................................................................ 56 
14.8 
Financial Compensation to Patients ................................................................ 56 
14.9 
Cost to the Clinic ................................................................................................ 56 
14.10 
Financial Considerations and Study Support ................................................ 56 
14.11 
Conflicts of Interest ........................................................................................... 56 
14.12 
Confidentiality ................................................................................................... 57 
14.13 
Principal Investigator Qualifications and Training ...................................... 57 
14.14 
Early Termination of the Study ....................................................................... 57 
14.15 
Protocol Deviations and Amendments .......................................................... 57 
14.16 
Final Report ........................................................................................................ 57 
 
NOTES to STUDY PROTOCOL REVIEWERS 
 NOTE 1: 
Throughout this protocol and case report forms, the term “investigator” may be 
used.  In such circumstances only an approved sub-investigator or the PI may execute the action.  
These actions specifically include decisions to enroll, start COOLSTAT therapy, stop COOLSTAT 
therapy and withdrawal the subject for any reason.  If any requirement is the sole jurisdiction of the 
Principal Investigator, it is specifically identified. The Site Principal Investigator will supervise the 
study and oversee that all clinical personnel assigned to this study have been trained to protocol 
requirements and device operation as necessary for their responsibilities. 
 
Additional study investigators (sub-investigators) may be designated and supervised by the Site 
Principal Investigator and shall conform to the requirements described below, including providing 
their curriculum vitae. 
 
PROTOCOL REVISION TABLES 
Rev 
Date 
Prepared By 
Reviewed By 
Approved By 
P2 
10/13/17 
--- 
--- 
 
P3 
8/8/18 
E. Bigelow 
B. Lipford 
B. Lipford 
P4 
1/30/19 
C. Hannan 
W. DeMore 
B. Lipford 
P5 
6/10/19 
C. Hannan 
 B. Lipford 
B. Lipford 
P6 
7/24/19 
C. Hannan 
B. Lipford 
B. Lipford 
A 
12/5/19 
C. Hannan 
W. DeMore 
B. Lipford 
B 
7/23/20 
C. Hannan 
W. DeMore 
B. Lipford 
C 
2/15/21 
C. Hannan 
W. DeMore 
B. Lipford 
D 
7/7/21 
C. Hannan 
W. DeMore 
B. Lipford 
 
Rev 
Details of Revision 
P2 
Original version approved by FDA for IDE and by UM IRB 

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P3 
Added revision table, corrected all references to the definition of fever to ≥38.3°C on pgs. 7, 
25, 36, and 37; Added BMI range exclusion criteria on p.35; Fixed typo on p. 34 
P4 
Expanded indications to include seizure and metabolic encephalopathy on pgs. 6, 7, 8, 10, 16, 
19, 23, 27, 32, 34, 38;  Added SpotOn as core temperature probe on pgs. 10, 18, 19, 26, 32, 36, 
37, 38, 39, 45; Allow otolaryngology residents to perform pre- and post-intervention nasal 
exams on pgs. 9, 11, 40, 52; Changed “systolic blood pressure” to “blood pressure” on pgs. 9, 
10, 23, 26, 34, 37, 40, 50; Changed Product Designer to Will DeMore on pg. 1. 
P5 
Removed site specific information to make protocol applicable to multiple investigational sites 
on pgs. 1, 5, 7, 8, 10, 11, 12, 18, 19, 20, 23, 25, 26, 27, 28, 31, 32, 36, 37, 38, 41, 42, 55, 56; Clarified 
hypothesis and statistical plan to account for cooling interruptions due to clinically required 
patient transport on pgs. 11, 12, 30, 31, 38, 39, 52; Allow tracheostomy patients on mechanical 
ventilator to be enrolled on pgs. 9, 20, 34, 35, 37, 41; Added section 6.11, which describes a 
staged approach to transition “history of cardiac arrhythmia” out of the exclusion criteria on 
p. 32; Fixed typos on p. 11, 12, 23, 24, 26, 30, 31, 34, 38, 39, 51, 52. 
P6 
Allow intensivist to perform pre-intervention nasal exams if an otolaryngologist is unavailable 
on pgs. 8, 10, 51. Fixed error in revision table on p. 5 
A 
Allow for enrollment of up to 70 subjects to account for a 55% screen failure rate (note that the 
total number of subjects who receive CoolStat therapy will remain unchanged at N = 30) on 
pgs. 9, 10, 29. Removed “tympanic” as specified core temperature probe on p. 39. Fixed typos 
on p. 7, 9, 36, 50. Note 2/5/2020: Revision changed from P7 to A upon PDM Pro transition.  
B 
Allow intensivist to perform post-intervention nasal exams if an otolaryngologist is 
unavailable on pgs. 10, 39, 52.  
C 
Update sponsor contact info on pg. 1. Revised descriptions of air flow paths to describe both 
double nostril and single nostril flow paths on pgs. 14, 17, 20, 52. Added description of serial 
data logger on p. 50. Provided criteria for assignment to double nostril vs single nostril flow 
on p. 52. 
D 
Added description for dose escalation procedures for subjects 21 through 30 on p. 52. Added 
new section for list of serious adverse events on p. 45.  
   
1.0 
Summary of Study Plan 
 
Study 
Objective 
The objective of this study is to evaluate safety and performance of the 
COOLSTAT® Transnasal Thermal Regulating Device in reducing temperature 
in a population of febrile subjects who meet the inclusion/exclusion criteria.  
Indication for 
use 
The CoolStat Transnasal Thermal Regulating Device is intended for 
temperature reduction to achieve normothermia, as an adjunct to anti-pyretic 
therapy, in adult patients with ischemic or hemorrhagic stroke, seizure, or 
metabolic encephalopathy who are intubated and sedated. 

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Intended use 
The COOLSTAT Transnasal Thermal Regulating Device is designed to be used 
inside a hospital or other healthcare setting for temperature reduction, 
operated by trained healthcare professionals.   
Device 
The COOLSTAT® Transnasal Thermal Regulating Device [hereafter 
COOLSTAT or CoolStat] cools febrile patients using dry filtered air at ambient 
temperature to induce an evaporative cooling energy exchange in the 
turbinates and upper airway.     
Prior testing 
to support 
safety 
A prototype system based upon CPAP equipment was evaluated in a porcine model 
which demonstrated no adverse events due to the airflow and showed cooling 
efficacy.  A similar prototype was evaluated in a non-significant risk, proof of concept 
study in humans which similarly demonstrated the safety of transnasal dry airflow.  
The clinical COOLSTAT device has been tested in a porcine model over 8 and 24 hour 
periods, which demonstrated safety and cooling efficacy.  
Study Design 
This will be a prospective, observational study of COOLSTAT in a neuro-ICU 
setting.  Below is a flow chart which summarizes the study protocol: 

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Phase 1 – Cooling Period*
- Subject cooled with COOLSTAT
- Manual data collection:
- every 5 minutes for 1st 30 minutes
- every 30 minutes for 1st 8 hours
- every 2 hours thereafter
- Target core temp maintained:
≥36C and ≤37.5C (see temp chart)
- Antipyretics continued per standard of care
- Stop cooling if core temp is <36 or >39C, or if 
tympanic temp is <34C
- Stop cooling if SBP or ICP above allowed limits 
sustained for > 5 minutes (see detail)
Phase 2 – short term observation
2 Hour Post-Cooling Observation:
- COOLSTAT removed from subject
- Manual data collection continues
every 15 minutes
- Subject may be cooled with other 
therapies  
End of Study
36 C
37.5 C
Therapy 
Target 
Range
Febrile
COOLSTAT Cooling Protocol
Phase 3 – Longer term observation
- Subject monitored for 22 hours
- ENT performs exam of upper airway      
within 24 hrs post Phase 1.
Subject 
temperature 
≤37.5C after
 4 hours?
Subject removed from 
the COOLSTAT, receives 
standard of care
No
Yes
(CONTINUES 
COOLING)
* Phase 1 Cooling Period:
- Cooling period will be limited to 8 
hours for first 10 subjects.
- Cooling period will be increased to 24 
hours if safety and performance 
criteria are met and it is 
approved by DSMB.
- SBP & ICP max allowed limits will 
follow standard care protocols for the 
indication being treated
Phase 0 – Monitoring
- CoolStat device installed but not turned on
- Temperature data collected for 30 minutes, with 
manual data collection every 5 minutes
- Monitor and record baseline SBP & ICP (if 
applicable)
 
Adverse 
Events 
Adverse Events:  Treating physicians may discontinue treatment at any time if 
adverse events are encountered or, in their opinion, alternate cooling methods 
are required on an urgent basis.  If at any point the physician switches to an 
alternate cooling method, the subject is not withdrawn from the study and data 
will continue to be collected manually for the remainder of the study period (if 
possible).  Follow-up continues per protocol.  Anticipated adverse events are 
detailed in the protocol Section 10. 

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Data 
Collection 
• 
Pre-therapy evaluation and decision to apply COOLSTAT Therapy 
when subject has met additional screening requirements, within 7 
days of enrollment.  This will include a visual exam by a board-
certified otolaryngologist or an otolaryngology resident (under 
supervision of board certified otolaryngologist) of the upper airway.  
The intensivist will perform the pre-therapy nasal exam if an 
otolaryngologist is not available. 
• 
Core and tympanic temperatures and blood pressure (SBP) will be 
recorded in the hospital’s data collection system as part of normal care, 
with alarms set at specified points (as noted herein). Data will also be 
recorded manually in CRF (see timing details below). 
• 
Tracheal tube placement will be recorded prior to initiation of 
COOLSTAT therapy (Phase 0), and checked and recorded in the CRF 
three times a day (every ~8 hours) for the remainder of the study. 
• 
Suctioned tracheal water volume will be recorded prior to the initiation 
of COOLSTAT therapy (during Phase 0), and recorded twice daily in 
the CRF for the remainder of the study. 
• 
COOLSTAT nasal mask will be removed every 4 hours for visual 
inspection of nasal area. Observations will be recorded in the CRF.  
• 
Level of shivering will be assessed and recorded in the CRF (see timing 
detail below). 
• 
Subjects will be monitored for stomach distention and signs of 
dehydration as part of standard of care. Observations of both will be 
recorded every 8 hours in the CRF.  
• 
Any intervention that may affect core temperature reading, such as a 
bolus of cold liquid passing temperature probe in the esophagus, will 
be manually recorded in the CRF.  
• 
Intracranial pressure (ICP), when available, will be collected manually 
in all study Phases (0-3) with other data (see timing details below). ICP 
monitoring is required for the first 5 subjects in this study.  
• 
Data from first 5 subjects, including ICP monitoring, will be reviewed 
by the study’s Data Safety Management Board prior to enrolling any 
subjects who do not have ICP monitoring in place. Specific attention 
will be paid to any increase in ICP that may be due to COOLSTAT use. 
• 
Upon occurrence of any adverse events, the subject’s medical records 
will be reviewed.  
• 
The COOLSTAT device will be automatically collecting air flow rate, air 
temperature supplied to the subject, air humidity supplied to the 
subject, air pressure, and patient core temperature data.  

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Phase 0 – Pre-Cooling Monitoring (30 minutes):  Manual temperature (core 
and tympanic), ICP (when available) and blood pressure data collection every 
5 minutes (and some additional observations, see above). 
Phase 1 – Cooling Treatment: Manual data collection will occur at a minimum: 
• 
5 minute intervals for first 30 minutes of cooling period. 
• 
30 minute intervals for first 8-hour cooling period. 
• 
2 hour intervals for remaining 16 hour of cooling (if applicable). 
Phase 2 – Short-Term Post-Cooling Monitoring: Manual data collection will 
occur at 15 minute intervals during this 2-hour period immediately following 
COOLSTAT cooling. 
Phase 3 – Long-Term Post-Cooling Monitoring: Manual data collection will 
occur at minimum four hour intervals through this 22-hour post-COOLSTAT 
cooling period. 
Any additional data collections and the reasons for them shall be documented 
in the study case form.   
Study 
Population  
70 adult febrile patients in the neurosciences intensive care unit, with ischemic 
or hemorrhagic stroke, seizure, or metabolic encephalopathy. Hemorrhagic 
stroke includes both intracerebral hemorrhage and subarachnoid hemorrhage 
stroke. Only the first 30 subjects who meet post-consent eligibility criteria will 
receive COOLSTAT therapy.  
Regimen 
 
COOLSTAT® Transnasal Thermal Regulating Device will be applied to 
patients at a pressure not to exceed 30 cm H2O (as automatically regulated by 
the device).   A closed-loop control system in the COOLSTAT will modulate 
and control air flow and maintain the subject’s core temperature between 36 °C 
and 37.5 °C, as measured by a hospital supplied embedded temperature sensor 
(esophageal, bladder, or 3M™ SpotOn™ temperature sensor). The device will 
be set to target of 36.5 °C. 
Duration of 
Study for 
Subject 
The study period for each subject can vary from 7 to 10 days, although the 
active cooling phase will be 24 hours or less.  The primary reason for the 
extended duration of the study (beyond the active cooling phase) is due to the 
unpredictable nature in which patients may develop a fever (refractory to 
antipyretics), and the brief procedural window before additional cooling 
therapy should be implemented.  This necessitates that we overenroll likely 
candidates (that may develop refractory fever) to be ready to apply the 
transnasal cooling therapy in short order, if a fever develops.  The time frames 
over which the study may occur are:    
• 
70 candidate subjects will be identified and enrolled (with consent), and 
will then remain enrolled but not activated for the COOLSTAT cooling 
protocol for up to 7 days.  During this time frame, the subject will be 

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inspected by board-certified otolaryngologist, otolaryngology resident, or 
intensivist and otherwise evaluated to see if the subject meets all 
eligibility criteria.  
• 
If the subject is determined to be eligible for COOLSTAT cooling, and the 
subject develops a refractory fever, he/she will  enter the cooling phase of 
the protocol, which will start with a monitoring period (for 30 minutes) to 
ensure the temperature and vitals of the subject continue to be acceptable 
and stable (Phase 0). Only 30 subjects will enter this phase of the protocol, 
as slightly more than half of the enrolled subjects are expected to be post-
consent screen failures. 
• 
Next, the subject will be cooled by the COOLSTAT for up to 24 hours 
maximum during Phase 1 (first 10 subjects will only be cooled for 8 hours) 
with a 2 hour short-term Post-Cooling Observational Phase (Phase 2). 
• 
An additional 22 hours of observation will occur (Phase 3), with a post-
cooling visual nasal exam by a board-certified otolaryngologist, 
otolaryngology resident, or intensivist. 
Estimated 
time to 
complete 
feasibility 
study 
This trial will last until 30 subjects complete COOLSTAT Therapy; it is 
estimated that this will take less than 1 year.  The study may be terminated at 
any time if there is insufficient data supporting the feasibility of COOLSTAT 
cooling or upon decision by the Sponsor that the study cannot achieve its stated 
objectives.  
Hypothesis 
The primary hypothesis regarding cooling performance is that at least 75% of 
the subjects will reach normothermia (core temperature ≤37.5 °C) within 4 
hours of starting COOLSTAT cooling. 
The primary hypothesis regarding temperature maintenance is that at least 75% 
of the subjects’ core temperatures remain between 36 °C and 37.5 °C for 80% of 
the steady state2 time following the initial achievement of 37.5 °C. 
Outcomes 
Performance Outcomes 
1) This feasibility study is intended to confirm that the COOLSTAT 
system can cool within expected performance parameters and can 
reach and maintain normothermic cooling therapy over the study 
period. Subjects are expected to reach normothermia (core 
temperature <37.5°C) within 4 hours of starting COOLSTAT cooling. 
Subject temperatures are expected to be maintained within a 1.5 °C 
temperature band, between 36 °C – 37.5 °C, for 80% of the steady state 
time following the initial achievement of 37.5 °C.1 
 
1 This recognizes that some subjects will have short periods of break-through fever over the course of the study. 
 
2   If a subject must be disconnected from the CoolStat device for transport from the NCCU to another unit (e.g., to 
radiology or angiography suite), they will be reconnected to the device at steady state if their core temperature 
 

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2) Data collected will help to confirm cooling models and the control 
system algorithm by examining subject cooling response as a function 
of air flow rate and properties of the air supplied to the subjects. 
3) The study will demonstrate that the COOLSTAT System can perform 
in the clinical setting and identify possible human and equipment 
interface refinements.   
 
Safety Outcomes  
Safety will be assessed by the following: 
4) The incidence and severity of all adverse events (including, but not 
limited to serious adverse events and non-related adverse events). 
5) Assessment as to any potential contribution to the adverse event that 
may be device related or related to transnasal cooling therapy. 
Secondary Outcomes  
This study may provide insight into the incidence of shivering, although the 
study design is not sufficiently powered to expect definitive conclusions.   
Statistical 
Methodology 
The primary efficacy analysis for temperature maintenance will be based on 
the evaluable population of subjects who achieve normothermia by 4 hours and 
continue cooling treatment with the COOLSTAT System. 
The proportion of subjects fulfilling success criteria and 90% confidence 
intervals will be reported and compared to the a priori minimum acceptable 
criteria:  
• 
at least 75% of the subjects will reach normothermia (core temperature 
≤37.5 °C) within 4 hours of starting COOLSTAT cooling, and 
• 
at least 75% of the subjects’ core temperatures remain between 36 °C and 
37.5 °C for 80% of the steady state time following the initial achievement 
of 37.5 °C. 
All adverse events (AEs) reported during the study will be presented in tabular 
format to include: time of onset, whether or not the patient continued in the 
study, the nature of intervention and resolution. The potential contribution to 
the AE by the device will be assessed by the attending physician who reports 
the AE and the investigator. 
Data Safety 
Monitoring 
Board 
A DSMB will be formed to monitor this study.  The DSMB will meet: 1) before 
any subjects are enrolled (to review the study), 2) after the first 5 subjects (all 
with ICP monitoring), 3) after the first 10 subjects (before proceeding to 24-hour 
 
upon being reconnected to the CoolStat is ≤ 37.5 °C. If the subject’s temperature is > 37.5 °C upon being reconnected 
to the device, the device will be given up to an additional 4 hour-period to bring the patient to normothermia (≤ 
37.5 °C). Once the subject’s core temperature is ≤ 37.5 °C, the device will be considered in steady state. 

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cooling treatment), 4) after each 6-month period of study, 5) at the end of the 
study, and 6) after any serious adverse event.  
A clinical monitor will also be used to periodically visit the study sites and 
monitor the activities of the study to ensure that the study protocol, consent 
activities and data collection are being completed in accordance with specified 
procedures.  
The Clinical Monitor and DSMB will be comprised of: 
• 
Paul Manberg, PhD - Clinical Monitor 
• 
Jose Suarez, MD (Johns Hopkins) – Chair of DSMB – Voting Member 
• 
Romergryko Geocadin, MD (Johns Hopkins) – DSMB Voting Member 
• 
Samuel Tisherman, MD (UMMC) – DSMB Voting Member 
• 
Daniel Herr, MD (UMMC) – DSMB Voting Member 
• 
Neeraj Badjatia, MD (UMMC) – PI (Non-Voting Member) 
• 
Harikrishna Tandri, MD (CSO, CoolTech) – Sponsor (Non-Voting 
Member) 
Additional details on the charter of the Clinical Monitor and the DSMB are 
provide as Appendices with the IDE application, including biographical 
information on each member. 

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2.0 
Literature review: Background and Rationale  
2.1 
Neurogenic Fever 
Fever is a common occurrence among patients with a brain injury or ischemic event, and 
studies have shown that fever can exacerbate the effects of that injury and result in poor 
patient outcomes [1, 2, 3, 4].  It is recommended to immediately cool these patients to at 
least a normothermic temperature, however there is no universally accepted gold 
standard of cooling [1, 2, 3, 4].  Generally, subjects are started on an antipyretic drug 
treatment [5].  If this is unsuccessful at lowering their temperature, then active cooling 
methods may be initiated.  Surface cooling methods such as ice bath and cooling blankets 
are sometimes used, but are not always effective and can induce a shivering response 
(which has significant neurological consequences) [4, 6].  Intravenous cooling methods 
have demonstrated some of the fastest patient temperature cooling rates, but require an 
invasive procedure to install a large catheter, which must be completed by a trained 
specialist and creates an infection site risk [6].  The COOLSTAT Transnasal Therapy 
Device [hereafter COOLSTAT or CoolStat] has the potential to be an easy and safe means 
to cool a febrile patient, and potentially with a lower risk of inducing a shivering response 
compared with surface cooling methods. 
2.2 
Principles of the COOLSTAT Technology 
The body naturally controls core temperature by regulating the balance between energy 
generated internally (basal metabolic rate and shivering) and energy lost to the 
environment through conduction, convection and evaporation (perspiration).  External 
cooling devices that are trying to reduce core temperature do so by shifting the energy 
balance to remove more energy than the body is capable of generating. Existing surface 
target temperature management (TTM) systems use cold pads on the skin to induce 
energy loss through conduction, while others use catheters with circulating cold fluids to 
remove energy, such as the Esophageal Cooling System (DEN140018).  The COOLSTAT 
employs evaporative cooling at the nasal turbinates and upper airway to remove energy 
from the body.  In all of these methodologies, basic thermodynamics govern the degree to 
which the core temperature is reduced. 
 
The COOLSTAT creates evaporative cooling by blowing dry, ambient air into the nose 
and over the nasal turbinates in a unidirectional fashion before flowing freely out of the 
mouth (as shown in the figure below for double nostril air flow) or the other nostril and 
the mouth (for single nostril air flow).  The nasal turbinates are highly vascularized, 
mucus-containing membranes with a large, convoluted surface area.  The primary 
purpose of the turbinates is to humidify inspired air before it reaches the sensitive tissue 
of the lungs.  As the dry air from COOLSTAT flows over the moist turbinates, it induces 
the liquid water (mucus) on the turbinates to change phase, from a liquid to a gas. 

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To complete the phase change, the liquid water molecules need energy, which is drawn 
from the turbinate membrane tissue.  Hence, the process locally extracts energy from the 
body, focused in the region of the turbinates, directly adjacent to the brain.   
 
Looking at this cooling effect on the rest of the body, the normal circulating blood through 
the turbinates replenishes the lost energy caused by the phase change.  This in turn cools 
the blood flowing through this region, which ultimately cycles back to the heart.  Basic 
thermodynamics requires that the core temperature of the body will slowly fall if the 
energy extraction from this process exceeds the heat generation of the body. 
 
It is worthwhile to note that the evaporative cooling process employed by the COOLSTAT 
removes energy without the use of anything that is cold.  The process uses only ambient 
temperature room air that has been dried through a desiccant.  It is noninvasive and there 
Tongue 
ET Tube 
Cuff Seal 
Endotracheal Tube 
(ET Tube) 
Air Flow Path   
(in gray) 
Comes in the nose and exits the mouth 
Saline 
Mist 
(Intermittent) 
Soft Nasal Pillows (2) 
(seal around nose) 
Saline 
supply line 
Air 
Supply 

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Confidential - PROTOCOL PAGE 16 of 57 
 
are no evaporative chemicals or drugs.  The nasal interface is a standard nasal pillow 
design that creates a seal around the outer diameter of each nostril.  The nasal pillows are 
noninvasive, with no tubing or parts inserted into the nose.  The device also includes air 
supply pressure limits, air filters and other features to prevent damage to the turbinates 
and upper air way, which will be discussed later. 
 
2.3 
Study Rationale 
Existing surface TTM systems impede patient care with large surface cooling pads that 
can limit patient access and cause surface skin care concerns.  Intravascular cooling 
devices require an invasive procedure to install a large catheter, which must be completed 
by a trained specialist, creating an infection site risk.  These systems are also generally 
intolerable in awake patients.  See Section 5.5.1 for the COOLSTAT’s primary anticipated 
benefits.  
 
This study will evaluate the performance and safety in a limited number of subjects with 
fever who require cooling therapy to achieve normothermia and who will be closely 
monitored in an intensive care setting.  We have previously explored the feasibility and 
safety of using dry nasal air as a means of cooling subjects, albeit in small feasibility study, 
in febrile subjects.  This study shall demonstrate the performance of the COOLSTAT 
Transnasal Thermal Regulating System under controlled conditions in febrile subjects. 
 
3.0 
Description of the COOLSTAT Device  
 
3.1 
Device Description 
The COOLSTAT® Transnasal Thermal Regulating Device is generally designed for 
temperature reduction in patients where clinically indicated.  For this study, the device 
will be limited to subjects with ischemic or hemorrhagic stroke, seizure, or metabolic 
encephalopathy. Hemorrhagic stroke includes both intracerebral hemorrhage and 
subarachnoid hemorrhage stroke. 
 
The COOLSTAT® Transnasal Thermal Regulating Device [hereafter COOLSTAT or 
CoolStat] cools without an invasive catheter or the use of any evaporative chemicals or 
cooling agents, and the process air and saline do not come in contact with any sterile body 
tissue, blood or other fluids.  COOLSTAT is not used in any way to support or assist with 
life support, patient breathing or respiratory functions. 
 
The COOLSTAT is a relatively small device, weighing less than 15 lbs, and can be 
mounted on an IV pole or placed next to a patient’s bed on a table or cart.  The primary 
functional component inside the device is a blower which is used to generate a flow of air.  

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Inlet air is supplied to the device from either a medical grade wall air port or it can be 
pulled into the device from the local ambient room air; the internal blower is then used to 
pump the air across a desiccant material to extract any moisture from the incoming air 
stream.  The dry air then travels to the patient via flexible air tubing with an in-line air 
filter, and is delivered to the patient with a custom nasal mask.  The flow of air enters the 
patient’s nose and exits the mouth (during double nostril air flow) or the mouth and other 
nostril (during single nostril air flow), inducing an evaporative cooling energy exchange 
in the turbinates and upper airway.  The blower inside the device provides the motive 
force to move the air supply over the desiccant material and across the patient’s 
turbinates.  If the air supply is taken from the wall air port, the pressure from this air 
source is dissipated across an orifice (in the device) to reduce it to slightly above 
atmospheric pressure (before entering the blower of the device).  The medical grade air 
from a wall port is only provided as an option to extend the life of the desiccant cartridge, 
since the air supply from the wall port is typically drier than ambient air.   
 
An Operator’s Manual for use during the Investigational Study has been developed and 
will be available for training and to keep at hand during device use.   
 
 
 
The subjects in this trial are already intubated.  As such, the air flow from COOLSTAT 
does not enter the patient’s lungs and is not used in any way to assist with life support, 
patient breathing or respiratory function.  For safety, the device monitors and limits the 
pressure and flow rate of the air supply to the patient, as well as the temperature of the 
air.  The pressure is limited to 30 cmH2O and the temperature to 38 °C in accordance with 
the CPAP ISO standard 80601-2-70.  Sensors in the device will alarm and reduce or stop 

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operation if the temperature or pressure exceeds safety limits.  A list of the software error 
codes and their functions are provided in the operator’s manual.   
 
The COOLSTAT is designed to operate primarily inside a hospital or other healthcare 
setting in a controlled environment.  This helps ensure that the temperature of the supply 
inlet air to the device is relatively controlled at ambient levels.  In addition, a passive heat 
exchanger inside the device is used to keep the air supply temperature within a safe and 
comfortable range. 
 
In addition, the device delivers isotonic saline solution directly to the nasal mucosa to 
reduce drying and to facilitate improved evaporative cooling. The device uses a peristaltic 
pump as the motive force to intermittently spritz a small amount of isotonic saline 
solution into the patient, where the amount of saline delivered is proportional to the 
airflow.  A standard saline bag used in the hospital provides the source of the isotonic 
saline solution, which is hung on a standard IV pole next to the device.  The saline bag is 
not provided as part of the device and is supplied by the hospital.  The saline is pumped 
to the patient and delivered via small misting nozzles in the nasal mask, in parallel with 
the delivery of the dry air.  To ensure a clean supply of saline to the patient, the saline 
never touches the device; it is contained within the delivery tubing from the saline bag to 
the patient.   
 
3.2 
Control System 
The COOLSTAT device can be operated in either an open loop cooling mode or a closed-
loop cooling mode.  In the open loop mode, the air flow of the device is set by the operator 
over a range of 5 flow settings (from low to high), limited by the max pressure supply of 
the device to ensure safety (discuss herein).  The energy removed by the device is expected 
to be proportional to the air flow setting and the duration of time used.  In the closed-loop 
control mode, the device’s control system is designed to lower the subject’s temperature 
as quickly as practical using a high flow rate of air provided by the blower.  As the 
patient’s temperature approaches a pre-set target temperature (as selected by the 
operating clinician), the air flow of the device is automatically reduced, at which point the 
blower driver controls to a target patient temperature by adjusting the flow rate.  The 
blower will use PID control (proportional-integral-derivative) to cool the patient to the 
target temperature by adjusting the flow rate between approximately 0 and 60 LPM.   
 
This study will use the closed-loop control setting only.  The COOLSTAT receives 
temperature feedback from an esophageal, bladder, or 3M SpotOn™ temperature sensor, 
all of which are standard sensors used at the study sites with other hospital devices.  The 
selection of which sensor will be at the discretion of clinical staff, following existing 

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protocols.  The SpotOn is currently used as a first line sensor since it has been validated 
by the University of Maryland Medical Center as providing a quality core temperature 
reading and is non-invasive.  While patient interventions, such as a bolus of cold liquid 
briefly flowing over an esophageal temperature probe, may temporarily alter the probe’s 
reading from the true core temperature, such events are brief and will not affect 
COOLSTAT function. The COOLSTAT control system prevents the machine from a rapid 
or exaggerated response to a brief change in core temperature input. Bladder temperature 
sensors are used less frequently, but are considered an acceptable core temperature sensor 
in the event that a subject is unable to have a SpotOn or esophageal temperature probe. 
The COOLSTAT has a display that shows both the patient’s current temperature (from 
the core temperature sensor) and the target temperature.  The integrity of the control 
system to control and maintain the subject’s temperature will be closely monitored in this 
study. 
 
4.0 
Indication for Use and Contraindications 
 
4.1 
Indication for Use 
The CoolStat Transnasal Thermal Regulating Device is intended for temperature 
reduction to achieve normothermia, as an adjunct to anti-pyretic therapy, in adult 
patients with ischemic or hemorrhagic stroke, seizure or metabolic encephalopathy who 
are intubated and sedated. Hemorrhagic stroke includes both intracerebral hemorrhage 
and subarachnoid hemorrhage stroke.  
 
4.2 
Contraindications 
All contraindications are listed below in the exclusion criteria.  
 
5.0 
Risk/Benefit Analysis 
 
5.1 
Analysis of Risks to Subjects and Potential Benefits 
The risks to the subjects in this study are broken into risks of the COOLSTAT device and 
risks to the subject since they will not be receiving standard of care.  Although summaries 
are provided below, detailed risk evaluations (e.g., hazards analyses and failure modes 
and effects) have been completed and are available as part of the IDE application.   
 
The most significant risk mitigation is that throughout this study, the subject will be under 
regular clinical and study supervision and can be easily and quickly switched to the 
standard of care for cooling therapy if necessary. 
 

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5.1.1 Risks Associated with Use of the Device 
Risks from the COOLSTAT device are summarized here based on its different systems, 
including the 1) air delivery system, 2) device and disposable setup, and 3) software.   
 
1. The Air Delivery System: The COOLSTAT System has similar operating parameters 
to a CPAP (Continuous Positive Airway Pressure) device used to treat sleep apnea.  
As a design intent to ensure safety, the COOLSTAT was designed following applicable 
requirements of ISO 80601-2-70, Medical electrical equipment -- Part 2-70: Particular 
requirements for basic safety and essential performance of sleep apnea breathing therapy 
equipment.  For example, the maximum air pressure allowed to be delivered to a 
patient when using a CPAP device is 30 cmH2O, to avoid potential overpressure and 
damage to the lungs.  The COOLSTAT has been conservatively designed to adopt this 
pressure limit.  This is conservative for this study since the patient’s lungs are isolated 
from overpressure via the intubation seal and at no point does the delivered air come 
in contact with the patient’s lungs.  This is considered an added level of protection to 
ensure an over pressure event cannot occur.  Any leakage past the intubation cuff 
would be detected and alarmed by the ventilation monitor. Endotracheal tube (ET) 
migration due to COOLSTAT use is not expected, but would be detected by the 
ventilation monitor alarm.  ET tube position will be recorded at COOLSTAT therapy 
initiation (Phase 0) and will be verified three (3) times a day, per standard of care, by 
visual inspection by clinical personnel. The COOLSTAT has also been designed to 
limit the maximum temperature of air flowing to the patient to 38 °C (conservative 
per the CPAP standard, which allows up to 43 °C).  The device continuously monitors 
both pressure and temperature that is supplied to the subject in real time and will 
reduce or turn air flow off to ensure that neither limit is exceeded.  It is also worth 
noting that the subjects to be in this proposed study will be intubated. Patients with a 
tracheostomy tube who are receiving mechanical ventilation will also be included, 
provided that they meet all of the eligibility criteria. The air supply by the COOLSTAT 
will run in the subject’s nose and out of their mouth.  The COOLSTAT will not be used 
in any way to support or assist with life support, patient breathing or respiratory 
functions. 
 
The COOLSTAT system differs from CPAP systems in that the mouth is required to 
be open during double nostril COOLSTAT therapy.  The mouth is normally closed 
during CPAP use, although there are reported cases of mouth leakage when using a 
CPAP, particularly when the CPAP devices were initially being developed and used; 
this was also at a time when the CPAP airflow was not pre-humidified.  This type of 
mouth leakage when using the CPAP creates a very similar end condition to that 
produced by the COOLSTAT.  A flow of air is created that goes in the nose and exits 

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the mouth.  The mouth leakage with CPAP reportedly caused headache and sore 
throats from overnight use, but no reported cases could be found where this mouth 
leakage caused serious damage of the tissue or membranes in the turbinates or upper 
airway [9, 10, 11]. 
 
Potential Nasopharyngeal Membrane Desiccation: The COOLSTAT also has the 
potential to desiccate the turbinates if used for extended periods.  To reduce this 
potential risk, the device has a design feature to replenish some of the water it has 
removed, i.e., the device delivers to the body a small amount of sterile, isotonic saline 
solution.  Clinical staff will be trained as part of the study procedure to monitor for 
signs of dehydration of the subject based on the World Health Organization (WHO) 
scale for dehydration, such as general appearance, sunken eyes, and skin turgor. 
Evaluation for dehydration will be recorded as noted in the CRF data collection forms. 
In addition, the study will monitor the amount of fluid suctioned off of the subject via 
tracheal suction, before COOLSTAT cooling is started, during COOLSTAT cooling 
and after COOLSTAT cooling.  This method will indicate whether excess fluid is being 
delivered, or there is a reduction in baseline fluid produced in the mouth and upper 
airway. The study team will examine this data after the first five (5) subjects, combined 
with the ENT assessments of the tissue quality of the upper away post-cooling, to 
assess the need to change the water supply setting on the COOLSTAT device.  
Tracheal suction volumes will be recorded by having a separate canister for tracheal 
fluids (apart from other suctioned fluids), and will be recorded at initiation of 
COOLSTAT therapy, and twice daily for the remainder of the study.  
 
No nasopharyngeal membrane desiccation was observed as part of long-term 
preclinical swine studies (8 and 24 hour cooling studies) using the final CoolStat 
device, which indicates the delivered saline effectively mitigates this risk.  Details of 
the preclinical study are provided as part of the IDE and IRB applications.  The 
COOLSTAT nasal mask will be removed every 4 hours during the study for visual 
inspection of nasal tissue and observations will be recorded in the CRF. Vaseline will 
be applied every 4 hours to ensure a good seal between the mask and the nostrils and 
to limit the amount of sealing pressure needed.  
 
Potential Preferential Brain Cooling: The COOLSTAT has the potential to 
preferentially cool the brain region, due to the location in which the cooling therapy 
is applied, close to the brain region.  This was seen in pig testing, where the pig brain 
was measured to drop about 2 to 3 °C degrees lower than the core [7].  This is 
considered an extreme comparison to humans since the pig nasopharynx has a unique 
countercurrent cooling mechanism called the “Rete Mirabile” which is an intricate 

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plexus of arterial and venous blood vessels that directly exchanges heat from the 
internal carotid artery thereby cooling the brain [19, 20]. Further the pig brain is about 
1/10th the volume of the human brain, and the turbinates of the pig are significantly 
larger compared to humans.  This creates a condition where the pig has a higher 
energy transfer rate and a smaller brain volume being cooled.  As such, the brain 
cooling in a human is expected to be significantly less than the pig.   
 
Previous human studies using a comparable transnasal cooling device (RhinoChill), 
showed preferential brain cooling of about 1 °C [16, 24], i.e., the brain temperature was 
about 1C cooler than the core temperature.  The RhinoChill cooling process is similar 
to the COOLSTAT but includes the use of a liquid perfluorocarbon, evaporative 
coolant that is sprayed in the nose, along with a high flow of oxygen at 60 LPM.  This 
is considered a more aggressive cooling process than the COOLSTAT, which does not 
use an evaporative coolant (other than a saline mist).  These studies, as well as other 
studies [21, 22], have also shown a reasonable correlation between brain temperature 
and tympanic temperature.  As such, it is proposed for this study that a separate 
tympanic temperature be monitored and recorded for each subject as a surrogate for 
brain temperature.  Given that the lower target core temperature limit for this study 
is 36°C, the estimated brain temp should be limited to about 35°C, with a worst-case 
limit of about 33°C (if we conservatively assume cooling that is comparable to the pig 
model).  This is expected to provide a safe margin to the subjects, given that humans 
are regularly cooled down to 32°C as part of standard of care for ischemic events and 
cerebral vascular injuries [23]. The tympanic temperature measurement will have a 
lower limit of 34°C and an upper limit of 39°C, at which points the hospital’s 
temperature monitor will be set to alarm. If the tympanic temperature is observed 
below 34 C for a sustained period of at least 5 minutes, use of COOLSTAT device will 
be discontinued on that subject. 
 
Potential Blood Pressure Increase and/or Intracranial Pressure Increase: There is a 
theoretical concern that the COOLSTAT has the potential to induce patient discomfort 
which results in a vascular response (caused by pain receptors) that can increase the 
subject’s blood pressure.  This phenomenon was not seen in our pig testing, but it was 
reported in a comparable transnasal cooling study (with the RhinoChill), which 
showed short term increases in systolic blood pressure (SBP) of up to 53 mm Hg [24].  
The RhinoChill is known to have significant irritation and discomfort to the patient 
due to delivery of the evaporative coolant and high flow air.  It has been reported that 
the RhinoChill is not tolerable in awake subjects without the use of anesthesia.  We 
believe the irritation and discomfort from the RhinoChill process produces an arousal 
and elevation of systemic blood pressure.  Conversely, the COOLSTAT is much more 

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tolerable, even when delivered to an awake subject, with only a slight sensation 
during use.  As such, we do not expect a similar response in blood pressure.  However, 
to account for this potential concern, this study will continuously monitor blood 
pressure during all stages of using the device. blood pressure will be monitored per 
standard of care for sustained elevation.  If SBP is observed above allowable levels 
sustained for >5 minutes despite standard of care intervention, use of COOLSTAT 
device will be discontinued on that subject.  Allowable limits for SBP will be followed 
per institutional standard for the indication being treated. The device can also be 
discontinued at the discretion of the treating physician for medical reasons. 
 
The COOLSTAT is not expected to cause an increase in intracranial pressure (ICP).  A 
previous human study using a comparable transnasal cooling therapy (RhinoChill), 
showed no effect on ICP [24].  Although no device-related change in ICP is expected, 
ICP monitoring will be required to be in place for the first 5 subjects enrolled in this 
study. The PI and the DSMB will review any subjects with elevated ICP to determine 
whether the increase was device related. Additionally, ICP data will be recorded for 
all subsequent study subjects who already have ICP sensors in place (as discussed 
further below in Section 6.9).  If ICP is observed above allowable levels sustained for 
>5 minutes despite standard of care intervention, use of COOLSTAT device will be 
discontinued on that subject.  The maximum allowable limit for ICP will follow 
standard of care limits, specific to the indication being treated. The device can also be 
discontinued at the discretion of the treating physician for medical reasons.  
Approximately half of the eligible patient population is expected to have ICP 
monitoring in place. This concern will also be mitigated by continuously monitoring 
of blood pressure as noted herein.  
 
Potential Pressure Ulcers from Nasal Mask: Although unlikely, it is possible for the 
nasal mask to be attached too tightly to a subject’s face and cause pressure ulcers. Two 
instances of pressure ulcers were observed in the 24-hour preclinical swine study. 
These findings were attributed to the use of clinical nasal masks on swine anatomy 
and to the required tightness to keep the masks in place on the swine while in supine 
position (see Preclinical Study Report for additional details). The CoolStat mask is 
quite similar to the CPAP masks that are regularly used without clinical supervision 
for long periods and are not known to cause pressure ulcers.  To further mitigate this 
risk, patients will have their nasal mask briefly removed every 4 hours to inspect for 
any potential irritation and/or formation of pressure ulcers. Additionally, Vaseline 
(petroleum gel) will be used to create a good seal between the nasal mask (nasal 
pillows) and the subject’s nose, as opposed to relying on strap tightness alone. 

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Vaseline may be reapplied every 4 hours during nasal mask removal for visual 
inspection. 
 
2. Device and Disposable Set-Up Risks: Device and disposable set-up risks will be 
mitigated by proper training of study staff who may interact with the device. The 
COOLSTAT has been evaluated for ease of use by preclinical study staff (independent 
of company and unfamiliar with device prior to the study). Device set-up and 
disposable use was generally found to be intuitive. The COOLSTAT hardware 
includes features like a unique connector for the nasal mask attachment that mitigate 
the risk of improper device use.  
 
There are two potential risks for disposable misuse during COOLSTAT treatment: 1) 
desiccant cartridges may be used longer than suggested and allowed to reach 
room/supplied air humidity level, and 2) failure to replace the saline bag providing 
the “spritz” delivery.  Although there are built-in device warning messages and 
alarms, desiccant cartridges may not be changed out in a timely manner as air 
supplied to the subject becomes more humid (and therefore less effective at drying 
air).  The result would be less effective evaporative cooling due to less dry air being 
delivered.  However, the blower would begin to deliver higher air flow (up to the 
pressure limit) to compensate for any decreased effectiveness (which would be 
registered by an increase in core temperature). Testing in hospital conditions (using 
wall air port as air source) has demonstrated an effective operating period for the 
desiccant cartridge from 2-3 hours on the low end, and up to 5-6 hours on the high 
end, which is likely a sufficient time to cool the subject to normothermia.  If the 
desiccant cartridge is not changed when indicated, cooling to the subject will likely be 
reduced and the subject’s temperature could begin to rise.  This will be detected by 
temperature alarms, as well as clinical and study personnel monitoring the subject. 
 
Saline is spritzed into the nose by the COOLSTAT nasal mask to both eliminate the 
risk of membrane desiccation and to facilitate more efficient evaporative cooling. If 
the COOLSTAT is allowed to deliver desiccated air without saline delivery, there 
exists a postulated risk of membrane desiccation.  In preclinical studies running the 
COOLSTAT for 8 hours at maximum flow rate of 60 LPM and also for 24 hours using 
the closed loop control system, no desiccation or irritation was found in the nasal 
turbinates or other upper airway tissue (based on post cooling exams by a board 
certified otolaryngologist).  During these studies only ~450 mL of saline was delivered 
over the course of 8 hours (running at continuous max flow).  These pig studies 
represent a conservative clinical scenario, as lower air flow will occur once the patient 
has achieved the target temperature and the device only blows air when required to 

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maintain the target temperature. As such, we don’t expect to need to change out the 
1L saline drip bag that will be used in the clinical study for the first 10 subjects 
(receiving 8 hours of cooling treatment).  The bag may need to be changed during use 
on subjects receiving 24 hours of cooling treatment, but likely only once.  As a 
conservative step, the status of the saline bag will be monitored and checked every 4 
hours, and recorded in the case report forms to help ensure the saline bag does not 
run dry.   
 
3. Software Risks: Detailed risk evaluations as part of CoolStat device software have 
been completed and are available as part of the IDE application. Generally speaking, 
a Software Integrity Level (SIL) was calculated for every software unit in the CoolStat 
system as a measure of that unit’s impact on the performance of the overall system.  
All software units deemed high risk based on this analysis have undergone formal 
inspection and statement coverage.  All other software units are covered by code 
review, in addition to system-level verification protocols.  As part of this process, the 
CoolStat firmware has gone through static analysis using PC-Lint, which is a 
command-line tool for performing static code analysis, indicating suspicious or plain 
wrong issues in source code.  
 
5.1.2 Risks Associated with Denying Standard of Care 
The standard of care for febrile patients in the NCCU starts with antipyretic treatment 
(acetaminophen 650 – 1000 mg orally) once a fever is detected, as specified by a 
temperature ≥ 38.3 °C (measured via an embedded core sensor).  After 1-2 hours, if the 
patient’s temperature is still above this limit, a temperature modulating device (TMD) is 
initiated with appropriate anti shivering regimen. Throughout the time period a TMD is 
utilized, acetaminophen administration is continued (650 – 1000 mg orally every 6 hours).   
 
For this study, the COOLSTAT will be initiated after approximately 1 or 2 hours of 
antipyretic administration (per institutional guidelines) and will replace the use of any 
other TMD.  This is an investigational study which generally does not provide benefits to 
the subject above the standard of care.  Anticipated advantages to using the COOLSTAT 
over traditional TMDs are listed in Section 5.5.1, but it is the goal of this study to start to 
assess the validity of these potential advantages.  If at any point the subject is not cooling 
properly or is otherwise unsafe from the use of the COOLSTAT, the subject can be quickly 
and easily switched to the standard of care cooling treatment.  Subject assessment at 4 
hours and 8 hours will be conducted consistent with the current standard of care. 
 
5.2 
Manner in Which Risks will be Minimized 
This study minimizes risks to participating patients in the following ways: 

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• 
Study subjects will be under regular supervision by trained clinical personnel 
specifically to monitor temperature, as well as to monitor for adverse events and 
changes in hemodynamic parameters throughout the study period, in addition to 
normal critical care nursing staff. 
• 
Changes in subject temperature happen over relatively long periods of time, 
usually over the course of hours (not seconds or minutes).  As such, if the CoolStat 
is not able to cool or hold desired temperature ranges, alternative cooling therapies 
are available and can be applied in relatively short order.    
• 
High and low monitoring alarms for the subjects will be set as follows: 
o The subject’s core temperature (either esophageal, SpotOn, or bladder) will 
be continuously monitored and recorded in the CRFs, with procedures to 
stop the CoolStat if the core temperature is <36°C for a sustained period of 
5 minutes, to limit the potential to overcool the subject. Subjects must have 
a core temperature of <39.5°C at the start of the cooling treatment.  If 
subjects have a temperature >39.0°C for over 4 hours, CoolStat treatment 
will be stopped and an alternative method of cooling will be initiated.  
Likewise, the CoolStat will be stopped if the subject has a sustained core 
temp > 39.5 C sustained for 5 minutes. 
o The subject’s tympanic temperature will also be continuously monitored 
by the hospital’s normal monitoring system and manually monitored and 
recorded in the CRFs.  The tympanic temperature will alarm in the 
hospital’s monitoring system if the tympanic temperature drops to <34°C, 
to limit the potential to overcool the subject’s brain.  Additionally, 
tympanic temperature will also alarm if the tympanic goes > 39°C, to limit 
the potential that the subject temperature gets too high.  If the temperature 
is observed <34 C for a sustained period of at least 5 minutes, or > 39 C for 
over 4 hours, use of COOLSTAT device will be discontinued on that 
subject.  Likewise, the CoolStat will be stopped if the subject has a 
sustained tympanic temp > 39.5 C sustained for 5 minutes. 
o The subject’s blood pressure (BP) will be will be continuously monitored 
per standard of care by clinical study team members.  If systolic BP is 
observed above a max allowable level sustained for >5 minutes, despite 
standard of care intervention, use of COOLSTAT device will be 
discontinued on that subject.   Allowable levels (per institutional standard) 
will be followed, specific to the indication being treated. 
o The subject’s intracranial pressure (ICP) will be will be monitored in the 
first five (5) subjects as a minimum, as well as others that have ICP 
monitoring in place pre-study.  If ICP is observed above a max allowable 
level sustained for >5 minutes, despite standard of care intervention, use 

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of COOLSTAT device will be discontinued on that subject.   The allowable 
level (per institutional standard) will be followed for the indication being 
treated. 
• 
Subjects may receive a bolus dose of meperidine (Demerol) prior to starting the 
COOLSTAT device to dampen a potential pain response to the COOLSTAT 
therapy.  This can be given 15 minutes prior to initiation of COOLSTAT therapy, 
and is expected to reduce any potential discomfort and associate blood pressure 
change that may occur due to initiation of cooling. Each study site will follow their 
standard guidelines for managing shivering and active cooling tolerability.  
• 
A Clinical Monitor and a DSMB have been appointed to this study to oversee the 
clinical study progress, patient compliance, investigator management, and data 
collection in a timely manner (see Section 14.5 for more details). 
• 
Device checkout testing will show the COOLSTAT has passed basic safety 
requirements.  Each device to be used in the study will be individually tested for 
safety and performance, including a device performance check once delivered to 
the study site.  A device will not be used if it does not pass checkout testing. 
• 
Disposable components in direct contact with the subject will be shown to meet 
biocompatibility and cleanliness standards. 
• 
Animal and pilot clinical studies have shown that transnasal cooling is effective 
with no detected clinical or device-related adverse events. 
• 
Identified potential risks have been mitigated through the COOLSTAT’s design 
and study procedures.  
 
5.3 
Justification for the Investigation 
This study will evaluate the performance and safety in a limited number of subjects who 
require cooling therapy to normothermia and who will be closely monitored in an 
intensive care setting.  The feasibility and safety of using dry nasal air as a means of 
cooling subjects was previously evaluated with both non-febrile and febrile subjects using 
a surrogate device (CPAP) [8, 28].  This study shall demonstrate the performance of the 
COOLSTAT Transnasal Thermal Regulating Device under controlled conditions in febrile 
subjects. 
 
5.4 
Description of Patient Population 
Details concerning the included patient population are provided in Section 8.0.   
 
5.5 
Alternative to this Treatment 
Currently, the first-line method to cool a febrile patient is administering antipyretics. 
Patients who continue to be febrile and are clinically indicated for cooling are often 
prescribed more aggressive target temperature management (TTM) methods using 

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surface or intravascular systems for restoring normothermia.  Multiple means of cooling 
febrile patients, including usage of ice packs and ice water, surface cooling devices, and 
catheter cooling devices are commonly available [3].  Examples of surface cooling devices 
include the CSZ Blanketrol and Arctic Sun Temperature Management System; examples 
of endovascular cooling devices include the Reprieve Endovascular Temperature Therapy 
System and Cool Line system [6]. 
 
5.5.1 Advantages of COOLSTAT Compared to Predicate Technologies 
The primary anticipated benefits of COOLSTAT when compared with alternative TTM 
methods are: 
• 
it can cool to and maintain normothermia with a simple nasal mask on the 
patient’s nose with minimal disruption to patient care,   
• 
it is portable and has an internal battery that will allow for continued cooling 
during short transport periods within the hospital (for miscellaneous short 
procedures), 
• 
it is relatively small and portable with mounting options on an IV pole or sitting 
next to the patient’s bed, 
• 
it does not require cold storage of fluids or ice, 
• 
it does not require the insertion of an invasive catheter, 
• 
it has the potential to be used earlier than predicate treatments since it is quick and 
easy to setup,  
• 
it is easy to use for long periods of time, needing minimal clinician interaction after 
setup, and  
• 
it is expected to reduce the incidence of shivering response when compared to 
surface cooling methods since the cooling method is from the inside out, which 
may not trigger temperature sensors located in the skin2 [6, 13]. 
 
5.5.2 Risks and Disadvantages of COOLSTAT Compared to Predicate 
Technologies 
Analytical modelling and prior studies have determined that the rate of energy removal, 
and hence the rate of patient cooling using transnasal cooling provided by COOLSTAT, 
is somewhere in the mid-range of cooling rates of alternative TTM systems for induced 
normothermia [2, 3, 4, 12].  Endovascular cooling has the ability to hold a targeted 
temperature with a high degree of stability [3, 6].  The COOLSTAT is not expected to be 
as precise, but should still hold temperature within the normothermic range of 36°C – 
37.5°C, according to analytical models and as demonstrated in 24-hour pig tests. 
 
2 Skin temperature receptors contribute to about 20% of the shivering response [13]. 

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6.0 
Study Design 
 
6.1 
Definitions 
 
AE 
Adverse Event 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ISO 
The International Organization for Standardization 
NCCU 
Neurosciences Critical Care Unit 
PI 
Principal Investigator 
SOP 
Standard Operating Procedure   
 
6.2 
Purpose and Objectives 
The objective of this study is to evaluate safety and performance of the COOLSTAT® 
Transnasal Thermal Regulating Device in reducing temperature in a population of febrile 
subjects who meet the inclusion/exclusion criteria.  Results of this study will provide 
information about the safety and functionality of the COOLSTAT device in a clinical 
setting to cool to and maintain subjects at normothermic temperature.   
 
6.3 
Primary Efficacy Endpoint and Success Criteria  
This feasibility study should confirm that the COOLSTAT system has the ability to safely 
and adequately achieve and maintain normothermic cooling therapy with its control 
system over a specified period for subjects who were enrolled in the study.  
 
This cooling aspect of the trial will be considered a success if at least 75% of the subjects 
achieve the following criteria: 
 
• 
Cooling Performance: The subjects reach normothermia (core temperature ≤ 37.5 
°C) within 4 hours of starting COOLSTAT cooling. 
• 
Temperature Maintenance:  The subjects are held within a 1.5 °C temperature 
band, between 36 °C – 37.5 °C, for 80% of the steady state time following the initial 
achievement of 37.5 °C.3 
 
6.4 
Safety Outcomes 
 
An important outcome of this study is to assess the safety of high flow rate transnasal air 
delivery by the COOLSTAT device.  The device safety will be addressed by the following: 
 
3 This recognizes that some subjects will have short periods of break-through fever over the course of the study. 

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• 
The incidence and severity of all adverse events (including non-device-related 
adverse events) and the potential contribution to the adverse event that may be 
device related. 
• 
Assessment by the investigator or their designee and attending physician(s) as to 
any adverse event that may be related directly to transnasal cooling. 
• 
Confirmation based on a visual exam of the turbinates and upper airway that no 
clinically significant abnormal findings were attributable to transnasal air flow or 
the COOLSTAT device. 
 
This study should also demonstrate that the COOLSTAT system can perform in the 
clinical setting. 
 
The study may provide insight into the incidence of shivering, although the study design 
is not sufficiently powered to expect definitive conclusions.  
 
6.5 
Investigational Duration and Follow-up  
This study will conclude when 30 subjects receive COOLSTAT Therapy. 
 
6.6 
Sample size calculations  
The sample size was determined from the calculation below, using the following 
assumptions: 
 
 
n: minimum sample size 
 
 
p0 = 0.9 
 
Assumed proportion of subjects successfully cooled 
p1 = 0.75  
 
Lowest acceptable proportion of subjects successfully cooled 
δ = |p1 – p0|= 0.15 
Difference between ideal and minimum acceptable 
Confidence (α): 90% 
z95 = 1.28 
Statistical Power (β): 80%  
z80 = 0.84 
 
n = 25 subjects completing treatment, therefore a sample size of 30 subjects was selected 
to allow for dropouts. The study will enroll up to 70 subjects, accounting for a 55% 
expected post-consent screen failure rate. Enrollment will stop once the 30th subject 
receives COOLSTAT therapy. 
 

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6.7 
Number of Investigational Sites  
This feasibility study will be conducted at up to four investigational sites. The University 
of Maryland Medical Center (UMMC), would continue to be the lead center. 
 
6.8 
Methods to Reduce Bias and Conduct of the Investigation 
This is an exploratory study that will be conducted in compliance with GCP guidelines, 
with analysis that is objectively based on temperature measurements with pre-specified 
success criteria, so bias is not expected to be a significant concern. 
 
6.9 
Intracranial Pressure Monitoring 
No material response increase in intracranial pressure (ICP) is expected due to the use of 
COOLSTAT therapy.  As noted herein, the first 5 study subjects will be required to have 
ICP monitoring in place in order to allay any related concerns. Additionally, ICP data will 
be collected manually for all subsequent subjects that already have intracranial pressure 
monitoring in place. The PI will report to the DSMB and Sponsor if a material change 
(increase) in ICP is attributed to the use of the COOLSTAT.  The DSMB will be reviewing 
the initial five (5) cases to assess the impact on ICP of using the COOLSTAT. 
 
6.10 
 Transition from 8-hour Cooling to 24-hour Cooling 
The first 10 subjects will only be cooled for an 8-hour period, the results of which will be 
reviewed by the DSMB.  For these first 10 subjects, if the subject still requires cooling at 
the end of 8 hours, the clinical site normothermia standard of care protocol will be used.  
If approved by the DSMB, the remaining subjects will transition to 24-hour cooling only 
upon satisfying all of the following criteria: 
 
• 
No significant adverse events (SAEs) attributed to CoolStat 
• 
CoolStat satisfied primary efficacy endpoint and success criteria on first 10 
subjects (as specified herein): 
o 8 out of 10 subjects were cooled to ≤ 37.5 °C within 4 hours (based on final 
study endpoint of 75% subject achievement of this criteria) 
o 8 out of 10 subjects had core temp maintained between 37.5 °C and 36 °C 
for 80% of the steady state time following the initial achievement of 37.5 
°C.  
• 
No findings of concern from ENT visual exam of upper airway post cooling 
• 
Tympanic > 34 °C and <39 °C during 8 hours of cooling, with no sustained 
period of more than 5 minutes < 34 C or more than 4 hours > 39 C. 
• 
No sustained increase of systolic blood pressure for >5 minutes despite standard 
of care interventions that were above UMMC standard limits (specific to the 
indication being treated). 
• 
DSMB reviews CRFs and agrees to increasing test period to 24 hours 

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• Subjects with a history of cardiac arrhythmia will continue to be excluded from 
the study for subjects #11-20, who will receive up to 24 hours of cooling. 
• In the absence of any reports of occurrence of arrhythmia in this set of 10 subjects, 
then history of cardiac arrhythmia may be removed from the exclusion criteria 
for the subsequent subjects after review and approval by the DSMB.  
• In the event that cardiac arrhythmia does occur during cooling in any of the 
remaining subjects, history of cardiac arrhythmia will be reinstated to the 
exclusion criteria.  
 
7.0 
Subject Recruitment and Enrollment 
7.1 
Patient Recruitment 
Patients will be recruited for participation in this study from the population of patients in 
the Neurosciences Critical Care Unit (NCCU) who have an ischemic or hemorrhagic 
stroke, seizure, or metabolic encephalopathy, are intubated, and their expected stay in the 
NCCU is > 24 hours.  We will only enroll patients with these diagnoses for whom the 
attending intensivist would otherwise prescribe an active cooling device to treat the 
patient’s fever. The investigator or their designee will review the patient’s medical history 
for eligibility based on the study’s inclusion/ exclusion criteria.  If the patient is 
determined to be eligible, either the patient or their legally appointed representative 
(LAR) will be approached by the PI or their designee to discuss the study and the patient’s 
potential enrollment.  Background on the study as well as risks will be provided as part 
of the informed consent form for review.  If the patient or their LAR agree to participate, 
they will then sign the informed consent form, knowing that the patient can withdraw 
from the study at any time. 
 
7.2 
Point of Enrollment and Therapy Initiation Defined 
A subject is considered enrolled in the study once the following have occurred: 
• 
informed consent has been given by the subject or their LAR, and  
• 
it is determined that the subject meets all of the inclusion criteria and none of the 
exclusion criteria. 
 
A subject may be approved for COOLSTAT Therapy once the following additional 
screening criteria have been met after enrollment: 
• 
the subject has developed a fever (core temperature > 38.3 °C) and has remained 
febrile for at least one hour after the administration of antipyretics (institutional 
6.11 Potential Inclusion of Subjects with a Past History of Cardiac Arrhythmia 

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standards will be followed with respect to duration of antipyretic administration 
before initiation COOLSTAT Therapy), 
• 
it is confirmed that the subject has a core temperature probe (either esophageal, 
SpotOn or bladder), and 
• 
an ENT exam is performed (if not done previously to enrollment) to evaluate for 
craniofacial abnormalities that would exclude the subject.  
 
If the subject does not meet these criteria within 7 days from enrollment, the subject will 
be withdrawn from the study as a post-consent screening failure and is not eligible for 
intervention.  No further follow-up will be required.  
 
Due to the unpredictable nature of fever development and persistence, the study will be 
overenrolled in anticipation of many patients not proceeding to fever refractory to 
antipyretic treatment. The Table of Events below demonstrates the sequence of study 
activities related to enrolling patients, and then monitoring for eligibility for COOLSTAT 
therapy.  
 
Table of Study Events 
 
Admitted to NCCU 
Enrolled– Observe for 
Fever up to 7 day 
Many enrolled patients will ultimately not be eligible as fever is 
unpredictable 
Develops Fever Refractory 
to Antipyretics Treatment  
Phase 0 
Phase I 
Phase II 
Phase III 
Evaluate for 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
X 
 
 
 
Obtain 
Informed 
Consent 
X 
 
 
 
 
 
 
ENT Exam 
 
 X 
X  
(if not 
during 
observation) 
 
 
 
X 
Antipyretic 
Treatment 
Upon 
Development 
of Fever 
X 
X 
X 
X 
X 
X 
X 

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Initiate 
COOLSTAT 
Treatment 
 
 
 
 
X 
 
 
Continuous 
Monitoring 
(ICU SOP)1 
 
X 
X 
X 
X 
X 
X 
Study Phase 
Description 
 
 
 
30 min. 
pre-
therapy 
monitoring 
8 or 24 
hrs. of 
therapy 
2 hrs. post-
therapy 
monitoring 
22 hrs. 
post-
therapy 
monitoring 
1Subject monitoring includes core and tympanic temperatures, blood pressure, intracranial 
pressure (when available), suctioned water volume, and level of shivering.  
 
8.0 
Study Inclusion and Exclusion Criteria 
 
8.1 
Inclusion Criteria 
Male or female subjects may be included in the study if he/she meets ALL of the following 
inclusion criteria: 
1. Admitted to the Neurosciences Critical Care Unit (NCCU). 
2. Patient has ischemic or hemorrhagic stroke, seizure, or metabolic encephalopathy. 
3. Patient is orally intubated or has tracheostomy tube and is mechanically ventilated. 
4. Planned stay in NCCU > 24 hours. 
5. Must have informed consent from the patient or the legally authorized 
representative (LAR) making decisions for the patient. 
 
8.2 
Exclusion Criteria 
A male or female subject will be excluded from the study if he/she meets ANY of the 
following exclusion criteria: 
1. Age < 18 years old or > 95 years. 
2. Intubation is contraindicated. 
3. With a coagulopathy. INR above 1.5 or PTT above 45 seconds. 
4. Hemodynamic instability, including elevated SBP for >5 minutes despite standard of 
care interventions (SBP ≥ 160 mmHg for intracerebral hemorrhagic stroke; SBP ≥ 220 
mmHg for subarachnoid hemorrhagic stroke or ischemic stroke). 
5. History of cryoglobulinemia. 

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6. History of sickle cell disease. 
7. History of serum cold agglutinin disease. 
8. Active/ongoing nose bleeds. 
9. Known or suspected pregnancy. 
10. Participation in another ongoing investigational study. 
11. Prisoners and/or patients for whom no LAR is available. 
12. Patient is in airborne/droplet disease isolation protocol. 
13. Patient is or suspected to be immunocompromised; 
14. Low platelet count defined as < 100k (thrombocytopenia). 
15. Nasal septal deviations (per CT scan; any degree). 
16. Chronic rhinosinusitis. 
17. Prior skull-based surgery. 
18. Penetrating cranial trauma. 
19. Recent nasal trauma or anterior base skull fracture. 
20. Presence of cardiac arrhythmias including: sustained tachycardia defined as heart 
rate above 120 beats per minute, or sustained bradycardia defined as heart rate 
below 60 beats per minute. 
21. Refractory hypoxemia defined as partial pressure of oxygen in arterial blood (paO2) 
below 60 torr or oxyhemoglobin saturation below 90% despite endotracheal 
intubation, mechanical ventilation, and provision of supplemental oxygen of up to 
0.60. 
22. Refractory hypercarbia defined as partial pressure of carbon dioxide in arterial blood 
(paCO2) above 50 torr despite endotracheal intubation and conventional mechanical 
ventilation. 
23. History of cardiac arrhythmia as listed above. 
24. BMI of ≤ 15 kg/m2 or ≥ 40kg/m2 
 
9.0 
Sequence of Investigational Assessments and Procedures 
 
9.1 
Study Team Member Activities to Assess Eligibility for Cooling  
Potential candidates for the study are evaluated by the Investigator or their designee.   

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1. The investigator or their designee must approve the candidate to be enrolled by 
confirmation of inclusion / exclusion criteria, including the informed consent received 
from the patient or the patient’s Legally Appointed Representative (LAR). 
2. Every 12 hours, from time of enrollment up to 7 days, the volume of fluid collected 
from tracheal suction will be recorded.  (The volume of oral fluid suctioned from the 
subject should not be collected with other suctioned fluids.)  These volumes will be 
averaged to be used as a baseline for comparison to fluid volumes collected during 
the use of the CoolStat device. 
3. The investigator may approve the enrollee for COOLSTAT therapy if all of the 
following are satisfied within 7 days of enrollment: 
• 
the subject has or develops a fever (core temperature > 38.3 °C, but <39.5 °C) and 
remains febrile for at least 1 or 2 hours (based on institutional standard) after the 
administration of antipyretics,  
• 
the subject is confirmed to have core temperature probe (esophageal, SpotOn or 
bladder), and 
• 
an ENT exam is performed (if not done previously to enrollment) to evaluate for 
craniofacial abnormalities that would exclude the subject.  
 
4. The investigator shall withdraw the subject if the above criteria are not met within 7 
days after “enrollment”. No further monitoring or follow-up is required for such 
subjects. 
9.2 
 Phase 0 – Monitoring Before Cooling  
1. Prior to starting the COOLSTAT device, clinical personnel will confirm that the subject 
is intubated and mechanically ventilated.  
2. The COOLSTAT device shall be brought into the subject’s room and the core 
temperature sensor (either esophageal - Smiths Medical Esophageal Stethoscope 
Temperature Sensor; Series 400. Model ES 400-12 – or bladder - Foley Catheters, 
BARDEX® I.C., Temperature-Sensing, Dual Connector 5 mL balloon, 16 French – or 
3M Spot On™ Temperature Monitoring System) will be plugged into the COOLSTAT 
device. The subject’s core temperature should be confirmed at this time to be ≥ 38.3 °C, 
but <39.5 °C, as displayed on the CoolStat device.   
3. Delivery of any medications or other fluids orally will be recorded on the CRF due to 
potential temporary effect on esophageal temperature probe. Even room temperature 
fluids may affect the temperature reading, and time of administration should be 
recorded.  
4. A tympanic temperature sensor will be placed in the subject’s ear and connected to 
the hospital’s temperature monitoring system to record temperature. The acceptable 
tympanic temperature range is 34 to 39°C, and the hospital system temperature alarms 
will be set to indicate any readings outside that range.  NOTE – in this study, tympanic 

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temperature is only considered as a surrogate for brain temperature for safety 
monitoring. Either esophageal or bladder temperature will be used as core 
temperature.  It can take about 5 to 10 minutes for the tympanic temperature sensor 
to reach a steady state monitoring condition when initially placed in the subject’s ear.   
5. The COOLSTAT device will be prepared and the set up initiated, but not turned on.  
COOLSTAT set up and operation procedures are provided in the Operator’s Manual, 
as well as a Quick Start Guide.     
6. The subject target temperature will be set to 36.5 °C on the CoolStat device. 
7. The subject’s core temperature will be monitored and recorded in the CRFs, from the 
esophageal, SpotOn, or bladder temperature sensor.  The acceptable core temperature 
range is 36°C to 39°C.  The patient may remain >39.0 °C but <39.5 °C for up to 4 hours, 
at which point the CoolStat treatment will be discontinued and an alternative cooling 
method initiated. Likewise, the CoolStat will be stopped if the subject has a sustained 
core temp > 39.5 C sustained for 5 minutes.  
8. Position of the endotracheal tube will be verified and recorded in CRF (distance 
measured at subject’s teeth), per normal procedure.  
9. For the first 5 subjects, ICP monitoring and measurement of < 20 mmHg will be 
confirmed.  
10. The subject will be monitored, without turning on the COOLSTAT, for 30 minutes to 
ensure the subject’s temperature is stable and febrile.  Over this time period, an 
assessment will also be made to assess blood pressure and ICP (if available) of the 
subject, which will be recorded in the CRFs.     
11. A bolus dose of meperidine (Demerol) may be given to the subject prior to starting the 
COOLSTAT device to dampen a potential pain response to the COOLSTAT therapy.  
This can be given 15 minutes into Phase 0 recording (and therefore 15 minutes prior 
to initiation of COOLSTAT therapy; see explanation below). 
12. Upon starting the cooling therapy, the provided stopwatch is started and the start time 
is recorded on the therapy monitoring form. The time will also be recorded from a 
room clock (with source noted) to facilitate alignment of data records.  
Each investigational site will follow their standard procedures for managing shivering 
and active cooling tolerability in their patients.  
9.3 
Phase 1 – Active Cooling Phase 
Subjects will receive COOLSTAT cooling treatment, with a maximum of 30 cmH2O of air 
pressure (as automatically controlled by the device).  The COOLSTAT will be operated in 
closed-loop control mode and will automatically modulate and control air flow and 
maintain the subject’s core temperature between 36 °C and 37.5 °C, as measured by the 
esophageal, SpotOn, or bladder temperature sensor.  The device will be set to target 36.5 
°C. 
 

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The COOLSTAT will attempt to cool to and maintain this temperature range over the 
phase period.  The core temperature will be recorded automatically by the COOLSTAT 
device, and is displayed on the COOLSTAT screen.   
 
While the COOLSTAT is in use, no other cooling therapies will be used other than 
antipyretics.  
 
Throughout Phase 1, the subject’s temperature and vital signs will be monitored per 
NCCU protocol, as well as data collected in the CRFs.  If any alarms occur, the appropriate 
action will be taken as described herein.  COOLSTAT device errors will be addressed via 
an available trained technician and study team training (See Operator’s Manual for a 
description of the possible device errors).   Treatment may be discontinued at any time if 
adverse events are encountered or alternate cooling methods are required on an urgent 
basis.  The Investigator or their designee must review any such emergency changes to 
therapy and complete an Adverse Event form detailing the reason for the change.  
 
Per standard of care in the NCCU, maximum allowed limits will be imposed for a 
sustained increase in SBP >5 minutes above existing SBP threshold limits (specific to the 
indication being treated) despite standard of care intervention.  In this event, COOLSTAT 
use will be discontinued for that subject. Once the COOLSTAT is discontinued due to SBP 
elevation, it will not be restarted for that subject.  However, the study team will continue 
to monitor SBP to see if it recovers back to baseline value after the COOLSTAT is turned 
off.  The Investigator or their designee must complete an Adverse Event form detailing 
the event and the value of the SBP prior to, during and after the COOLSTAT was used.   
 
Similarly, per standard of care in the NCCU, a maximum allowed limit will be imposed 
for a sustained increase in ICP >5 minutes above max threshold despite standard of care 
intervention (using existing max institutional limits for the indication being treated).  In 
this event, COOLSTAT use will be discontinued for that subject.  Once the COOLSTAT is 
discontinued due to ICP elevation, it will not be restarted for that subject.  However, the 
study team will continue to monitor ICP to see if it recovers back to baseline value after 
the COOLSTAT is turned off.  The Investigator or their designee must complete an 
Adverse Event form detailing the event and the value of the ICP prior to, during and after 
the COOLSTAT was used. See Section 10.0 on procedures following the occurrence of an 
Adverse Event. 
 
The Investigator or their designee will perform an initial cooling assessment 4 hours after 
COOLSTAT cooling has begun to determine if the subject has reached normothermia (≤ 
37.5 C) sometime within the 4-hour cooling period. Starting from the initiation of 
normothermia, a subject’s core temperature may fluctuate (within about 36.0-37.5 C), but 

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if the core temperature >39.0C for 4 hours, CoolStat treatment will be stopped and the 
subject will be switched to an alternative cooling method.  If normothermia (≤ 37.5 C) is 
not achieved within the 4-hour period, the Investigator or their designee will remove the 
subject from the COOLSTAT device.  The subject will be classified as a treatment failure 
and placed on standard of care treatment at the discretion of the Investigator or their 
designee and manual data collection will continue per the instructions for Phase 2 in 
Section 9.4.  NOTE – if the Investigator feels that the subject’s temperature is approaching 
the target and the subject is being adequately cooled, CoolStat device operation can be 
allowed to continue beyond the 4-hour period.  The Investigator should note if this is the 
case in the CRF. 
 
If a subject must be disconnected from the CoolStat device for transport from the NCCU 
to another unit (e.g., to radiology or angiography suite), they will be reconnected to the 
device at steady state if their core temperature upon being reconnected to the CoolStat is 
≤ 37.5 °C. If the subject’s temperature is > 37.5 °C upon being reconnected to the device, 
the device will be given up to an additional 4 hour-period to bring the patient to 
normothermia (≤ 37.5 °C). Once the subject’s core temperature is ≤ 37.5 °C, the device will 
be considered in steady state. Only the total steady state time will be used for analysis. 
Subjects who are disconnected from the CoolStat for transport may be given a bolus of 
cold saline before transport. This will be determined by the clinical provider a case-by-
case basis. 
 
The COOLSTAT does not have a re-warming function.  If the subject’s core temperature 
drops below 36 °C, warming therapies can be initiated at the discretion of the Investigator 
or the attending clinician(s).  The subject can stay on the COOLSTAT and continue with 
the study as long as core temperature can be adequately controlled at the discretion of the 
Investigator or the attending clinician(s).  Any change to therapy must be recorded in the 
case report form. COOLSTAT therapy will be discontinued if tympanic temperature 
drops below 34C for a sustained period of at least 5 minutes. 
 
The CoolStat nasal mask will be removed at least every 4 hours to inspect nasal tissue for 
the development of any pressure sores.  Petroleum gel may be applied to facilitate a strong 
seal below the nasal mask pillows and the nostrils without requiring much pressure from 
the mask straps.  
 
The COOLSTAT therapy will be discontinued at the end of Phase 1, at which point the 
subject can be placed on alternate cooling therapies at the discretion of the attending 
clinician.   
 

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9.4 
Phase 2 – Post-Therapy Monitoring Phase 
After Phase 1, the COOLSTAT will be stopped by pressing the ‘Start/Stop’ button on the 
control panel of the device.  Once the device is in the pause mode, the nasal mask will be 
removed from the subject and the temperature probe disconnected from the COOLSTAT, 
however, the hospital core temperature sensor  will remain connected to the subject, or it 
can be replaced with the esophageal, SpotOn, or bladder sensor at the discretion of the PI.  
This will conclude any cooling with the COOLSTAT.  Manual data collection will continue 
for two hours after COOLSTAT cooling has concluded to capture the subject’s response 
post-cooling.   
 
Any new cooling therapies can be applied to the subject as directed by clinicians, but will 
need to be noted in the case report forms.  Phase 2 ends at the conclusion of this two-hour 
observational period.  The COOLSTAT must be prepared for the next subject according 
to the procedures in Section 9.8. 
 
9.5 
Phase 3 - Post-Cooling Follow-up 
For the next 22 hours, the subject’s vital data will continue to be manually collected every 
4 hours, and a qualified board-certified otolaryngologist or otolaryngology resident 
(under the supervision of a board-certified otolaryngologist) will perform a follow-up 
examination of the upper airways within 24 hours of the end of Phase 1 COOLSTAT 
Therapy.  The intensivist will perform the post-therapy nasal exam if an otolaryngologist 
is not available. 
9.6 
Tasks during Cooling  
Once the COOLSTAT cooling has commenced, data will be manually collected and 
recorded on the supplied Therapy and Observation Record (requirements are also listed 
in Section 12.7).  Data collection activities will be performed throughout the therapy phase 
(Phase 1.)  These activities will include: 
• 
Note the time when collecting data during this time interval. 
• 
Note and record blood pressure and ICP values, prior to starting COOLSTAT, as 
well as during its use and after it is turned off. 
• 
Record any antipyretic or other medications given and its dose during this time 
interval. 
• 
Record the subject’s core and tympanic temperatures displayed on the CoolStat 
and hospital monitor.   
• 
Assess and record the subjects’ level of shivering according to the Bedside 
Shivering Assessment Scale (scale written on the Data Record). 
• 
Record any anti-shivering actions taken during this time interval. 
• 
Check that the nasal mask has not inadvertently shifted during the study, and 
readjust if necessary during Phase 1. Apply a small amount of Vaseline to nasal 

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pillows to facilitate a good seal to nostrils without needing to apply much 
pressure. 
• 
Briefly remove the nasal mask every 4 hours to inspect for any sign of pressure 
ulcer. Reapply Vaseline to facilitate good seal between nasal pillows and nostrils. 
• 
Check that the saline bag is periodically dripping to ensure it is supplying saline 
to the disposable set during Phase 1 and record. 
o If the saline bag is observed to have <500 mL of saline remaining, replace 
saline bag with 1L bag to ensure continuous availability of saline.  
o Note when a bag is replaced on the Data and Observation Record. 
• 
Record the tracheal volumes of fluid collected in the canisters from the tracheal 
tube at COOLSTAT therapy initiation (Phase 0) and twice daily for the remainder 
of the study. Oral fluids should be suctioned into a third canister and should not 
be included in the fluid volume measurements. 
• 
Record if there was any AE during this time interval (a separate AE form must be 
completed.) 
• 
Per standard of care, verify correct positioning of the endotracheal tube and record 
(three times daily). Exam subject for abdominal distension and record every 8 
hours. 
• 
There is an increased risk of insensible losses during the cooling period.  Clinical 
providers will be made aware of this and advised to take this into account as they 
monitor for possible dehydration and provide maintenance IV fluids for study 
participants. Clinical and study personnel will evaluate the patient for any signs 
of dehydration and record every 8 hours. 
• 
Device alarms will be responded to as described during training and in the error 
table in the COOLSTAT Operator’s Manual.  An alarm for high relative humidity 
of air delivered to the patient is to be expected; it indicates that the desiccant 
cartridge needs to be changed according to instructions in the manual. 
9.7 
Anti-Shivering Regimen  
Shivering during cooling increases oxygen consumption and generates heat that interferes 
with the cooling process.  If the subject starts shivering, anti-shivering regiment will be 
performed following existing hospital routines.  A shivering response due to the 
application of an active, external cooling system is not unexpected.  Any anti-shivering 
protocol that is used will be documented in the subject’s case forms.  The subjects will be 
actively monitored for signs of shivering.  The proactive use of prophylactic anti-shivering 
agents should not be used. 
9.8 
Turning Off and Clean-up  
At the end of Phase 1, the COOLSTAT device will be turned off by pressing the 
‘Start/Stop’ button.  At this point, the nasal mask will be removed from the subject by 
loosening the head straps.  The temperature connection to the COOLSTAT will be 

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removed from the device.  The nasal mask component and the desiccant cartridge will be 
disposed of per standard hospital protocols.  Specific steps are detailed below: 
1. Power off COOLSTAT device using the power switch per Operator’s Manual. 
2. Disconnect the nasal mask component from the COOLSTAT and dispose of mask 
assembly. 
3. Open device lid and remove and dispose of desiccant cartridge. 
4. Remove saline bag from IV hanger, record the remaining amount of fluid in the bag, 
and dispose of the bag and any remaining saline per standard hospital protocols.   
5. Wipe down external device surfaces with standard, hospital supplied wipes.   
6. Return the device to the designated storage area (per study team personnel).   
9.9 
Subject Study Completion 
The study Subject Completion Form section of the therapy case form is to be completed 
after 22 hours of additional follow-up (end of Phase 3).   
 
10.0 Adverse Events, Warning, and Precautions 
For this Feasibility IDE Clinical Trial, the definitions outlined in the FDA Guidance for 
Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs – Improving 
Human Subject Protection (January 2009) will be applied to adverse events. 
 
The investigational device exemption (IDE) regulations define an unanticipated adverse 
device effect (UADE) as “any serious adverse effect on health or safety or 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 investigational plan or application (including a supplementary plan or application), 
or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects” (21 CFR 812.3(s)).  UADEs must be reported by the 
clinical investigator to the sponsor and the reviewing IRB, as described below:  
 
 
• 
For device studies, investigators are required to submit a report of a UADE to the 
sponsor and the reviewing IRB as soon as possible, but in no event later than 10 
working days after the investigator first learns of the event (§ 812.150(a)(1)).  
 
• 
Sponsors must immediately conduct an evaluation of a UADE and must report the 
results of the evaluation to FDA, all reviewing IRBs, and participating 
investigators within 10 working days after the sponsor first receives notice of the 
effect (§§ 812.46(b), 812.150(b)(1)). 
 

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o The IDE regulations, therefore, require sponsors to submit reports to IRBs 
in a manner consistent with the recommendations made above for the 
reporting of unanticipated problems.  Possible exceptions would include 
situations in which the specificity or severity of the event is not consistent 
with the description in the investigator’s brochure, or it can be determined 
that the observed rate of occurrence for a serious, expected AE in the 
clinical trial represents a clinically important increase in the expected rate 
of occurrence. 
 
To report an adverse event or unanticipated adverse device effect, the 
proximate investigator will complete an Adverse Event Form.  All adverse 
events must be reported to the sponsor immediately (within 24 hours of 
becoming aware of the event).  It is also the responsibility of the Principal 
Investigator to inform the representative of the center’s IRB according to 
the IRB policies and procedures.   
 
10.1 
Adverse Event Definitions 
On the Adverse Event Form, each adverse event will be classified as anticipated or 
unanticipated; device related or not device related; and classified as mild, moderate or 
severe.  The severity classification will be determined by the investigator proximate to the 
event, who will use his or her clinical judgment and assign a severity classification based 
in the following definitions. 
• 
MILD  (resolved without intervention within study period) 
• 
MODERATE (medical intervention required, not life threatening, did not alter 
study course)  
• 
SEVERE  (potentially life-threatening and required immediate intervention, could 
or has altered study)  
 
10.2 
Unanticipated Adverse Device Effect (Event) 
An Unanticipated Adverse Device Effect (UADE) will be defined as per FDA Regulation 
21 CFR 812.3(s) as “any serious adverse effect on health or safety or 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 
investigational plan or application (including a supplementary plan or application), or 
any other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects”.  
 

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As per FDA regulations 21 CFR §812.150(a)(1), §812.46(b), and §812.150(b)(1), all UADEs 
must be reported by the clinical investigator to the sponsor and the reviewing IRB, as 
described below: 
• 
An investigator is required to submit a report of a UADE to the sponsor and the 
reviewing IRB as soon as possible, but in no event later than 10 working days after 
the investigator first learns of the event (§ 812.150(a)(1)). 
• 
The sponsors must immediately conduct an evaluation of a UADE and must 
report the results of the evaluation to FDA, all reviewing IRBs, and participating 
investigators within 10 working days after the sponsor first receives notice of the 
effect (§§ 812.46(b), 812.150(b)(1)). 
10.3 
 Actions in Response to Adverse Events 
 
During training, the study team member will learn the appropriate actions to take in 
response to an adverse event.  These actions may include, but are not limited to:  
• 
Suspending COOLSTAT Cooling: COOLSTAT cooling may need to be removed 
from the subject at the discretion of the investigator or their designee.  This would 
involve stopping the air flow and removing the nasal mask, but otherwise keeping 
the device on and continuing to collect temperature data for the study period. 
• 
Switching to Alternative Cooling Method: The investigator or their designee may 
switch the subject onto an alternative cooling method if it is deemed necessary for 
the subject’s safety; the subject will be completely removed from the COOLSTAT 
device.  Manual data will continue to be collected for the following 22 hours. 
• 
Removing the Device Without Alternate Cooling: The COOLSTAT can be 
completely removed from the subject without starting alternate cooling if, at the 
discretion of the investigator or their designee, the safety of the subject is at risk 
and/or cooling is no longer needed. 
10.4 
Anticipated Adverse Events 
• 
Nose bleeds (epistaxis) 
• 
Shivering 
• 
Pressure or skin breakdown because of mask 
• 
Aspiration 
• 
Nasal congestion 
• 
Over-cooling 
• 
Insufficient cooling 
• 
Increase in insensible losses (subject dehydration) 
• 
Induced brain hypothermia 
• 
Adverse effects on systemic blood pressure 

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10.5 
Serious Adverse Events 
• 
Severe nasal mucosal ulceration 
• 
Severe oral mucosal ulceration 
• 
Uncontrolled epistaxis requiring stopping of therapy or intervention 
• 
CSF rhinorrhea  
• 
Any other potentially life threatening event requiring immediate intervention 
• 
Any other unanticipated device related adverse event. 
 
10.6 
Technical Device Failures 
Technical device failures will be recorded on a device performance CRF, and evaluated 
for possible adverse effects for the patient.  For the purposes of this study, a technical 
device failure is defined as a failure of the COOLSTAT system to perform its intended 
function when used in accordance with the Instructions for Use, or to perform any aspect 
of the study protocol.   
 
If a device failure results in an adverse experience for the patient, this adverse experience 
should be recorded on the Adverse Event Form. Device failures that do not result in an 
adverse effect for the patient will be noted on the device performance report form, but 
will not be considered an adverse event in and of themselves. 
 
10.7 
Warnings 
Note: These warnings are specific for the investigational device. 
• 
Use of the COOLSTAT device should only be undertaken by a study team member 
who is thoroughly familiar with the proper use of the device as provided in all 
provided instructional and guidance documents, and only under the supervision 
of the clinical investigator. 
• 
Do not attempt to service the COOLSTAT device.  COOLSTAT includes 
potentially hazardous moving parts and the risk of electrical shock if the device 
cover is removed.  Contact CoolTech for all servicing needs. 
• 
The COOLSTAT device should only be used with appropriately grounded 
electrical outlets. 
• 
When setting a target temperature, the user should exercise care and proper device 
procedures to avoid incorrect therapy – the COOLSTAT device may have the 
ability to overcool the patient below normothermia temperatures. 
 
10.8 
Precautions 
Note: These precautions are specific for the investigational device. 
• 
Proper placement of the core temperature sensor is important for COOLSTAT to 
appropriately cool subjects – clinicians are responsible for properly placing the 

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sensor in accordance with standard practice. Esophageal, SpotOn, and bladder 
temperature probes are acceptable core temperature sensors for use with 
COOLSTAT. 
• 
COOLSTAT disposables are for single subject use only.  Do not reuse and do not 
use with multiple subjects. 
 
10.9 
Follow-up of Unresolved Events 
Any unresolved adverse events, adverse device effects and/or unexpected adverse device 
effects still unresolved when the subject ends the study will be followed until they are 
resolved but no longer than 24 hours. 
 
11.0 Investigational Medical Devices 
 
11.1 
Description of Investigational Medical Devices 
The investigational medical device will be labeled “CAUTION - Investigational Device. 
Limited by Federal (or United States) Law to Investigational Use”.  This will help to ensure 
that the investigational products are not accidently used for other non-trial related 
procedures.  (Any original equipment manufacturers labeling will not be removed but 
shall be over-labelled for the purpose of the IDE labeling.) 
 
11.2 
Product Packaging and Labelling 
The device (hardware/software) will not have a separate package.  Labelling will be 
directly on its enclosure.   
 
The disposables are split into two different packages – each set of tubing manifold and 
nasal mask is sealed in a plastic bag, and each desiccant cartridge is sealed in a heat seal 
foil pouch to protect from moisture.  A photograph of disposable labels is included in the 
Operator’s Manual. 
 
11.2.1 Device Operating Instructions 
All safety and operational information are included in the Operator’s Manual. 
 
11.2.2 Device Package Labels 
The device labels will include the following information: 
• 
“CAUTION – Investigational Device. Limited by Federal (or United States) Law to 
Investigational Use.” 
• 
“COOLTECH LLC 
40 East Cross St. 
Baltimore, MD 21230” 

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• 
Study name 
• 
Device name 
• 
Device serial number 
• 
“Be familiar with device operation before use” 
11.2.3 Disposable Package Labels 
The disposable labels will include the following information: 
• 
“CAUTION – Investigational Device. Limited by Federal (or United States) Law to 
Investigational Use.” 
• 
“COOLTECH LLC 
40 East Cross St. 
Baltimore, MD 21230” 
• 
Lot number 
• 
Expiration date (Use by date) 
• 
“NON-STERILE” 
11.3 
Required Experience and Training 
The investigators and any site personnel directly involved in the study or protocol 
execution must be trained in accordance with their responsibilities about the COOLSTAT 
device and protocol requirements at the study initiation visit; and whenever new 
investigator or study personnel are added.  The training will be documented in the 
training case form.  Only qualified personnel may handle the device. 
 
11.4 
Storage and Handling 
The COOLSTAT device, the desiccant cartridges, and the mask disposable sets will be 
stored at room temperature and maintained by designated study personnel in a locked 
room.  The equipment may only be handled by designated study personnel.  
 
11.5 
Accountability of Investigational Medical Devices 
Receipt, use and return of the medical devices will be documented on a device transport 
log. Additionally, each subject’s therapy record case form must identity devices 
(hardware and disposables) specifying the device by serial number, and all reference 
numbers for disposables used.  All “service” conducted per unit will also be maintained 
in a service record log maintained for each unit, including records of removal of any unit 
from the study premises for any reason.  Each used disposable set must be accounted for 
on the transport log and by patient ID.  Use and disposal of disposables will be recorded 
on CRFs (e.g. number of desiccant cartridges used).  In the event of a desiccant cartridge 
or nasal mask malfunction or failure, the faulty item will be bagged and retained until 
communication with Sponsor to determine follow up procedures to failure mode analysis.  
 

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12.0 Data Collection and Management 
 
12.1 
Case Report Forms 
The data for this study will be collected using Case Report Forms (CRFs), not including 
the data collected by the COOLSTAT device.  Blank template forms are provided. 
 
Prior to the start of the clinical trial, the study center will be provided with a sufficient 
number of Case Report Forms and these may be replenished as needed. All entries are to 
be made in blue or black ink and are to be legible.  All information in the CRFs should be 
in English.  All corrections made on paper based forms are to be completed by placing a 
single line through the incorrect data, leaving the incorrect data clearly visible (e.g. 352 
325), and the individual making the correction must initial and date the correction.  
Erasure by any method is not allowed. The personal data recorded on all documents will 
be regarded as confidential. 
 
The investigator will be responsible for the timely and accurate completion of specific 
CRFs (or certain areas on the CRF) for an individual subject for whom he/she may be 
responsible, wherein an investigator’s signature is required.  Where so designated trained 
study personnel may record information on case report forms.  
 
Except for adverse event forms which have a limited time to be completed and forwarded, 
each set of CRFs for a specific subject must be completed as soon as practical as each 
subject completes (or is withdrawn from the study).   
 
Completed CRFs shall be transmitted to the Sponsor in a timely manner. Original case 
forms shall be stored in a designated area convenient for the Monitor and Principal 
Investigator.  The Principal Investigator shall review data from the study at any time 
throughout the course of the study.  The monitor and PI may request data queries in the 
event of incomplete records or recording discrepancies.  
 
12.2 
Review and Query of Completed CRFs 
Any corrections of data (by PI or Sponsor) after CRF pages have been collected will be 
done by way of a written query. The query should state the question or data to be 
clarified.  The query and correction will be included with the Sponsor’s copy of the 
CRF and retained together with the original CRF in the Principal Investigator’s files. 
 
The receipt of the scanned form must be verified by an alternative method, such as an 
email to indicate forms have been sent to the Sponsor.  The exact method for transmission 
will be detailed in the Investigator’s Manual and may change from time to time based 

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upon Sponsor and Investigator’s needs.  Any such changes shall be documented and 
approved by the Sponsor and PI in advance.  In any case, the Principal Investigator shall 
retain the original and make the original Case Report Forms (with any associated data 
queries) available to the Sponsor’s designated Monitor at each monitoring visit.   
 
12.3 
Retention of Records and Documentation 
The clinical investigator will be required under FDA Regulation 21 CFR §812.140(d) to 
retain all copies of the records for a period of 2 years after the latter of two dates: (1) the 
date on which the investigation in terminated or completed, or (2) the date that records 
are no longer required for purposes of supporting a premarket application.  In all cases, 
the investigator must contact the sponsor prior to disposing of any records related to the 
clinical investigation.  Included in the records to be maintained are signed Clinical 
Protocols, source records for any data, copies of any paper Case Report Forms, signed 
consent forms, ethics committee approval letters, product use records, and any 
correspondence concerning the clinical trial. 
 
12.4 
Data Management 
The processing of all data on the Case Report Forms will be the responsibility of the 
sponsor.  All data recorded from the Case Report Forms to data analysis software will be 
subject to independent verification for accuracy.  Comparison of the data entries will then 
be performed and any resulting discrepancies adjudicated by an independent third 
person with reference to the Case Report Form.  All data queries will be resolved with the 
assistance of monitoring staff and documented in writing as described above. 
 
The Monitor will use controlled Standard Operating Procedures in all aspects of data 
management, data verification, archiving and retention. 
 
12.5 
Collection of Medical History Data for Patient 
The following medical history data will be collected from each subject: 
• 
Normal or abnormal eyes, ears, nose, throat 
• 
Normal or abnormal neurological 
o CVA (cerebrovascular accident) 
o TIA (transient ischemic attack) 
o Shunt for hydrocephalus 
o CEA (carotid endarterectomy) 
o Myasthenia gravis 
o Seizures 
o Multiple sclerosis 
o Encephalitis 

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o Meningitis 
o Subdural hematoma 
o Epidural hematoma 
• 
Normal or abnormal gastrointestinal 
• 
Normal or abnormal respiratory 
o Current/past tobacco use 
• 
Normal or abnormal cardiovascular 
• 
Normal or abnormal genitor-urinary 
• 
Normal or abnormal musculoskeletal 
• 
Normal or abnormal dermatological 
• 
Normal or abnormal endocrine 
o Diabetes 
o Hypothyroidism 
o Hyperthyroidism  
• 
Drug/alcohol use 
• 
Normal or abnormal hematological 
• 
Normal or abnormal hepatic 
• 
Allergies and drug intolerance 
 
12.6 
Collection of Data by Device 
Each second, the COOLSTAT device will be automatically collecting air flow rate, air 
temperature supplied to subject, air humidity supplied to subject, air pressure, and the 
subject’s core temperature data.  This data is automatically stored to a micro SD card, with 
a new file started with each device power-on.  The SD card is embedded in the device and 
is not accessible unless the device external housing is removed, which would require the 
use of tools. A serial data logger will be used to transfer device data from the CoolStat to 
a secure data storage cloud. This will allow the study Sponsor and monitor to review and 
verify the source data in a timely manner, without requiring the retrieval of devices.  The 
data collected by the COOLSTAT has a time and date stamp, but no other subject 
identifying information.  Therefore, in order to tie the data to a specific subject, the time 
and date stamp will be matched to the time that was manually recorded when the subject 
began COOLSTAT therapy.  All data collected by the COOLSTAT will be subject to audit 
by the study monitor and may not be used in analysis of the effectiveness of cooling if not 
verifiable.   
 
To validate the data saved by the COOLSTAT, testing will be performed on each 
COOLSTAT unit to ensure the expected outputs result from a range of inputs.  The data 
for each sensor (flow rate, air temperature, humidity, and pressure, and subject’s core 
temperature) is compared with readings from an external calibrated sensor.  Multiple 

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conditions will be tested for each sensor to ensure the saved data are accurate over 
expected operating ranges. 
 
The COOLSTAT’s screen displays the subject’s current temperature measurement for 
reference during the trial (this data is automatically collected by the COOLSTAT) – this 
measurement is the same as the core temperature displayed on the hospital monitor.   
 
12.7 
Collection of Manual Data 
Subject core and tympanic temperatures, blood pressure, intracranial pressure (when 
available), suctioned water volume, and level of shivering will be monitored and recorded 
in the Therapy and Observation Record throughout the therapy period.  Data to be 
collected during the course of the study is detailed in Section 9.0. 
 
Data collection will occur at a minimum 5 minute intervals for the first 30 minutes of 
cooling, 30 minute intervals during the first 8 hours, and then every 2 hours for the 
remaining 16 hours (if applicable).  During Phase 2, data collection will occur at a 
minimum of 15 minute intervals.  After Phase 2, manual data will continue to be collected 
at a minimum of every 4 hours for the next 22 hours. 
 
13.0 Statistical Analysis Plan   
The primary efficacy analysis for cooling performance will be based on the evaluable 
populations of subjects who undergo cooling treatment with the COOLSTAT System. 
Analysis will be performed on treatment initiated and treatment completed populations.  
Subjects who achieve normothermia (core temperature ≤ 37.5 °C) within 4 hours of starting 
COOLSTAT treatment and maintain normothermia for the duration of the treatment will 
be determined to have been treated successfully. 
 
The primary efficacy analysis for temperature maintenance will be based on the evaluable 
population of subjects who maintain normothermia (core temperature between 36 °C and 
37.5 °C) for at least 80% of the time following the initial achievement of 37 C will be 
determined to have been treated successfully.  
 
The proportion of subjects fulfilling success criteria and 90% confidence intervals will be 
reported and compared to the a priori minimum acceptable criteria:  
• 
at least 75% of the subjects will reach normothermia (core temperature ≤37.5 °C) within 
4 hours of starting COOLSTAT cooling, and 
• 
at least 75% of the subjects’ core temperatures remain between 36 °C and 37.5 °C for 
80% of the steady state time following the initial achievement of 37.5 C. 
 

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Continuous measurements will be summarized using the mean and standard deviation.  
Categorical variables will be reported using percentages and confidence intervals.  Data 
collected will be plotted to demonstrate the change in core temperature from baseline.  
 
An exploratory analysis of participant subgroups will be performed, stratified by stroke 
presentation (ischemic versus hemorrhagic). Cooling performance and AEs will be 
evaluated by subgroup. 
 
Double nostril air flow and single nostril air flow subjects will not be merged or directly 
compared. The results from subjects treated with single nostril flow will be analyzed 
separately from subjects treated with double nostril air flow.  
Subjects 1 through 20 will be assigned to the double nostril air flow treatment group: 
• 
Subjects 1 through 10 will be treated for 8 hours (N=10) 
• 
Subjects 11 through 20 will be treated for 24 hours (N=10) 
 
Subjects 21 through 30 will be assigned to the single nostril air flow treatment group  
• 
Subjects 21 through 30 will be treated for 24 hours (N=10). 
• 
Subjects 21 through 30 will be treated using a dose escalation model: 
o Dosing for this cohort (flow rate) will begin at 30 LPM. 
o The dose will be increased by 10 LPM if 3 consecutive subjects complete the 
study protocol with no serious adverse events (as listed in section 10.5) or 
unanticipated adverse device events.  
o Up to three doses will be evaluated in this cohort (30 LPM, 40 LPM, 50 
LPM). 
• 
The purpose of this cohort is to assess the safety of and optimal dose for the single 
nostril air flow configuration of the CoolStat. 
• 
Each subject will be examined for adverse events, serious adverse events, and 
unanticipated adverse device events by an intensivist or otolaryngologist within 
24 hours of completing CoolStat therapy.  
• 
Each flow rate cohort must be evaluated by an intensivist or otolaryngologist prior 
to advancing the protocol to the next increased flow rate cohort.  
 
 
13.1 
Primary Performance Outcome Analysis 
The primary hypothesis regarding cooling performance is that at least 75% of the subjects 
will reach normothermia (core temperature ≤ 37.5 °C) within 4 hours of starting 
COOLSTAT cooling. 
 

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The primary hypothesis regarding temperature maintenance is that at least 75% of the 
subjects’ core temperatures remain between 36 °C and 37.5 °C for 80% of the steady state 
time following the initial achievement of 37.5 C. 
 
13.2 
Secondary Performance Outcome Analysis 
To analyze the COOLSTAT’s impact on the shivering response, the incidence of anti-
shivering actions will be assessed.   
 
13.3 
Safety Assessment 
 
13.3.1 Nasal Examination 
To ensure the COOLSTAT has not resulted in damage to the subject’s nasal passages, a 
nasal examination is performed before and after testing by a board-certified 
otolaryngologist or otolaryngology resident (under the supervision of a board-certified 
otolaryngologist).  These exams may be performed by a board-certified otolaryngologist 
or otolaryngology resident (under the supervision of a board-certified otolaryngologist), 
or by an intensivist if an otolaryngologist is unavailable. The post-test exam must occur 
within 24 hours after cooling has completed.. 
 
In the pre-test exam, the clinician will examine the subject for the following: 
1. Deviation of nasal septum 
2. Nasal polyps 
3. Ulceration of the mucosa 
4. Nasal bleeding / bloody discharge 
5. Nasal septal perforation 
 
In the post-test exam, the clinician will examine the subject for the following: 
1. Ulceration of the mucosa 
2. Nasal bleeding / bloody discharge 
3. Nasal septal perforation 
 
13.3.2 Adverse Events 
All adverse events will be analyzed to determine if the cause is from the COOLSTAT 
device or other related activities from the study protocol.   
 
14.0 Study Management and Responsibilities 
 

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14.1 
Informed Consent 
A subject (or LAR) may withdraw their consent to participate in this study at any time.  If 
the subject withdraws, standard of care will be provided.  
 
14.2 
Withdrawal of Subjects 
A subject may be withdrawn from the study for the following reasons: 
• 
if it is the subject or their LAR desire to withdraw,  
• 
if it is medically necessary, as judged by the investigator, or  
• 
if the subject does not receive COOLSTAT therapy within 7 days of enrollment, or 
if after enrollment it is determined that the patient may not receive COOLSTAT 
Therapy due to disqualifications at the pre-therapy evaluation. 
 
If a subject is withdrawn from the study, the date and reason for the withdrawal will be 
recorded in the case report form provided. 
 
14.3 
Urgent Change in Therapy 
If it is determined by the investigator that alternate cooling methods are required, the 
subject is removed from COOLSTAT therapy but data will continue to be manually 
collected according to the schedule outline starting in Phase 2 and continuing through the 
remainder of the protocol to subject completion. 
 
14.4 
Investigator Responsibilities 
It is the responsibility of the Principal Investigator to supervise and ensure adequate 
training for any personnel involved in the conduct of the study, including the Study 
Coordinator and nursing staff who may be involved in the performance of the study.  If 
any other physicians in the institution agree to participate in the trial, the Principal 
Investigator agrees to:  
• 
obtain agreement with the Sponsor to add the additional investigator(s),  
• 
obtain all required information from the additional investigator(s) which 
document qualifications (and release of this information to the FDA and IRB), 
• 
add the investigator to the Investigator Agreement list, and advise the additional 
investigator(s) as to their obligations under regulation and institutional policy, 
and 
• 
supervise the investigator’s participation in the study in so far as necessary to 
ensure consistency of practice and data collection. 
 
The Principal Investigator (or the investigator proximate to the oversight of the specific 
subject in the study) is responsible for the accuracy and timeliness of the data collection 
under his/her direction. (Data collected by the COOLSTAT device is not the responsibility 

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of the Investigator. Such data are retrieved from the data storage card in the device by a 
technician as directed and trained by the Sponsor.)    
 
The investigator is responsible for ensuring that the study is performed according to the 
protocol. The investigator shall co-sign the informed consent form to indicate the patient 
is accepted as an enrolled subject in the study. 
 
All unused product must be returned to the Sponsor at the end of the study.  The Principal 
Investigator shall permit the Sponsor to conduct pre-announced site monitoring visits and 
a site close-out visit, including a review of product and accessory use and retrieval. 
 
14.5 
Study Monitoring and Data Safety Review Boards 
 
A Clinical Monitor will be hired by the Sponsor and will be independent of UMMC and 
the study site.  The Clinical Monitor will be generally responsible to periodically visit the 
study site and monitor the activities of the study to ensure that the study protocol, consent 
activities and data collection are being completed in accordance with specified 
procedures.   
 
The DSMB will be generally responsible for safeguarding the interests of study 
participants, assessing the safety and efficacy of study procedures, and for monitoring the 
overall conduct of the study.  The DSMB will review adverse event data, other safety data, 
quality and completeness of study data, and enrollment data at each meeting to ensure 
proper trial conduct.  The DSMB is required to provide recommendations about starting, 
continuing, and stopping the study.   
 
Additional details on DSMB’s meeting schedule, composition and activities are described 
in the Appendices provided as part of the IDE application. Briefly, the DSMB is composed 
of voting members from both within UMMC as well as other institutions outside of 
UMMC. The DSMB will be meet: 1) before any subjects are enrolled, 2) after the first 5 
subjects (all with ICP monitoring), 3) after the first 10 subjects (before proceeding to 24-
hour cooling treatment), 4) after each 6-month period of study, 5) at the end of the study, 
and 6) after any serious adverse event. 
 
IDE Study close-out report will summarize all data collected and detail any statistical 
analysis conducted on the raw data.   
 

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14.6 
Institutional Review Board 
Prior to the initiation of this clinical investigation, the investigator must submit the 
protocol, patient information sheet, patient consent form and any other documents as may 
be required to the appropriate Investigational Review Board (IRB) for review and 
approval.  The investigator shall obtain from the IRB, documentation showing that the 
IRB is duly constituted and registered with the US FDA.  The investigator, and any other 
member of the clinical study team, if a member of the IRB, must not participate in the 
decision-making. 
 
A signed and dated letter granting approval must be provided to the Sponsor prior to the 
initiation of the clinical investigation. A copy of the IRB approval and all investigator 
qualifications will be submitted promptly to FDA under IDE amendment prior to 
initiation of the study at the proposed site.  Identification of the IRB Chairperson, and its 
contact information will be provided to the sponsor.   
 
14.7 
Cost to the Subjects 
Enrolled subjects in the study will not be charged or financially responsible for the cost of 
the investigational device, the disposables used, or any procedures that occur as a part of 
the study protocol.  The study sponsor will pay the usual and standard costs of treatment 
or hospital care received as a direct result of a study-related injury that are not covered by 
a health insurer (provided the costs are not the result of care required to treat the 
underlying disease or condition).  Back-up standard of care is provided by the clinical 
center according to their own protocol.  Costs associated with standard of care or any 
other treatments will be billed as it normally would without participating in the study. 
 
14.8 
Financial Compensation to Patients 
Patients will not receive compensation for participating in this study.  
 
14.9 
Cost to the Clinic 
The Investigational device and associated supplies will be made available to the 
participating clinical site at no charge throughout the clinical study. 
 
14.10 Financial Considerations and Study Support 
The investigational sites are receiving financial compensation for all personnel time and 
any direct costs associated with this study. 
 
14.11 Conflicts of Interest 
Investigators will not participate if they have a known conflict of interest.  Proper 
reporting and divulgation of potential conflict of interest shall be the policy of the Sponsor 

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and investigators throughout the course of the study.  If any new conflict of interest 
develops during the course of the study, clear reporting to stake holders will be expected 
and will follow the best practices and regulatory requirements currently in place.  
Financial interests shall be reported when and as required. 
 
14.12 Confidentiality 
All efforts will be taken throughout the study to maintain compliance to all rules and 
regulations surrounding patient confidentiality, including all forms of protected health 
information defined under HIPPA.   
 
14.13 Principal Investigator Qualifications and Training 
The Principal Investigator shall have clinical expertise in neurocritical care and 
neurogenic fever.  .  The Principal Investigator, under the terms described in Section 14.4 
may identify and designate co- or sub-investigators and designate their level of 
responsibility, if different than described in this protocol for such additional investigators. 
 
14.14 Early Termination of the Study 
Both the Sponsor and the Principal Investigator reserve the right to terminate the study at 
any time.  In terminating the study, the Sponsor and the Principal Investigator shall assure 
that adequate consideration is given to the protection of the subject’s interests and that all 
required reports are filed to the FDA and IRB in a timely manner. 
 
14.15 Protocol Deviations and Amendments 
Any amendments to the approved protocol will be approved by FDA prior to 
implementation.  Deviations from the protocol are not allowed.  All deviations from the 
protocol shall be promptly reported to the Sponsor and Principal Investigator for 
determination of the impact on the study, any risks to study subject(s) that may have 
occurred as a result of the deviation, and any reporting obligations to the IRB and FDA. 
 
14.16 Final Report 
The final report will be compiled by the Sponsor and reviewed by each participating 
investigator and the Principal Investigator.  The report will be submitted to FDA as part 
of the IDE process.  Use of the data may be submitted in support of future premarket 
notifications, publications or additional investigational studies.