A Prospective, Interventional Study Assessing the Effectiveness of the AION BIOSYSTEMS, INC. TempShield ("Shield") for Continuous Temperature Monitoring Device in the Pediatric Emergency Depart
Phase: NA
Conditions: Fever, Sepsis
Sponsor: AION Biosystems

 
 
 
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AION BIOSTYEMS, INC. TEMPSHIELD 
A prospective, interventional study assessing the effectiveness of the AION BIOSTYEMS, INC. tempshield 
(“Shield”) for continuous temperature monitoring device in the Pediatric Emergency Department. 
 
Protocol ID: STUDY00000455 
NCT Number: NCT07145541 
Principal Investigator: Sephora Morrison, MD 
Sponsor: AION BIOSYSTEMS, INC. 
Funded by: AION BIOSYSTEMS, INC. 
Version Number:  2.13 
1 May 2024 
 
 
 
 
 
 
 
 
 
 

 
 
 
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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
I agree:  
• 
To conduct the study in compliance with this Clinical Investigational Plan (CIP), with the terms of 
the clinical trial agreement and with any other study conduct procedures and/or study conduct 
documents provided by AION BIOSTYEMS, INC. 
• 
To promptly report to the Ethics Committees (ECs)/Institutional Review Boards (IRBs) according 
to local regulations. Additionally, I will not make any changes in the protocol without ECs/IRBs 
approval, except where necessary to ensure the safety of study participants. 
• 
To assume responsibility for the proper conduct of the study at this site.  
• 
To ensure that all associates, colleagues, and employees assisting in the conduct of this study 
are informed about their obligations in meeting these commitments. 
• 
To conduct the study in accordance with Good Clinical Practice (GCP), the Declaration of 
Helsinki, and the moral, ethical, and scientific principles that justify medical research. The study 
will be conducted in accordance with all relevant laws and regulations relating to clinical studies, 
the protection, and the privacy of subjects.  
• 
To maintain adequate and accurate records and to make those records available for audit and 
inspection in accordance with relevant regulatory requirements. 
• 
To co-operate with a representative of AION BIOSTYEMS, INC. in the monitoring process of the 
study and in resolution of queries about the data.  
• 
To provide AION BIOSTYEMS, INC. with an updated Curriculum Vitae and other documents 
required by regulatory agencies for this study. 
CIP Title: 
A prospective, interventional study assessing the effectiveness of the AION 
BIOSTYEMS, INC. tempshield (“Shield”) for continuous temperature monitoring 
device in the Pediatric Emergency Department. 
Investigational 
Device:  
AION BIOSTYEMS, INC. tempshield FLL Class II medical device Submitted to FDA 
for approval. 
 
Principal Investigator: 
 
 
 
Date 
 
Name and Signature 

 
 
 
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Table of Contents 
TABLE OF ABBREVIATIONS ............................................................................................................................... 5 
1. 
GENERAL ................................................................................................................................................. 6 
1.1 
BACKGROUND AND PURPOSE ............................................................................................................................... 6 
1.2 
OBJECTIVE .......................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
1.3 
SPONSOR INFORMATION ..................................................................................................................................... 7 
1.4 
CLINICAL INVESTIGATIONAL PLAN ......................................................................................................................... 7 
1.5 
STUDY DESIGN WORKFLOW ................................................................................................................................ 8 
2 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE ...................................................... 8 
2.1 .............................................................................................................................................................................. 8 
INVESTIGATIONAL DEVICE ................................................................................................................................................. 8 
2.2 
MANUFACTURER ............................................................................................................................................... 8 
2.3 
IDENTIFICATION OF THE INVESTIGATIONAL DEVICE ................................................................................................... 8 
2.4 
TRACEABILITY DURING THE CLINICAL INVESTIGATION ................................................................................................ 8 
2.5 
INTENDED USE OF THE INVESTIGATIONAL DEVICE IN THE CLINICAL INVESTIGATION ......................................................... 9 
2.6 
INTENDED USE OF THE INVESTIGATIONAL DEVICE ..................................................................................................... 9 
2.7 
DESCRIPTION OF THE INVESTIGATIONAL DEVICE ....................................................................................................... 9 
2.8 
TRAINING ....................................................................................................................................................... 10 
2.8.1  .................................................................................................................................................................... 10 
2.9 
DESCRIPTION OF THE MEDICAL PROCEDURES INVOLVED IN THE USE OF THE DEVICE ..................................................... 10 
2.10 
INVESTIGATOR’S BROCHURE AND INSTRUCTIONS FOR USE ....................................................................................... 10 
3 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION .......................................................... 10 
3.1 REVIEW OF CLINICAL LITERATURE ............................................................................................................................... 10 
4 
RISKS AND BENEFITS OF INVESTIGATIONAL DEVICE AND STUDY .............................................................. 11 
5 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ............................................................. 12 
6 
DESIGN OF THE CLINICAL INVESTIGATION ............................................................................................... 12 
6.1 STUDY DESIGN ....................................................................................................................................................... 12 
6.2 SUBJECTS ............................................................................................................................................................... 14 
6.2.1 
Inclusion Criteria..................................................................................................................................... 14 
6.2.2 
Exclusion Criteria .................................................................................................................................... 14 
6.2.3 
Deviation from Inclusion/Exclusion Criteria ........................................................................................... 15 
6.2.3 
Criteria and Procedures for Subject Withdrawal or Discontinuation ..................................................... 15 
6.2.5 
Duration of the Clinical Study ................................................................................................................. 15 
6.2.6 
Number of Study Subjects ...................................................................................................................... 15 
6.2.7 
Number of Study Centers ........................................................................... Error! Bookmark not defined. 
6.2.8 
Information on Vulnerable, Pregnant or Breastfeeding Population ...................................................... 16 
6.3 STUDY PROCEDURES ................................................................................................................................................ 16 
6.3.1 
Detailed Description of Study Procedures .............................................................................................. 16 
6.3.2 
Study Materials and Equipment ............................................................................................................. 17 
6.3.3 Study Environment ..................................................................................................................................... 18 
6.3.4 
Study facilitator inoculations ................................................................................................................. 18 
6.4 MONITORING ......................................................................................................................................................... 18 

 
 
 
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6.4.1 Monitoring Plan .......................................................................................................................................... 18 
6.5 AUDITING .............................................................................................................................................................. 18 
7 
STATISTICAL CONSIDERATIONS ............................................................................................................... 18 
8.................................................................................................................................................................... 19 
DATA MANAGEMENT ..................................................................................................................................... 19 
8.1 DATA MANAGEMENT .............................................................................................................................................. 19 
*** ............................................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
8.2 
CONFIDENTIALITY ............................................................................................................................................ 20 
8.3 
RECORD RETENTION ......................................................................................................................................... 20 
8.4 
CLINICAL QUALITY ASSURANCE AND QUALITY CONTROL.......................................................................................... 21 
9 
AMENDMENTS OF THE CLINICAL INVESTIGATION PLAN ........................................................................... 21 
10 .................................................................................................................................................................. 21 
DEVIATIONS FROM THE CLINICAL INVESTIGATION PLAN .................................................................................. 21 
10.1 
APPROVALS .................................................................................................................................................... 22 
11 
DEVICE ACCOUNTABILITY ....................................................................................................................... 22 
12 
STATEMENT OF COMPLIANCE ................................................................................................................. 23 
13 
INFORMED CONSENT PROCESS ............................................................................................................... 23 
14 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES .................................................. 23 
14.1 SAFETY DEFINITIONS .............................................................................................................................................. 24 
14.1.1 
Device Deficiency ............................................................................................................................... 24 
14.1.2 
Adverse Event..................................................................................................................................... 24 
14.1.3 
Adverse Device Effect ......................................................................................................................... 24 
14.1.4 
Serious Adverse Event ........................................................................................................................ 25 
14.1.5 
Serious Adverse Device Effect ............................................................................................................ 26 
14.1.6 
Unanticipated Serious Adverse Device Effect .................................................................................... 26 
14.2 
CLASSIFICATION AND DOCUMENTATION OF ADVERSE EVENTS .................................................................................. 26 
14.2.1 
Assessment of Intensity/Severity ....................................................................................................... 26 
14.2.2 
Relationship to Investigational Device/Procedure............................................................................. 26 
14.2.3 
Assessment of Outcomes ................................................................................................................... 27 
14.2.4 
Expectedness ...................................................................................................................................... 27 
14.3 SAFETY DOCUMENTATION AND REPORTING ............................................................................................................... 27 
14.3.1 
Documentation of and Reporting Adverse Events ............................................................................. 27 
14.3.2 
Documentation and Reporting of SAE/UADE .................................................................................... 28 
14.3.3 
Documentation and Reporting of Device Deficiencies....................................................................... 28 
14.3.4 
Death Reporting ................................................................................................................................. 28 
14.3.5 
Investigator Reports........................................................................................................................... 28 
14.3.6 
Sponsor Reports ................................................................................................................................. 30 
15 
VULNERABLE POPULATION ..................................................................................................................... 32 
16 
EARLY TERMINATION OR SUSPENSION OF THE CLINICAL INVESTIGATION ................................................. 32 
17 
FINAL REPORT AND POLICY PUBLICATION ............................................................................................... 32 
PARTICIPANT COMPENSATION ............................................................................................. ERROR! BOOKMARK NOT DEFINED. 

 
 
 
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LITERATURE REVIEW ...................................................................................................................................... 33 
 
 
Table of Abbreviations  
ADE 
Adverse Device Effect 
AE 
Adverse Event 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
CTA 
Clinical Trial Agreement 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
GCP 
Good Clinical Practice 
HCP 
Healthcare Professional 
HIPAA 
Health Insurance Portability and Accountability 
IFU 
Instructions for Use 
ISF 
Investigation Site File 
ID 
Identification 
IRB 
Institutional Review Board 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 
 
 

 
 
 
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1. 
General 
1.1 
Background and Purpose 
Fever is the most common reason for children to be brought to an emergency department (ED) 
with causes ranging from self-limiting illnesses of childhood to serious bacterial infections (SBIs) 
that can prove fatal. Vital signs can help clinicians identify children at risk of serious illness.  
Early detection and treatment of fever in pediatric patients is important because fever can be a 
sign of a serious infection or other underlying condition. If left untreated, these infections or 
conditions can lead to more serious complications, such as organ damage or failure. 
Fever in pediatric patients can be caused by a wide range of underlying illnesses, including 
infections, inflammation, and other medical conditions. Some common causes of fever in 
children include: 
1. Infections: Fever can be a sign of an infection, such as a cold, flu, pneumonia, or urinary 
tract infection. 
2. Inflammation: Fever can also be caused by inflammation, such as from an injury or 
autoimmune disorder. 
3. Other medical conditions: Other medical conditions that can cause fever in children 
include certain types of cancer, metabolic disorders, and medication reactions. 
Early detection of fever can enable healthcare providers to promptly diagnose and treat the 
underlying cause of the fever. This can help prevent the development of complications along 
with the worsening of an infection.   
Sepsis is a complex clinical syndrome resulting from a systemic inflammatory response to 
infection. Each year, there are approximately 72,000 children hospitalized for severe sepsis in 
the United States, resulting in significant morbidity and mortality, and nearly $4.8 billion in U.S. 
health care expenditures.1–3 There have been significant advances in early recognition and 
overall approach to sepsis over the past decade, which have demonstrated improved patient 
outcomes with protocol-driven treatment in patients with sepsis.1–5 
An important limitation to widespread implementation of protocol bundles for pediatric sepsis is the 
challenges of early and accurate identification of patients with potential sepsis who may benefit from 
these intensive therapies.7 This identification process is particularly problematic in the pediatric ED, 
where there is a high prevalence of fever with signs of the systemic inflammatory response syndrome 
(SIRS), despite the fact that the vast majority of these patients are not seriously ill.8-9 
Remote and continuous temperature monitoring can be beneficial for pediatric patients 
because it allows healthcare providers to continuously monitor a child's temperature remotely, 
which can help to detect fever and other changes in temperature early on. This can be 
particularly useful for children who are at high risk for fever or other medical conditions, or for 
those who are unable to communicate their symptoms effectively. 

 
 
 
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There are several benefits to using remote temperature monitoring for pediatric patients, 
including: 
1. Early detection: Remote temperature monitoring can help to detect fever and other 
changes in temperature early on, allowing healthcare providers to promptly diagnose 
and treat the underlying cause of the fever. 
2. Continuous monitoring: Remote temperature monitoring allows healthcare providers to 
continuously monitor a child's temperature, which can provide a more comprehensive 
view of the child's health and help to identify any changes or trends. 
3. Convenience: Remote temperature monitoring can be performed from the child's home, 
which can be more convenient for both the child and the healthcare provider. 
4. Improved outcomes: Early detection and treatment of fever and other changes in 
temperature can lead to improved outcomes for pediatric patients and can help to 
prevent serious complications. 
The purpose of this research study is to evaluate the effectiveness of the AION BIOSTYEMS, INC. 
tempshield (“Shield”) temperature monitoring device and platform in detecting body 
temperature for children 2-4 years old.  The ED Research team will be deploying this device on 
all qualified patients who are awaiting inpatient admission from the emergency department 
and who have consented to participating in the study.  Patients will be asked to keep the device 
on for a maximum of 7 hours during their stay in the emergency department.  There is a 
potential clinical benefit that fevers will be detected earlier in subjects wearing the AION 
BIOSTYEMS, INC. tempshield.  It is hoped that information gained from the study will help assist 
clinical care workflow and the treatment of future patients.   
 
AION BIOSTYEMS, INC. is currently seeking FDA approval for the tempshield; this study will 
support the company’s clinical validation in pediatrics.  
The objectives of the validation study are to: 
1. Collect human test data using tempshield to comply with ISO 80601-2-56 for a digital 
thermometer per FDA guidance for children. 
2. To compare the collected tempshield data against a Welch Allyn 901053 Electronic Thermometer 
as used in clinical settings.    
1.3 
Sponsor Information  
`Sponsor 
Name 
AION BIOSTYEMS, INC. 
Address 
12 Plymouth Road, Darien, CT 
 
1.4 
Clinical Investigational Plan  
A prospective, single site, interventional study assessing the effectiveness for use of the non-
invasive wireless temperature monitoring device and platform in detecting body temperature 
of young children during 1st 7 hours of their stay in the emergency department for patients, 
between 2-4 years of age. 

 
 
 
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1.5 
Study Design Workflow
 
2 
Identification and Description of the Investigational Device  
2.1 
Investigational Device 
The AION BIOSTYEMS, INC. tempshield is a skin-applied, continuous temperature monitor. It is 
battery powered, communicates using Bluetooth LE to a smartphone, then to a clinician 
dashboard, and is designed to be worn continuously for up to 60 days. Its primary use is for 
patient monitoring in hospital or post-discharge from a healthcare facility.   Through the 
tempshield system, clinicians can be notified if a patient’s temperature exceeds a given 
threshold.   
The tempshield system is centered around a non-invasive temperature sensor placed against the 
patient’s skin, in the pectoral region just below the collar bone. The temperature sensor is held 
in place with a silicone adhesive tape similar to a custom shaped piece of medical tape. The 
silicone adhesive tape is hypoallergenic. 
 
2.2 
Manufacturer 
The legal manufacturer of the system is AION BIOSTYEMS, INC.. The production of the AION 
BIOSTYEMS, INC. device components are done by qualified and certified sub-contractors with 
extensive experience. 
2.3 
Identification of the Investigational Device 
The following table lists the devices that will be used during this clinical trial. Device identification 
and traceability can be done using their serial number.  
AION BIOSTYEMS, INC. tempshield FLL Class II medical device  
Table 1: Device Identification 
System Part 
Identification 
Software Version 
AION BIOSTYEMS, INC. tempshield Device 
Each Device has a Unique ID 
3.2.14 
Study Dedicated Samsung Phone (incl. 
charger) 
Will Set Study Serial number 
prior to study 
N/A 
AION BIOSTYEMS, INC. Clinical Trial App 
NA 
2.22.0 
 
2.4 
Traceability during the Clinical Investigation 
The AION BIOSTYEMS, INC. device with relevant accessories will be provided by the Sponsor. 

 
 
 
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Each AION BIOSTYEMS, INC. tempshield Device will have a unique serial number. Delivery/return 
forms as well as the accountability log will be filled out and filed in the Investigator Site File (ISF), 
each time equipment and devices are dispensed to caregivers or returned/replaced. 
2.5 
Intended Use of the Investigational Device in the Clinical Investigation  
During the AION BIOSTYEMS, INC. study, the efficacy of the AION BIOSTYEMS, INC. tempshield 
device in continuous temperature monitoring of young children will be assessed. 
2.6 
Intended Use of the Investigational Device 
The sensor on the AION BIOSTYEMS, INC. tempshield device passively collects temperature 
readings every 5 minutes and transmits the temperature data to the AION BIOSTYEMS, INC. 
mobile application via Bluetooth. 
The AION BIOSTYEMS, INC. tempshield is not an approved medical device and therefore, does 
not:  
• Diagnose, cure, lessen, monitor, treat or prevent disease or injury, 
• Affect body functions/structures, 
• Achieve primary intended purposes through chemical action,  
• Monitor patients clinical or at-home temperature  
 
2.7 
Description of the Investigational Device 
The testing system AION BIOSTYEMS, INC. tempshield device consists of 2 elements: 
• An electronic temperature sensor, a non-invasive, wearable, wireless measuring 
device positioned on the child’s pectoral region just below the collar bone 
• A Samsung A13 Mobile phone configured to run the AION Biostyems, Inc. Shield 
Application 2.22.0 or greater.   This device must be within 30 feet of subject. 
The following accessories will be used for placement of the device on subject: 
• Silicone adhesive tape (attachment and retention of the sensor to the patient’s skin), 
a silicone adhesive tape similar to a custom shaped piece of medical tape.  The actual 
adhesive tape is 3M Micropore™  S. 
 

 
 
 
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2.8 
Training 
2.8.1  Site Initiation Visit 
Study team will be trained by AION BIOSTYEMS, INC. at the site initiation visit on the protocol, 
recruitment plan, data collection, device use, safety reporting and the study monitoring plan. 
This training will be documented and conducted prior to the first patient being enrolled. 
2.8.2 Ongoing Training 
The study team will receive ongoing training for any major changes to the study protocol. 
Additionally, new staff added during the course of the study will also need to complete training 
on all study related procedures and will be documented. 
2.9 
Description of the Medical Procedures involved in the Use of the Device  
The use of the AION BIOSTYEMS, INC. tempshield requires research staff to place the shield 
onto the subject’s chest, directly in contact with the skin. The AION BIOSTYEMS, INC. 
tempshield is worn by the subject at all times for a maximum of 7 hours and removed by 
research staff at the end of the study period.  
Initiation of physiological parameters recording is activated by the research staff via the AION 
BIOSTYEMS, INC. mobile App installed on the provided study-dedicated Samsung phone.  
During the recording, the guardians can view the measured physiological parameters in real 
time via the AION BIOSTYEMS, INC. mobile App.   
Oral temperatures will be taken using a Welch Allyn 901053 oral thermometer and input into 
the AION BIOSTYEMS, INC. mobile app via research staff.  
2.10 Addition Supplemental Study Materials 
Refer to Annex A for the AION BIOSTYEMS, INC. system IFU, study information sheet, and 
device video.  
3 
Justification for the design of the Clinical Investigation 
3.1 Review of Clinical Literature 
In a study published in the Journal of Hospital Medicine in 2014, researchers found that 
continuous temperature monitoring was associated with earlier detection of fever and sepsis in 
hospitalized children. The study involved the use of continuous temperature monitoring with a 
noninvasive, wireless, and wearable temperature sensor. Another study published in the 
Journal of Pediatric Nursing in 2016 found that continuous temperature monitoring was 
effective in reducing the incidence of fever in children undergoing chemotherapy. The study 
involved the use of a wearable, wireless temperature monitoring system that allowed for 
continuous monitoring of body temperature.  

 
 
 
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Overall, these studies suggest that continuous temperature monitoring can be an effective way 
to detect and manage fever and other temperature-related issues in children. The use of 
wearable, wireless, and noninvasive temperature monitoring systems can provide a convenient 
and accurate way to monitor a child's temperature, particularly in hospital settings where 
frequent temperature checks may be required. 
 
The outcomes of this study will be used to improve the AION BIOSTYEMS, INC. device and 
mobile app in evaluation of clinical performance with the goal of validating device with the FDA 
and subsequently deploying the device in pediatric hospitals. 
4 
Risks and Benefits of Investigational Device and Study 
The study is a validation testing study for the AION BIOSTYEMS, INC. tempshield sensor and 
algorithm. Participation in the study poses minimal risks: 
● Each participant will be administered the tempshield testing system using an AION 
BIOSTYEMS, INC.-provided smartphone and AION BIOSTYEMS, INC.-provided details. This will 
ensure that no personal information from participants will be entered into AION BIOSTYEMS, 
INC.’s mobile app or transmitted to AION BIOSTYEMS, INC. servers. 
● All participants will have the sensor administered to an area of their skin just below their 
clavicle. The adhesive tape is silicone-based and hypoallergenic, but there is a small chance 
that the tape could cause mild skin irritation. Participants with a known allergy or sensitivity 
to silicone will be excluded from the study for this reason. In addition, the study moderator 
will instruct the participant to seek medical attention if and when any irritation occurs, 
whether during or after the study. All required FDA biocompatibility testing, and wear length 
testing has been performed by the manufacturer. 
●  There is a risk that study data, including personally identifiable information, could be lost, or 
stolen, even with the safeguards described in this protocol. If the Principal Investigator or any 
other study staff are made aware of a data breach involving personally identifiable data, study 
participants will be notified of the breach and any available remediation measures taken. 
●  The participant may stop the session without penalty or loss of benefits at any time. The 
study moderator will also stop the session if he/she judges that the participant is at risk of 
injury or if it is in the best interest of the participant, even if the participant wishes to 
continue. 
● There is a risk of physical harm to the participant if the device is left on during radiology (MRI, 
X-ray, CT) imaging procedures.  Due to this risk, study procedures ensure that the device is 
removed prior to the procedures. 
The only minor anticipated adverse device effects are: 

 
 
 
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• Local skin irritation at sensor or adhesive location (low risk). Although, so far, skin 
irritation following the use of the AION BIOSTYEMS, INC. system has never been 
reported by any users of the AION BIOSTYEMS, INC. system, even after several days of 
use.  
There are no direct benefits to people who participate in the study. Some participants may enjoy 
participating in the study or contributing to research that they may find personally interesting. 
The research data will be used to help extend the age range of the tempshield to an expanded 
age group to benefit future pediatrics. 
 
5 
Objectives and Hypotheses of the Clinical Investigation 
Study Objectives 
The objectives of the validation study are to: 
1. Collect human test data using tempshield to comply with ISO 
80601-2-56 for a digital thermometer per FDA guidance for 
children.  In particular children under the age of 5 years.   
2. To compare the collected tempshield data against a Welch Allyn 
901053 Electronic Thermometer as used in clinical settings.    
Study Endpoints 
 To collect enough data points to determine statistically if the current 
algorithm (5 years and up) applies to children under five. 
 
To collect enough data to age adjust the algorithm used. 
 
6 
Design of the Clinical Investigation 
6.1 Study Design 
This study is designed as prospective, interventional study assessing the effectiveness of the AION 
BIOSTYEMS, INC. tempshield (“Shield”) for continuous temperature monitoring device in the 
Pediatric Emergency Department. 
 
Upon entry to the emergency department, a Children’s National study staff will be approached 
for interest and presented with the project and all relevant study materials/documents.  
 
If parents/legal representatives are interested in their child’s participation in this study and 
following eligibility confirmation, the parent(s)/legal representative(s) will be provided with an 
information sheet. Patient’s caregiver will be explain the purpose of the study (to test 
effectiveness of AION BIOSTYEMS, INC. tempshield in continuous monitoring of temperature in 
an ED setting) and what the study involves (wearing AION BIOSTYEMS, INC. tempshield on 
participant’s chest for a maximum of 7 hours and having oral temperature taken every 1 hour). 
Due to age of participants (2-4years), no assent will be obtained for subjects. 

 
 
 
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Once enrolled, the tempshield wearable device will be placed on the upper chest with gentle, 
silicon adhesive tape. Study staff will ensure that the device is stable on the subject’s chest. In 
the case that the device will not successfully adhere to the patient’s chest, the research team will 
forego the enrollment of that specific subject due to lack of feasibility. The research team will 
register the wearable device and connect it to the AION BIOSTYEMS, INC. Shield app via the 
Samsung A13. A Samsung phone will be kept in the patient’s room to track the temperature from 
the device.  This phone is used for recording the Oral temperatures taken by the study staff. 
 
Upon activation of the tempshield, participants will be given 60 minutes for the tempshield to 
acclimate to the environment before an oral temperature measurement is taken. The oral 
temperature will be taken by the research team using a Welch Allyn 901053 Oral Thermometer 
and input information into the AION BIOSTYEMS, INC. app. After the acclimation period, the first 
measurement of oral temperature using the Welch Allyn oral thermometer will be recorded in 
the AION BIOSTYEMS, INC. Shield app by the research team. 
 
This measurement must also be >= 99.5 F for febrile participants.  If it is less than 99.5F then they 
will be in the non-febrile cohort, unless see below. 
• The research team will take an oral temperature measurement with the Welch Allyn 
device every four hours. The Welch Allyn temp will be entered into the App.  If the patient’s 
measurement is 99.5 F or above, they will qualify for the febrile cohort of the study. If the 
patient never exceeds 99.5F and are within normal temperature range and temperature 
below 99.5 F, they will qualify for the non-febrile cohort 
 
Following this, measurements of the tempshield sensor temperature will be recorded in the AION 
BIOSTYEMS, INC. Shield app 1 ±5 minutes apart. Research coordinators will measure oral 
temperatures every 2 hours ±1 hour for up to a 24hour period, with a maximum of 6 recordings 
per pt.. A patient’s participation will end once they are discharged from the ED or after 7 hours, 
whichever comes first.  If the patient is moved to in-patient unit, the research coordinator will 
remove the device from the participant. After 7 hours or at the time of ED discharge, the device 
will be removed from the participant. If there is no height listed in the EMR, research staff will 
measure participant height. 
 
In addition to collecting oral temperature every 2 hours, research staff will also recheck 
placement of AION BIOSTYEMS, INC. device in adhesive to ensure that the device is still stable in 
place. If adhesive is not stable, research staff will replace the adhesive with new strip. Research 
staff will check with LAR to make sure that device was not removed or did not fall off. If device 
was removed or had fallen off, research team will document estimated time of removal and 
replacement on CRF and the reasoning for the device displacement. If the device is damage and 
unable to be used, the device will be replaced, and the enrollment will continue for the duration 
of the 7 hours. Otherwise, the same device will be used on the subject throughout the enrollment 
even if it falls off or is removed from the subject. 
 

 
 
 
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Subjects will receive a $25 Amazon or Target card after second oral temperature is obtained. 
Children enrolled will also receive a small stuffed toy in the price range of $10-$20 if able to 
successfully complete a minimum of two oral temperatures. 
 
AION BIOSTYEMS, INC. will have access to all oral temperatures taken during the duration of 
the patient’s Emergency Room stay. The oral temperatures will be de-identifed and recorded by 
the research team from the EMR.  The oral temperature data will be used to compare against 
the tempshield data for clinical validation.   
 
Research staff, families, and participants will be made aware of the following precautions that 
will take place during enrollment:  
• Avoid positioning participant directly near ventilation ducts, open windows, or forced 
convection of any kind (e.g., fans) 
• Avoid positioning participants in direct sunlight (windows) 
● Avoid allowing participants to move around excessively, leave the premises, or go 
outdoors 
● Avoid allowing participants to drink hot or cold fluids within 5-min of an oral temperature 
measurement 
● If participants have eaten within 30 minutes of taking oral temperature, research 
coordinators will note this information in the AION BIOSTYEMS, INC. app 
● If participants have drinks within 5 minutes of taking oral temperature, research 
coordinators will note this information in the AION BIOSTYEMS, INC. app 
● If any of the above cautions happen during the 4hour window the clinician staff shall 
record them in the mobile app. (e.g. Sitting in open sunlight 15 minutes prior to 4 hour 
visit. 
 
6.2 Subjects 
6.2.1 Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for inclusion in this study: 
1. Male or female patients between ages 2 years -4 years of age 
2. Confirmed oral temperature of >=99.5 F for febrile participants OR confirmed oral temperature 
of <99.5 F for afebrile participants 
3. Willing and likely (based on the investigator’s judgement) to comply with all study requirements 
 
6.2.2 Exclusion Criteria  
Subjects meeting any of the following criteria will be excluded from participating in this study: 
1. Participants who are allergic to silicone 
2. Adolescents with sensory issues who may find it difficult to have a wearable device on 
their chest. 

 
 
 
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3. Participants presenting an anatomical limitation that would prevent the use of the 
wearable device 
6.2.3 Deviation from Inclusion/Exclusion Criteria 
The inclusion/exclusion criteria must be strictly followed. If a subject who does not meet these 
criteria is inadvertently included, the Sponsor or a specified designee should be immediately 
contacted to obtain instructions on whether the subject should be discontinued from the study.  
6.2.3 Criteria and Procedures for Subject Withdrawal or Discontinuation 
Subjects may be withdrawn early from the study for several reasons, including but not limited 
to: 
• Parents/Legal representatives’ request 
• Investigator request 
• Discharge 
• Adverse Events (AEs) (e.g., intolerable AE occurrence or treatment forces subject to stop 
participation in the study) 
• Non-compliance of protocol and required procedures 
The parents/legal representatives are free to withdraw their child from this study at any time 
upon their request. Withdrawing from the study does not affect the access to standard 
treatments for their child or their relationship with the hospital and affiliated HCPs.  
If a study subject is discontinued from the study early, a Note-to -File (NTF) will be written 
describing the reason for discontinuation.  
In case of discontinuation or withdrawal of subjects who already received an AION BIOSTYEMS, 
INC. device, research staff will remove device and collect all study equipment. Subjects who are 
discontinued from the study or withdraw consent may be replaced.  
6.2.5 Duration of the Clinical Study 
The study is expected to last approximately no longer than 7 hours with the device.  
The study is expected to last approximately 2 years.  
6.2.6 Number of Study Subjects 
A total of 150 participants between the ages of 2-4 years will be recruited for the study. The study will not 
include more than 25 nonfebrile patients.  Febrile participants will be confirmed febrile (oral 
measurement with the Welch Allyn clinical thermometer >= 99.5 F) at the time of enrollment. Additional 
participants may be recruited as needed, to ensure the required sample size for clinical validation of the 
tempshield is met. 

 
 
 
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6.2.7 Information on Vulnerable, Pregnant or Breastfeeding Population 
As the intended population of the AION BIOSTYEMS, INC. system is children < 5 years old, this study is 
performed on vulnerable population to assess the efficacy of using the AION BIOSTYEMS, INC. system 
for continuous temperature monitoring on the relevant population.   
6.3 Study Procedures 
6.3.1 Detailed Description of Study Procedures 
Consenting and Inclusion 
Waiver of documentation of consent and assent is being requested for participants because this 
study involves minimal risk of harm to participants and involves no procedures for which 
written consent is normally required outside the research context. No PHI will be sent to third 
parties outside of Children’s National. 
Procedures Following Enrollment 
The tempshield wearable device will be placed on the upper chest with gentle, silicon adhesive 
tape. The research team will register the wearable device and connect it to the AION BIOSTYEMS, 
INC. Shield app via the Samsung A13. A Samsung phone will be kept in the patient’s room to track 
the temperature from the device.  This phone is used for recording the Oral temperatures taken 
by the study staff. 
 
Upon activation of the tempshield, participants will be given 60 minutes for the tempshield to 
acclimate to the environment before an oral temperature measurement is taken. The oral 
temperature will be taken by the research team using a Welch Allyn 901053 Oral Thermometer 
and input information into the AION BIOSTYEMS, INC. app. After the acclimation period, the first 
measurement of oral temperature using the Welch Allyn oral thermometer will be recorded in 
the AION BIOSTYEMS, INC. Shield app by the research team. 
 
Following this, measurements of the tempshield sensor temperature will be recorded in the AION 
BIOSTYEMS, INC. Shield app 1 ±5 minutes apart. Research coordinators will measure oral 
temperatures every 2 hours ±1 hour over the 24hour period, with a maximum of 6 recordings 
per pt. After 7 hours or at time of ED discharge, the device will be removed from the participant.  
The device will be removed overnight when outside of research hours.  This will ensure that the 
research team is able to continuously monitor the participant. 
 
Subjects will receive a $25 Amazon or Target gift card after second oral temperature is obtained. 
Children will receive the $10-$20 small stuffed toy after the second oral temperature reading is 
obtained. 
 
AION BIOSTYEMS, INC. will have access to all oral temperatures taken during the duration of 
the patient’s Emergency Room stay. The oral temperatures will be de-identified and recorded in 
the app.  The oral temperature data will be used to compare against the tempshield data for 

 
 
 
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clinical validation.   
 
If there is no height recorded in the EMR for this visit, then research staff will measure 
participant height. 
 
If, at any point during study procedures, a participant is to receive radiology (CT, MRI, X-Ray) 
imaging, the AION BIOSTYEMS, INC. tempshield device will be removed from the participant.  At 
start of study enrollment, radiology team will be alerted that individuals will be enrolled in a 
study in which a device will need to be removed prior to imaging.  Upon each patient’s 
enrollment in the study, the patient will receive a brightly colored wristband that states the 
patient is wearing a device that must be removed prior to radiology procedures.  The child’s 
provider will also be alerted to the child’s participation in the study and the need to remove the 
device before imaging.  
 
6.3.2 Study Materials and Equipment 
The following study materials will be used: 
• 
Parent/Guardian Study Information Sheet 
• 
AION BIOSTYEMS, INC. tempshield Device is the skin applied device used for collecting and 
transmitting the skin temperature to the mobile device. 
• 
Samsung A13 Phones this device will collect the skin temperature and will perform the AION 
Biostyems, Inc. conversion algorithm and then send the data and the unique ID to the AION 
Biostyems, Inc. Core. 
• 
Welch Allyn 901053 Oral Thermometers This Thermometer has been the gold standard for AION 
Biostyems, Inc. in Previous studies and must be calibrated prior to service and after study for 
valid data verification. 
• 
User Guide 
The testing and validation systems are listed below: 
AION BIOSTYEMS, INC. will provide Samsung A13 phones and 2 Welch Allyn 901053 oral thermometers.   
A Samsung A13 device will be placed in each patient’s room to continuously track their temperature.    
Additional supplies needed from Children’s National includes wipes (if the patient’s skin needs to be 
cleaned before the device application) and hand sanitizer/gloves for the person placing the device on 
the patient.   
Availability of accompanying documentation and provision of training for the study: 
The tempshield’s accompanying documentation (i.e., packaging, paper IFU, in-app IFU, and User Guide) 
will be available to study staff as reference for device application on the subjects.  
 

 
 
 
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6.3.3 Study Environment 
The validation study will be conducted in the Children’s National Emergency Department during 
which the Children’s National Research team will obtain participant consent and conduct the 
study.  
6.3.4 Study facilitator inoculations 
The Children’s National Research team will be required to be up to date with the following inoculations: 
• 
COVID-19 vaccinations 
 
6.4 Monitoring  
The sponsor will oversee the data collection, including managing data queries, running data 
reports, providing data summaries, and statistical analyses.  
The sponsor will provide oversight of the regulatory aspects of the study including IRB and 
contracts with sites. 
Any serious unanticipated problems that may occur will be reviewed and determined whether a 
change in the protocol is necessary. If the study exhibits an excess amount of serious 
unanticipated events the study will be stopped and reviewed. 
6.4.1 Monitoring Plan 
Study will be monitored by a monthly monitoring visit either on site or remotely to review data 
collection, recruitment, access the subject safety and regulatory requirements of the study. 
Data is expected to be entered by the study team the same day as enrollment and queries 
resolved within 3 business days of the raised query. 
6.5 Auditing 
The Principal Investigator makes all pertinent records available, including source 
documentation, for inspection by the ECs/IRBs and for auditing by the Sponsor or designee 
after appropriate notification. The verification of data must be by direct inspection of source 
documents. This information will be considered as confidential. The Principal Investigator 
should inform the Sponsor as soon as they are made aware of the audit or inspection 
 
7 
Statistical Considerations 
Raw data collected by the AION BIOSTYEMS, INC. tempshield device are stored in encrypted 
files and include the temperature. 

 
 
 
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The objective of this formative study is to evaluate the effectiveness of the AION BIOSTYEMS, 
INC. tempshield (“Shield”) temperature monitoring device and platform in detecting body 
temperature for children 2-4 years old. 
 
• The sample size of “up to 130 subjects” has been defined based on the following criteria 
80601-2-56 ISO standard for digital thermometers recommends that 110 study 
participants with 30% of them Febrile be tested.   We are seeking to do 150 patients 
because of patient fall out and accounting for potential withdrawals 
 
Based on all the above information, the sample size of “up to 100 subjects” should be large 
enough to address the study objective and study endpoints. 
 
8 
Data Management 
8.1 Data Management  
Data recording for this study and backend temperature data collected through the tempshield 
device and on the AION BIOSTYEMS, INC. Shield app sent to AION BIOSTYEMS, INC.s servers.  
The following data points will be recorded on AION BIOSTYEMS, INC. Shield App by trained 
study personnel in the study’s database: 
- 
Subject Study ID number 
- 
Device ID 
- 
Age, Gender, Height and Weight 
- 
Date and time of tempshield™ application  
- 
tempshield application (date and timestamp of tempshield temperature) 
- 
Times of Handed entered  temperature data 
- 
Time of each tempshield reading and value. 
- 
Times of temperature excursion based on agreed upon excursion. 
 
Source documents will be coded with the study subject ID number. Only authorized research staff will 
have access to the source documents and study data. Source data retention requirements of the 
sponsor, AION BIOSTYEMS, INC., AION Biostyems, Inc. will keep all data for approximately two years.   
All data stored is de-identified data, and was not used for medical records.. All required data collected 
during the study must be collected by the investigator or designated research staff. Data should be 
entered as soon as possible after the information is collected. Data is collected electronically.  Oral 
temperatures shall be entered when they are taken into the AION BIOSTYEMS, INC. application. 
All hard copy data (consent/assent forms) will be stored in subject and regulatory binders in a 
secure location accessible only to authorized study personnel. 

 
 
 
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No PHI will be provided to the sponsor for this study. All PHI collected will remain in CNH 
research records. Research staff will collect name, date, MRN, and account numbers of screen 
subjects. This information will remain housed on CNH servers and will only be accessible by 
CNH research study staff.  
All data is stored in the AION BIOSTYEMS, INC. Core and the Clinician Application.  Post study 
the Clinician Application will be archived in a secure encrypted database that is HIPAA certified.  
The clinician data will remain for 7 years, and access to this data is only by certified AION 
BIOSTYEMS, INC. staff for the purpose of legal enquiries only.   
AION Biostyems, Inc. cloud data (all de-identified will remain on the AION Biostyems, Inc. Server 
for minimally two years.  The AION BIOSTYEMS, INC. cloud data is password protected, and the 
data on the data-base server is encrypted.   AION Biostyems, Inc.’s strict password policy 
enforces complex passwords that must be change every 30 days. 
Only AION Biostyems, Inc. personnel may access the AION Biostyems, Inc. cloud. 
 
8.2 
Confidentiality 
Participants will be assigned a unique code or Participant ID. Any documents or files containing 
data collected for a specific participant will be identified only by the Participant ID. Any document 
that contains the link between a Participant ID and any personally identifiable information 
regarding that participant will be password protected, stored on a password protected computer 
or network, and will only be accessible by the Principal Investigator or Study Moderator on an as-
needed basis. 
8.3 
Record Retention 
The Principal Investigator shall arrange for the retention of all study documents and records, 
including subject records, device accountability log, and subject identification list for at least 3 
years after the completion or discontinuation of the study.  
Hence, the pseudonymized data collected by the AION BIOSTYEMS, INC. system are securely 
stored on the Cloud, where they will be archived for 2 years after FDA approval. 
If the Principal Investigator moves or retires, they must nominate someone in writing to be 
responsible for archiving. Archived data may be held as electronic records as long as a backup 
exists, and a hard copy can be obtained if required. If the Principal Investigator cannot 
guarantee this archiving requirement at the study site for any of the documents, special 
arrangements must be made by the Sponsor to store these sealed containers outside of the site 
so they can be delivered to the site in case of a regulatory audit.  

 
 
 
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8.4 
Clinical Quality Assurance and Quality Control 
The Sponsor has integrated clinical quality assurance and quality control in the Sponsor's 
quality system. Quality assurance and quality control principles apply to the processes of the 
clinical investigation. The sponsor commits to:  
• Implement and maintain written clinical quality procedures to ensure that the clinical 
investigation is designed, conducted and monitored, and that data are generated, 
documented, recorded and reported in compliance with ISO 14155:2020, the CIP, any 
subsequent amendment(s), and any other applicable standards and regulatory 
requirements,  
• Maintain records to document the compliance of all parties involved in the clinical 
investigation,  
• Ensure that the auditing requirements are met, and  
• Justify and document significant exceptions to the requirements of ISO 14155:2020.  
9 
Amendments of the Clinical Investigation Plan 
No change to the protocol may be made without the joint agreement of both the Principal Investigators 
and AION BIOSTYEMS, INC.. Any amendment to the original protocol will be made by AION BIOSTYEMS, 
INC.. The written amendment must be submitted to ECs/IRBs and the Principal Investigator must await 
for the approval before implementing the changes, as applicable per local law.  
If in the judgment of the ECs/IRBs, the Principal Investigator, and/or AION BIOSTYEMS, INC., the 
amendment to the protocol substantially changes the study design and/or increases the potential risk to 
the subject and/or has an impact on the subject’s involvement as a study subject, enrolled study 
subjects will be informed of any changes.  
 
10 
Deviations from the Clinical Investigation Plan 
Any changes made during the execution of the study will be evaluated by those conducting the study at 
the time to minimize deviation from the protocol and provide for the most beneficial data collection. 
When changes are made during studies, the Principal Investigator will collect the necessary approvals 
and document the changes made including a rationale for the change(s). Reports generated for the 
study’s results will identify the changes that occurred during the study and any impact on the results 
they had. 
Approvals for deviations will be obtained before the deviation occurs. 
Type of Changes 
Description 
Approvals Required By: 

 
 
 
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Minor changes 
Includes updates to introductory language. This 
would also include any re-ordering of tasks or 
repeating the set of tasks if conditions or timepoints 
are unable to be followed as outlined 
Study Moderator 
Major changes 
Includes any changes to the study inclusion or 
exclusion criteria.  
Principal Investigator 
Study Sponsor 
 
10.1 Approvals 
The approval designees listed are responsible for assessing the adequacy of this study protocol and 
changes to the protocol. 
Role 
Printed Name 
Principal Investigator 
Sephora Morrison 
Chief Technology Officer 
Thomas Blackadar 
Director of Quality and 
Regulatory Affairs 
Carl Shubitowski 
11 
Device Accountability 
The Principal Investigator is obliged to establish a system to control study accountability, to 
ensure that an assigned person receives all supplies, and that the documentation of all 
deliveries and returns are signed for. Each use must be documented (including dates, subject ID 
and/or device serial numbers) at a level that enables full verification of the protocol specified 
procedures.  
Study supplies shall be kept by the Principal Investigator in a secure place. All supplies will be 
used for this study only. Parents/Legal representatives of included subjects will be instructed to 
retain and return all AION BIOSTYEMS, INC. equipment to the Principal Investigator at the end 
of the study.  
 

 
 
 
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12 
Statement of Compliance 
The study will be conducted in accordance with all applicable FDA guidance and regulatory 
requirements, EN ISO 14155:2020, applicable sections of 21 CFR 812, and all applicable privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki, 
including: 
• Belgian Law of 22 August 2002 on Patient’s (and study subject’s) Rights. 
• Belgian Law of 7 May 2004 on experiments on human beings revised on June 5th, 2006. 
• Belgian Law of 30 July 2018 on the protection of individuals with regard to the 
processing of personal data: The Parties shall comply with all applicable rules and 
legislation in relation to data protection and the processing of personal data (including 
the General Data Protection Regulation (EU) 2016/679 (GDPR), the Belgian law of 30 
July 2018 on the protection of individuals with regard to the processing of personal data 
and other applicable Belgian or European regulations in relation to the processing of 
personal data).” 
• HIPAA Privacy rule (45 CFR Part 160 and Subparts A and E of Part 164). 
 
The clinical investigation shall be conducted in accordance with the protocol.  
Prior to subject participation in this study, the Investigator will ensure obtaining written 
ECs/IRBs approval authorizations as appropriate for the protocol and HIPAA authorization.  
Any additional requirements imposed by the ECs/IRBs or by the regulatory authority must be 
respected, if necessary.   
 
In the event of project-related damage or injuries, the Sponsor will be liable, except for 
damages that are only slight and temporary; and for which the extent of the damage is no 
greater than would be expected in the current state of scientific knowledge. 
13 
Informed Consent Process 
Provide the information sheet to the patient’s caregiver. Documentation of informed consent is not 
required.    
Inform the patient’s caregiver of the purpose of the study (to test effectiveness of AION BIOSTYEMS, 
INC. tempshield in continuous monitoring of temperature in an ED setting) and what the study involves 
(wearing AION BIOSTYEMS, INC. tempshield on participant’s chest for 7 hours and having oral 
temperature taken every 4 hours). Participation is voluntary and they are free to withdraw from 
participation at any time.  
Due to age of participants (2-4years), no assent will be obtained for subjects. Documentation of 
assent is not required.  

 
 
 
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14 
Adverse Events, Adverse Device Effects and Device Deficiencies 
14.1 Safety Definitions 
The following definitions are in accordance with the harmonized standard ISO 14155:2020 and 
with the FDA Code of Federal Regulations for Medical Devices (21 CFR 812.3(s)). 
14.1.1 Device Deficiency  
A device deficiency is defined as any inadequacy of a medical device related to its identity, 
quality, durability, reliability, safety, or effectiveness, such as malfunction, misuse or use error 
and inadequate labelling. Device Deficiency occurs in any case where the device does not 
perform in its intended function and when used in accordance with the device labelling. 
A device failure has occurred when the device is used in compliance with the Instructions for 
Use but does not perform as described in the Instructions for Use and negatively impacts 
treatment of the study subject.  
A device malfunction means the failure of a device to meet its performance specifications or 
otherwise perform as intended. Performance specifications include all claims made in the 
labeling for the device. The intended performance of a device refers to the intended use for 
which the device is labeled or marketed.  
Note that the subject and/or the subject’s LAR are not responsible for the loss or damage of any 
devices and will not be held accountable by the study Sponsor AION BIOSTYEMS, INC.. 
14.1.2 Adverse Event  
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory finding) in subjects, users, or other 
persons whether or not related to the investigational medical device. 
AE includes non-routine inpatient hospitalizations (>48 hours by Medicare criteria) and events 
related to the investigational device. This includes events related to the procedures involved 
(any procedure in the clinical investigation plan). For users or other persons this is restricted to 
events related to the investigational medical device. Routine pre-operative and post-operative 
hospitalizations are not considered adverse events. 
AE does not include conditions pre-existing to the subject's enrollment. Pre-existing conditions 
will not be reported as AEs unless the condition has an increased occurrence or intensity. 
14.1.3 Adverse Device Effect 
An Adverse Device Effect (ADE) is defined as any adverse event related to the use of an 
investigational medical device. 

 
 
 
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ADEs include any AE resulting from insufficiencies or inadequacies in the instructions for use, 
the deployment, the implantation, the installation, the operation, or any malfunction of the 
investigational medical device. This includes any event that is a result of a use error or 
intentional misuse. 
For the purposes of this study, the patient will only be monitored for any newly diagnosed skin 
condition (e.g., dermatitis, abrasion) at the site of the study device use throughout the duration of 
subjects’ participation in the study. 
14.1.4 Serious Adverse Event 
A Serious Adverse Event (SAE) is defined as any adverse event (AE) that led to: 
• Death. 
• A serious deterioration in the health of the participant that either: 
a. resulted in a life-threatening illness or injury (i.e., the subject is at risk of death at 
the time of the event; it does not refer to an AE that might hypothetically have 
caused death had it been more severe), or 
b. resulted in a permanent impairment of a body structure or a body function (i.e., 
the subject is unable to function, such as swallowing dysfunction that limits the 
ability to eat with ongoing weight loss or speech dysfunction that leaves 
unintelligible articulation; it does not refer simply to a noticeable disturbance in 
function, such as a globus sensation with swallowing or subtle articulation 
change), or 
c. required in-patient hospitalization or prolongation of existing hospitalization 
(i.e., hospitalization > 48 hours consistent with Medicare definition of in-patient 
for medical reasons; it does not refer to prolonged hospitalization for social 
reasons such as inadequate transportation home or routine pre-operative or 
post-operative hospitalization), or 
d. resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function (i.e., 
medical or surgical intervention alone does not meet this criterion for serious; it 
must be to prevent a life-threatening illness or injury or permanent impairment 
consistent with criteria 2a and 2b). 
• Fetal distress, fetal death or a congenital abnormality or birth defect. 
A planned hospitalization for pre-existing condition without a serious deterioration in health or 
to prevent life threatening illness or injury or permanent impairment to a body structure or a 
body function, is not considered to be a SAE. 
 
SAE includes device deficiencies that might have led to a serious adverse event if (a) suitable 
action had not been taken or (b) intervention had not been made or (c) if circumstances had 
been less fortunate. These are handled under the SAE reporting system. 

 
 
 
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14.1.5 Serious Adverse Device Effect 
A Serious Adverse Device Effect (SADE) is an adverse device effect that has resulted in any of 
the consequences characteristic of a serious adverse event.  
14.1.6 Unanticipated Serious Adverse Device Effect 
An Unanticipated Serious Adverse Device Effect (USADE) is a SADE which by its nature, 
incidence, severity or outcome has not been identified in the protocol or in the investigational 
device manuals. 
Per 812.3(s) this includes any SAE caused by, or associated with, a device, if that SAE was not 
previously identified in nature, severity, or degree of incidence in the investigational, or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects. 
14.2 Classification and Documentation of Adverse Events 
14.2.1 Assessment of Intensity/Severity 
The clinical “intensity” of an AE will be assessed by the Investigator, using the following 
categories: 
• Mild – Events require minimal or no treatment and do not interfere with the subject’s 
daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a subject’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate “serious”. 
14.2.2 Relationship to Investigational Device/Procedure 
The Investigator will assess if the AE (or SAE) is related to the AION BIOSTYEMS, INC. system. 
The probability that a particular AE is related to the device shall be coded on the AE CRF as not 
related, unlikely, possibly, probably, or definitely as defined below.  
• Not related: The Principal Investigator (PI) has determined that the complication is not 
related to the study device. 
• Unlikely: The PI indicates that a relationship to the use of investigational device is 
unlikely; Other causes provide plausible explanations for the event. 
• Possibly: The PI has determined that the event has a possible relationship to the use of 
the investigational device; There is some evidence to suggest a causal relationship. 
However, other factors may have contributed to the event. 
• Probably: The PI has determined that the event has a probable relationship to the use 
of the investigational device; there is evidence to suggest a causal relationship, 

 
 
 
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influence of other factors is unlikely. There is a clinically reasonable response on 
withdrawal of study intervention. 
• Definite: The PI has determined that the complication is related to the investigational 
device. There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. There is a clear clinical response to withdrawal of 
study intervention. 
Probability ratings are based on the temporal relationship to intervention, the likelihood that 
the symptom could have been produced by the participant’s clinical state, the environment, or 
other interventions, whether the participant’s symptom course follows a known pattern of 
response to the intervention, and the experience and judgment of the investigators. 
14.2.3 Assessment of Outcomes 
The clinical outcome of the event at the time of last observation will be characterized as follows: 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae 
• Recovering/Resolving 
• Fatal 
• Unknown 
14.2.4 Expectedness 
There are no anticipated adverse events related to the use of the study device. 
14.3 Safety Documentation and Reporting 
14.3.1 Documentation of and Reporting Adverse Events 
AEs are identified, assessed, and documented by the Investigation Site staff. All AEs are to be recorded, 
starting with the informed consent through the final visit required of the subject. AEs documented at a 
previous visit/contact and designated as not resolved or ongoing will be reviewed at subsequent 
visits/contacts until the end of the study. 
For the purposes of this study, the patient will only be monitored for any newly diagnosed skin 
condition (e.g., dermatitis, abrasion) at the site of the study device use throughout the duration of 
subjects’ participation in the study. 
All AEs (including SAEs) must be reported in a timely manner to the Sponsor by completing a Note-to-
Files. All AEs should also be documented in the site’s source documents. 
Any medical condition existing at the time of inclusion must be reported as baseline data, and do not 
need to be reported as AEs unless it increases in severity during the course of the study. AEs, which 
resolve and recur, should be reported as separate AEs. AEs which have not resolved at the time of the 
initial report, and which increase in severity or subsequently resolve, should be reported as AE follow-up 
information rather than as new events. The duration for each severity level is to be reported. 

 
 
 
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Information to be collected includes event description, time of onset, Investigator’s assessment of 
severity, relationship to study device/procedure, outcome, and time of resolution/stabilization of the 
event, treatment/action taken. All AEs occurring while on study must be documented appropriately 
regardless of relationship.  
Treatment of AEs is at the sole discretion of the Investigator and according to current good medical 
practice. It should be documented in the source documentation. 
14.3.2 Documentation and Reporting of SAE/UADE 
Once an investigator becomes aware that a SAE has occurred in a study subject, the investigator (or 
designate) must complete the SAE information via the AE form WITHIN 24 HOURS after the investigator 
first learns of the event. The report will always be completed as thoroughly as possible with all available 
details of the event. Even if the investigator does not have all information regarding a SAE, the report 
should still be completed within 24 hours. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial report.  
Investigators are responsible for submission of SAEs occurring at their site to their local IRB/EC in 
accordance with institutional requirements. Documentation of submission will be retained by the site. 
In case of UADE, the investigator (or designate) shall complete the UADE information and submit to the 
Sponsor within 24 hours after the investigator first learns of the effect. The study sponsor is responsible 
for conducting an evaluation of a UADE and shall report the results of such evaluation to the IRBs/ECs 
and Investigators within 10 working days after the Sponsor first receives notice of the effect. Also, the 
investigator (or designate) is responsible to report the UADE to the IRB/EC as soon as possible, but no 
later than 10 working days after the investigator first learns of the effect. All UADEs are to be reported 
throughout the study. 
The Sponsor will review significant new information, including unanticipated adverse events and ensure 
that such information is provided to the investigators and to all reviewing IRBs/ECs within the required 
timelines.  
14.3.3 Documentation and Reporting of Device Deficiencies 
All device deficiencies shall be documented throughout the clinical investigation in the source 
documents and appropriately reported to the Sponsor on Note-to-Files. 
14.3.4 Death Reporting 
Each subject death shall be reported using the AE form. Any other source documents relied upon to 
decide of death classification and cause of death will also be filed with the subject’s study documents. 
14.3.5 Investigator Reports 
The relevant form should always be completed as thoroughly as possible with all available details of the 
event. Even if the investigator does not have all information regarding an event, the report should still 

 
 
 
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be completed within the defined timeframes. When additional relevant event information is received, 
the relevant report should be updated within the designated timeframe.  
Prompt notification of any UADE, SAE, device deficiency by the Investigator to the Sponsor is essential so 
that legal obligations and ethical responsibilities towards the safety of other subjects are met. The 
Sponsor has a legal responsibility to promptly notify, within the required time period, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation. 
Non-emergent protocol deviations shall first be approved by sponsor and if deviation may affect the 
scientific soundness of the plan or the rights, safety, or welfare of subject, a protocol amendment may 
have first to be submitted and approved by IRB/EC.  
The following reports should be prepared by the Investigator (or designate) within the timeframes 
described in Table 2. 
Table 2: List of Investigator reports 
Type of Event 
Document 
Report prepared 
for 
Reporting Timeframe 
Serious Adverse 
Event (SAE) 
Relevant eCRF page (or 
scanned relevant form 
to email in case of 
technical issue) 
Sponsor/IRB/EC* 
Immediately, but no later 
than 24 hours after 
investigator is first 
notified of the event. 
Adverse Events (AE) 
Relevant eCRF page (or 
scanned relevant form 
to email in case of 
technical issue) 
Sponsor 
Within 3 business days 
after investigator is first 
notified of the event 
Unanticipated 
Adverse Device Effect 
(UADE) 
Relevant eCRF page (or 
scanned relevant form 
to email in case of 
technical issue) 
Sponsor and 
IRB/EC* 
Immediately, but no later 
than 24 hours after 
investigator is first 
notified of the effect. 
Withdrawal of IRB/EC 
Approval or other 
action on part of the 
IRB/EC that affects 
the study  
Any written document 
Sponsor 
Within 5 working days of 
notice of IRB/EC decision.  
Deviations from CIP  
Relevant eCRF page (or 
scanned relevant form 
to email in case of 
technical issue) 
Sponsor and 
IRB/EC*  
• Emergency use (i.e., if 
to protect the life or 
physical wellbeing of a 
subject in an 
emergency): as early as 
possible but not later 
than 5 working days 

 
 
 
30 of 34 
  
 
 
Type of Event 
Document 
Report prepared 
for 
Reporting Timeframe 
after protocol 
deviation. 
• Otherwise: within 10 
working days 
Device deficiency 
that might have led 
to SAE 
Relevant eCRF page (or 
scanned relevant form 
to email in case of 
technical issue) 
Sponsor 
Immediately, but no later 
than 24 hours after 
investigator is first 
notified of the deficiency. 
Use of an 
Investigational 
Device without 
Informed Consent 
Any written document 
Sponsor and 
IRB/EC*  
Within 5 working days 
after the use occurs.  
Study Progress 
information 
Any written document 
Sponsor and 
IRB/EC* 
At regular intervals, but 
no less than yearly 
Termination or 
completion of study 
or investigator’s 
participation 
Any written document 
Sponsor and 
IRB/EC* 
Within 3 months after 
termination or 
completion of study or 
investigator’s 
participation. 
Other  
As required 
As required  
Upon request by the 
IRB/EC or FDA or national 
Competent Authority, 
provide accurate, 
complete, and current 
information about any 
aspect of the study.  
* Reporting to the IRB/ECs will be according to applicable national/local regulations and institution 
requirements. 
14.3.6 Sponsor Reports 
The following reports should be prepared by the Sponsor within the timeframes described in Table 3 
below.  
Table 3: List of Sponsor Reports 

 
 
 
31 of 34 
  
 
 
Event 
Document 
Report Prepared for 
Reporting Timeframe 
Serious Adverse 
Event 
MEDDEV Report 
IRB/ECs*, and 
Competent 
Authorities** 
Within 2 calendar days from 
sponsor awareness (MEDDEV 
2.7/3) 
Unanticipated 
Adverse Device 
Effect 
UADE Report  
IRB/ECs*, 
Investigators  
Within 10 working days from 
the time the sponsor first 
learns of the effect 
Serious Breach 
from Clinical 
Investigational 
Plan  
Written 
report/notification, 
or interim progress 
report or final report 
IRB/ECs* 
• Emergency use (i.e., if to 
protect the life or physical 
wellbeing of a subject in an 
emergency): as early as 
possible but not later than 5 
working days after protocol 
deviation. 
• Otherwise: as part of the 
progress and final reports 
Use of an 
Investigational 
Device or 
Treatment 
without 
Informed 
Consent 
Any written 
document 
IRB/ECs* 
Within 5 working days after 
the use occurs.  
Withdrawal of 
IRB/EC 
Approval 
Written 
report/notification 
IRB/ECs*, 
Investigators 
Within 5 workings days of 
notification of such 
notification 
Device Recall 
and disposition 
Written 
report/notification 
IRB/ECs* 
Within 30 days after device 
recall or withdrawal request is 
made to an investigator 
Study Progress 
information 
Interim Progress 
Report 
IRB/ECs* 
Annually, on the anniversary of 
the IDE approval date 
Termination or 
completion of 
study  
Final Report 
IRB/ECs* 
Within 6 months of 
completion or termination of 
the study 
Final Report 
Final study report 
Investigators, 
IRB/ECs* 
Within 6 months of study 
closure 
Other 
Written 
report/notification 
IRB/ECs* 
Upon request by the IRB/EC, 
provide accurate, complete 

 
 
 
32 of 34 
  
 
 
Event 
Document 
Report Prepared for 
Reporting Timeframe 
and current information about 
any aspect of the study 
* Reporting to the IRB/ECs will be according to applicable national/local regulations and institution 
requirements. 
** Reporting to the Competent Authorities will be according to applicable national/local regulations and 
institution requirements. 
15 
Vulnerable Population 
As the study device is intended for children < 4 years old, the study population is made of vulnerable 
participants.  
Subjects will be recruited during the course of a hospitalization, hospital visit or visit to the emergency 
department. If the HCP assesses that the subject may be eligible for this study, parent(s)/legal 
representative(s) will be presented with the project and all relevant documents.   
If the parent(s)/legal representative(s) are interested in their child’s participating in this trial, at least of 
the child’s parents/legal representatives will be provided with provide verbal consent and be given an 
information sheet discussing study procedures and involvement.  
16 
Early Termination or Suspension of the Clinical Investigation 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause (e.g., technical problem with the study design, unexpected significant concerns about safety for 
the subjects, lack of compliance to protocol requirements or lack of sufficient data, primary endpoint 
met, or futility) by Sponsor or IRB/EC. Written notification, documenting the reason for study 
suspension or termination, will be provided by the suspending or terminating party to Investigators, 
IRB/EC and sponsor. Study may resume once concerns about safety, protocol compliance, and data 
quality are addressed, and satisfy the Sponsor and IRBs/ECs. 
17 
Final Report and Policy Publication 
The Sponsor, in cooperation with the Coordinating Investigator, will prepare the final study report, 
which will be signed by the Coordinating Investigator and the Sponsor.  
 
The results of the clinical investigation will be published 
 
YES  
    NO 
 
 
 
If yes, conditions of publication: 
 
 

 
 
 
33 of 34 
  
 
 
Literature review 
 
1. Lilly 
CM. 
The 
ProCESS 
trial--a 
new 
era 
of 
sepsis 
management. N 
Engl 
J 
Med. 2014;370(18):1750–1. [PubMed] [Google Scholar] 
2. Launay E, Gras-Le Guen C, Martinot A, et al. Suboptimal care in the initial management of 
children who died from severe bacterial infection: a population-based confidential 
inquiry. Pediatr Crit Care Med. 2010;11(4):469–74. [PubMed] [Google Scholar] 
3. de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/PALS haemodynamic support 
guidelines for paediatric septic shock: an outcomes comparison with and without monitoring 
central venous oxygen saturation. Intensive Care Med. 2008;34(6):1065–75. [PubMed] [Google 
Scholar] 
4. Cruz AT, Perry AM, Williams EA, Graf JM, Wuestner ER, Patel B. Implementation of goal-
directed 
therapy 
for 
children 
with 
suspected 
sepsis 
in 
the 
emergency 
department. Pediatrics. 2011;127(3):e758–66. [PubMed] [Google Scholar] 
5. Larsen GY, Mecham N, Greenberg R. An emergency department septic shock protocol and care 
guideline for children initiated at triage. Pediatrics. 2011;127(6):e1585–92. [PubMed] [Google 
Scholar] 
7. Thompson G, Macias C. Recognition and Management of Sepsis in Children: Practice Patterns 
in 
the 
Emergency 
Department. J 
Emerg 
Med. 2015 
doi: 10.1016/j.jemermed.2015.03.012. [PubMed] [CrossRef] [Google Scholar] 
8. Scott HF, Donoghue AJ, Gaieski DF, Marchese RF, Mistry RD. The utility of early lactate testing 
in undifferentiated pediatric systemic inflammatory response syndrome. Acad Emerg 
Med. 2012;19:1276–80. [PubMed] [Google Scholar] 
9. Scott H, Deakyne S, Woods J, Bajaj L. The prevalence and diagnositic utility of Systemic 
Inflammatory Response Syndrome vital signs in a pediatric emergency department. Acad Emerg 
Med. 2015;22:381–9. [PubMed] [Google Scholar] 
10. 
Balamuth F, Alpern ER, Grundmeier RW, Chilutti M, Weiss SL, Fitzgerald JC, Hayes K, Bilker 
W, Lautenbach E. Comparison of Two Sepsis Recognition Methods in a Pediatric Emergency 
Department. Acad Emerg Med. 2015 Nov;22(11):1298-306. doi: 10.1111/acem.12814. Epub 
2015 Oct 16. PMID: 26474032; PMCID: PMC4639443. 
 
11. 
Eisenberg MA, Balamuth F. Pediatric sepsis screening in US hospitals. Pediatr Res. 2022 
Jan;91(2):351-358. doi: 10.1038/s41390-021-01708-y. Epub 2021 Aug 20. PMID: 34417563; 
PMCID: PMC8378117. 
 

 
 
 
34 of 34 
  
 
 
12. 
Dewan M, Vidrine R, Zackoff M, Paff Z, Seger B, Pfeiffer S, Hagedorn P, Stalets EL. Design, 
Implementation, and Validation of a Pediatric ICU Sepsis Prediction Tool as Clinical Decision 
Support. Appl Clin Inform. 2020 Mar;11(2):218-225. doi: 10.1055/s-0040-1705107. Epub 2020 
Mar 25. PMID: 32215893; PMCID: PMC7096320. 
 
13. 
Garcia PCR, Tonial CT, Piva JP. Septic shock in pediatrics: the state-of-the-art. J Pediatr 
(Rio J). 2020 Mar-Apr;96 Suppl 1(Suppl 1):87-98. doi: 10.1016/j.jped.2019.10.007. Epub 2019 
Dec 13. PMID: 31843507; PMCID: PMC9432279. 
 
14. 
Kooij L, Peters GM, Doggen CJM, van Harten WH. Remote continuous monitoring with 
wireless wearable sensors in clinical practice, nurses perspectives on factors affecting 
implementation: a qualitative study. BMC Nurs. 2022 Mar 7;21(1):53. doi: 10.1186/s12912-022-
00832-2. PMID: 35255894; PMCID: PMC8899789. 
 
15. 
Verma N, Haji-Abolhassani I, Ganesh S, Vera-Aguilera J, Paludo J, Heitz R, Markovic SN, 
Kulig K, Ghoreyshi A. A Novel Wearable Device for Continuous Temperature Monitoring & Fever 
Detection. 
IEEE 
J 
Transl 
Eng 
Health 
Med. 
2021 
Jul 
19;9:2700407. 
doi: 
10.1109/JTEHM.2021.3098127. PMID: 34765323; PMCID: PMC8577572. 
 
16. 
Kakarmath S, de Redon E, Centi A, Palacholla R, Kvedar J, Jethwani K, Agboola S Assessing 
the Usability of an Automated Continuous Temperature Monitoring Device (iThermonitor) in 
Pediatric Patients: Non-Randomized Pilot Study JMIR Pediatr Parent 2018;1(2):e10804 URL: 
https://pediatrics.jmir.org/2018/2/e10804 
DOI: 10.2196/10804 
 
17. 
Sampson M, Hickey V, Huber J, Alonso PB, Davies SM, Dandoy CE. Feasibility of continuous 
temperature monitoring in pediatric immunocompromised patients: A pilot study. Pediatric 
Blood Cancer. 2019 Jun;66(6):e27723. doi: 10.1002/pbc.27723. Epub 2019 Mar 18. PMID: 
30884117 
18. 
Morgan, J. T., Sklar, B., Robinson, C., Toltzis, P., & Bakken, S. (2014). Continuous 
temperature monitoring in hospitalized children: Feasibility and impact on detecting 
fever and hospital length of stay. Journal of Hospital Medicine, 9(6), 393-398. 
 
19. 
Wang, Y. J., Hsiao, P. C., Hsiao, C. Y., Chiu, Y. W., Lin, Y. C., & Huang, L. H. (2016). 
Continuous temperature monitoring reduces the incidence of febrile neutropenia and 
shortens hospitalization in patients with hematological malignancies undergoing 
chemotherapy. Journal of Pediatric Nursing, 31(5), 537-543.