Demonstration of an Artificial Intelligence Based Closed Loop Glucose Control System as a Therapeutic Modality in Type 1 and Type 2 Diabetic Patients
Phase: NA
Conditions: Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2
Sponsor: Ideal Medical Technologies

 
DEMONSTRATION OF AN ARTIFICIAL INTELLIGENCE BASED CLOSED LOOP 
GLUCOSE CONTROL SYSTEM AS A THERAPEUTIC MODALITY IN TYPE 1 AND 
TYPE 2 DIABETIC PATIENTS 
NCT Number: 05644730 
Principal Investigator: Dr. Francisco Pasquel 
August 22, 2022 

DEMONSTRATION OF AN ARTIFICIAL INTELLIGENCE BASED CLOSED-LOOP 
GLUCOSE CONTROL SYSTEM AS A THERAPEUTIC MODALITY IN TYPE 1 AND 
TYPE 2 DIABETIC PATIENTS 
Protocol Number: IMT 2022-1 
National Clinical Trial Identified Number:  NA 
Principal Investigator: Dr. Francisco Pasquel 
Sponsor: Ideal Medical Technologies 
Sponsor Contact: Dr. Leon DeJournett 
Funded by: Ideal Medical Technologies 
Version Number:  1.0.7 
22 August 2022 
 
 
Summary of Changes from Previous Version: 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
Explanation of 
glucose control 
software (Page 19) 
1. Removed reference to fuzzy logic. 
2. Added improved explanation 
around fact that the FUSION 
devices glucose control software is 
an expert based rule system, or 
knowledge based system. 
 
1. The FUSION system does not 
use fuzzy logic. 
2. To better describe the basis for 
how the FUSION systems 
glucose control software works. 
Termination 
Criteria (Pages 62-
64) 
1. Removed redundant termination 
criteria section (8.1.1.7). 
2. Addition of DKA, Severe 
Hyperglycemia and HHS. 
3. Addition of excessive volume 
administration with defined fluid 
limit to stop study. 
4. Addition of any unanticipated 
adverse device effect (UADE). 
5. Removed confusing term “halting 
criteria”. 
 
1. To protect subjects if device 
cannot prevent development of 
DKA, Severe Hyperglycemia, or 
HHS. 
2. To protect subjects from 
excessive volume loading. 
3. To protect subjects from 
harmful device effects. 
4. To use consistent terminology 
to describe a permanent 
stopping of the study. 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
6. Defined criteria for stopping study 
on one subject, and for entire 
study. 
5. To clarify stopping criteria for 
study personnel. 
Discharge criteria  
(Pages 103-104) 
1. Defined criteria that need to be 
met before subject may be 
discharged from the CRC, including 
glucose measurement criteria and 
length of time they need to be 
observed after the end of the 
closed loop glucose control 
session. 
 
1. To better describe for the study 
nurse the  criteria that need to 
be met prior to discharge. 
Frequency of 
Reference Glucose 
Values (Pages 103-
104) 
1. Clarified how often Reference 
Glucose Values will be obtained 
under different circumstances. 
1. To clarify for study personnel 
the circumstances under which 
Reference Glucose Values will 
be checked every 10, 30 or 60 
minutes. 
Diabetic 
Ketoacidosis 
screening (Page 54) 
1. Added criteria to screen for 
diabetic ketoacidosis if the 
Reference or Dexcom G6 CGM(s) 
have been greater than 200 mg/dL 
for more than one hour 
consecutively. 
1. To screen for diabetic 
ketoacidosis if the subject is 
experiencing persistent 
hyperglycemia. 
Screening prior to 
initiation closed 
loop glucose 
control session 
(Time 0 to 5 hours, 
page 54). 
1. Added screening criteria to make 
sure subjects are not in DKA 
before entering the study, and to 
also make sure they are not 
acutely ill with any other illness, 
prior to starting the study. 
 
1. To prevent using the FUSION 
system on an acutely ill or 
unstable subject. 
Use of device – 
Electrostatic 
Discharge (Protocol 
2, page 97) 
1. Added instructions to mitigate 
against risk of introducing an 
electrostatic discharge to the 
FUSION system. 
1. To prevent an electrostatic 
discharge from adversely 
affecting the performance of 
the FUSION system. 
Length of use of 
medication syringes 
(time 5 to 29 hours, 
page 59) 
1. Added instructions to not use the 
medication syringes for a period of 
time exceeding 24 hours. 
1. To avoid using the medication 
syringes for a period of time 
exceeding 24 hours, as the 
biocompatibility of the 
medications in the syringes is 
unclear for a period of time 
exceeding 24 hours and is thus 
not FDA approved. 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Necessary 
equipment (time 0 
to 2 hours, Pages 
53-54) 
1. Specified equipment to be on hand 
in the CRC, including cardiac 
monitor, pulse oximeter, blood 
pressure cuff, and resuscitation 
cart. 
1. To make sure CRC has adequate 
equipment on hand to both 
monitor and resuscitate the 
subject. 
Synopsis (page 4) 
1. Increased study size from two type 
2 diabetic subjects to two type 1 
diabetic subjects and six type 2 
diabetic subjects. 
1. To update the study size. 
Labs (page 6) 
1. Added hemoglobin to screening 
labs 
1. To exclude subjects who do 
not have normal hemoglobin 
levels, given that the study 
subjects may have up to 80 mL 
of blood drawn during the 
course of the study. 
Rescue Medicine 
(Pages 38 & 62) 
1. Added Glucagon 
1. To give additional option for 
treatment of hypoglycemia. 
Meal Plan 
(Page 58) 
1. Changed closed loop control 
session start time to 1200 with 
first meal being lunch 
1. To allow CGM’s time to warm 
up and verify their accuracy, 
prior to starting the study 
Entire Document 
1. Changed length of study to 32 
hours 
2. Changed interval for checking 
Reference Glucose Values to 
every 10-60 minutes 
3. Changed document version year 
to 2022 to reflect year submitted 
to IRB, and version number to 
1.0.7 
1. To ensure consistency within 
the document 
2. To ensure consistency within 
the document, and to cover all 
possible intervals between 
Reference Glucose Values 
3. To update document to coincide 
with year of submission to IRB 
and most recent version 
number 
Protocol 1 
(Page 95) 
1. Changed carrier solution for 
FUSION systems insulin and 
dextrose infusions from normal 
saline to ½ normal saline 
1. To reflect agreement with FDA 
to use a hypo-osmotic carrier 
solution to minimize risk of vein 
irritation from infusion of 
hyper-osmolar D10 normal 
saline solution used by the 
FUSION system 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Study Data 
Identification 
(Pages 79) 
1. Clarified that only de-identified 
data will be used in the study 
1. To ensure protection of the 
study subjects and any study 
subject data obtained through 
the subject’s participation in 
the study 
Role of IMT 
Personnel 
(Pages 85) 
1. Clarified role IMT personnel will 
have in the study – limited to use 
of the FUSION system with no 
study subject interaction, no 
provision of study subject 
medical care, and no extraction 
or analysis of the study data 
1. To prevent IMT personnel from 
becoming involved in study 
subject medical care and to 
protect the integrity of the 
studies data for purposes of 
future regulatory submissions 
Method of use of 
the Dexcom G6 
CGM system by the 
FUSION system 
(Page 39) 
1. Stated that the FUSION system 
uses a simple average of the two 
Dexcom G6 CGM systems to 
effect glucose control. 
2. Clarified that the FUSION system 
will continue to operate for up to 
4 hours on the glucose data from 
only one Dexcom G6 CGM. 
3. Clarified that the FUSION system 
will continue to operate for up to 
20 minutes if no glucose data is 
available from either Dexcom G6 
CGM system. 
1. To clarify for study personnel 
how the FUSION system uses 
the data from the two Dexcom 
G6 CGM systems. 
Method of 
communication 
between the 
Dexcom G6 CGM 
transmitter and 
receiver 
(Page 40) 
1. Stated that the Dexcom G6 CGM 
Sensor/Transmitter pair 
communicate with the Dexcom 
G6 CGM Receiver via Bluetooth. 
2. Stated that the method of 
communication of the Dexcom G6 
CGM system has not been altered 
in any way by IMT personnel. 
1. To clarify for the study 
personnel that IMT has not 
altered, in any way, how the 
Dexcom G6 CGM system 
functions. 
Method and 
accuracy of data 
extraction of 
glucose values from 
the Dexcom G6 
CGM Receiver by 
the FUSION system 
1. Stated that the FUSION system 
uses a software Driver to extract 
the glucose values from the 
Dexcom G6 CGM Receiver. 
2. Also noted that the FUSION 
system is connected to the 
Dexcom G6 CGM Receiver by a 
serial data cable. 
1. To clarify for study personnel 
how the FUSION system 
extracts glucose data from the 
Dexcom G6 CGM Receiver. 
2. To clarify for study personnel 
that the Dexcom G6 Receiver 
transfers its data to the 
computer running the FUSION 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
(Page 40) 
systems software via a data 
cable. 
Reference Glucose 
Values 
(Pages 37-38) 
1. Stated that results from the Nova 
StatStrip Hospital Glucose Meter 
System glucose meter will be 
used as Reference Glucose Values 
2. Stated that if the retrograde hand 
vein is no longer available for 
blood draws for Reference 
Glucose Values, that capillary 
blood from a fingerstick could be 
used as a Reference Glucose 
Value. 
1. To clarify that only the Nova 
StatStrip Hospital Glucose 
Meter System will be used to 
analyze whole blood samples 
Reference Glucose Values. 
2. To increase the likelihood of 
finishing the study if the 
retrograde hand stops 
functioning. 
Human subject 
data 
(Pages 29-30) 
1. Listed demographic and glucose 
metric results from the first two 
subjects treated with the FUSION 
system, as well as glucose versus 
time graphs with overlayed 
infusion data. 
1. To note the performance 
characteristics of the FUSION 
system in its first in human 
study. 
Risk assessment – 
compression 
artifact 
(Pages 30, 41, and 
106) 
1. Noted risk of a false low glucose 
value from compression of the 
local Dexcom G6 sensor site due 
to subject laying on this site. 
2. Documented accuracy of 
posterior upper arm site for 
Dexcom CGM in clinical study, to 
inform FDA of the validity of 
using this alternative site. 
3. Clarified that the two Dexcom 
CGM’s should be placed on 
contralateral sides if a 
replacement CGM is placed in the 
posterior upper arm position(e.g., 
right abdomen and left arm) 
1. To document this additional 
risk and clarify for the study 
nurse steps needed to mitigate 
this risk. 
2. To inform FDA that the 
posterior upper arm site is a 
valid site for CGM placement. 
3. To decrease risk of subject 
compressing both CGM’s at 
the same time. 
Risk assessment – 
Volume overload 
(Pages 41-42) 
1. Documented the tendency of the 
FUSION system to deliver 
approximately 25% of the 
subject’s total daily fluid needs. 
1. To reinforce for study 
personnel the importance of 
selecting out subjects with 
renal or cardiac disease who 
are more likely to suffer side 
effects from volume overload. 
2. To clarify for study personnel 
the need to monitor the 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
subjects for signs of excessive 
volume overloading 
Recovery Period 
(Pages 107-109) 
1. Defined the subcutaneous insulin 
dosing provided after the 
conclusion of the closed loop 
glucose control session. 
1. To clarify for study personnel 
the method for transitioning 
the subjects from the closed 
loop glucose control session to 
glucose control via 
subcutaneous insulin 
injections or CII via an insulin 
pump. 
Reference Glucose 
Value 
(Throughout the 
document) 
1. Defined the term “Reference 
Glucose Value” and used 
consistently throughout the 
document. 
1. To clarify for study staff the 
difference between a 
Reference Glucose Value and a 
CGM glucose value. 
CGM Placement 
(Pages 104-105 ) 
1. Noted proper position for CGM 
placement, including alternative 
placement site. 
1. To clarify for study staff the 
proper abdominal position for 
CGM placement, and to alert 
them of the availability of 
using the posterior upper arm 
position as an alternative 
placement site. 
Instructions for 
Subject Prior to 
Visit 3 
(Page 53) 
1. Clarified the timing to withhold 
oral anti-hyperglycemic 
medications prior to visit 3. 
1. To clarify for study staff and 
the subjects when they should 
begin to withhold their oral 
anti-hyperglycemic 
medications prior to visit 3. 
Hypoglycemia 
Treatment 
(Page 62) 
1. Clarified when to treat 
hypoglycemia and its related 
symptoms. 
2. Clarified the treatment methods 
available for hypoglycemia. 
3. Defined and documented the 
need to treat neuroglycopenia. 
1. To clarify and educate the 
study staff when and how to 
treat hypoglycemia. 
Halting versus 
Termination 
Criteria 
1. Removed the term “Halting 
Criteria” from the document. 
2. Clarified the different criteria for 
terminating the study on one 
subject versus terminating the 
entire study. 
1. To consistently use one term 
(e.g., “Termination Criteria”) 
to signify the permanent end 
of the study on either one 
subject or the entire study. 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
(Throughout 
document) 
3. Added excessive blood removal 
during visit 3 as a termination 
criterion (Page 102). 
4. Added excessive volume 
administration from FUSION 
system. 
2. To clarify for study staff the 
different criteria for 
terminating the study on one 
subject versus terminating the 
entire study. 
Criteria to Replace 
CGM’s 
(Pages 105-106) 
1. Clarified criteria whereby the 
CGM(s) should be replaced. 
1. To clarify this issue for study 
staff. 
CGM Validation 
Criteria 
(Page 105) 
1. Clarified criteria whereby the 
CGM should be calibrated. 
2. Clarified that either one or both 
CGM’s may need calibration at 
the same time. 
3. Clarified that it is possible to go 
the entire study without 
calibrating the CGM’s. 
1. To clarify this issue for study 
staff. 
Noted new FUSION 
system alarm 
features 
(Page 106) 
1. To document the Compression 
Artifact and CGM Discrepancy 
(e.g., CGM’s > 20% different than 
their averaged value) alarms 
added to the FUSION system 
1. To alert study staff to these 
new features of the FUSION 
system 
Added C-Peptide to 
study labs 
(Page 6) 
1. To test for lack of endogenous 
insulin production in type 2 
diabetic subjects. 
1. To avoid inadvertent 
classification of type 1 diabetic 
subjects as type 2 diabetic 
subjects. 
Risk Assessment 
(Pages 41, 44-45 ) 
1. Added Volume Overload, Severe 
Hyperglycemia, DKA, and HHS to 
risk assessment section. 
1. To clarify for study staff that 
these are risks of this study, 
including during the closed 
loop glucose control session. 
Updated Exclusion 
Criteria 
(Page 50) 
1. Added any form of renal failure 
or congestive heart failure to 
exclusion criteria. 
2. Added low C-Peptide levels as an 
exclusion criteria for type 2 
diabetic subjects. 
1. To prevent exacerbation of an 
underlying chronic health 
condition due to excessive 
fluid loading from the FUSION 
system. 
2. To prevent use of the FUSION 
system on more than two type 
1 diabetic subjects. 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Updated Care 
provided in visit 3 
(Page 100) 
1. Clarified the insulin dosing given 
to subjects in the 5 hour period 
prior to starting the closed loop 
session on visit 3. 
2. Clarified that the study nurse will 
give all insulin injections in the 
CRC. 
3. Clarified that the insulin given to 
subjects in the CRC will be 
provided by the CRC (e.g., subject 
may not use their own insulin). 
1. To clarify these issues for 
study staff and the subjects. 
2. To increase control over the 
care provided to the subjects 
during visit 3. 
Pre-Study 
assessment at 
beginning of visit 3 
(Page 54) 
1. Clarified the labs to be performed 
on the subjects prior to 
proceeding with the closed loop 
session on visit 3. 
2. Documented which Ketone meter 
will be used during the above 
assessment. 
1. To clarify this issue for study 
staff. 

  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 5 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale- Glycemic Control in the ICU ................................................................................ 7 
2.2 
Study rationale – COVID-19 ............................................................................................................. 11 
2.3 
Study rationale – Fusion AI based artificial pancreas system ..................................................... 19 
3 
fusion system testing Background ............................................................................................................. 20 
3.1 
Simulation studies .............................................................................................................................. 20 
3.2 
animal studies .................................................................................................................................... 23 
3.3 
human study ....................................................................................................................................... 28 
4 
Risk/Benefit Assessment ............................................................................................................................. 36 
4.1 
Known Potential Risks ...................................................................................................................... 36 
4.2 
Known Potential Benefits .................................................................................................................. 39 
4.3 
Assessment of Potential Risks and benefits .................................................................................. 39 
4.3.1 
Failure of Dexcom G6 continuous glucose monitor(s) ............................................. 39 
4.3.2 
Use of innacurate CGM glucose value for glucose control ...................................... 40 
4.3.3 
Use of False low CGM values due to compression of sensor site ......................... 41 
4.3.4 
Excessive volume loading from FUSION system ...................................................... 42 
4.3.5 
failure of ability to obtain a reference glucose sample ............................................. 42 
4.3.6 
Failure of Reference Glucose Analyzer ...................................................................... 43 
4.3.7 
Failure of control algorithm to perform as expected ................................................. 43 
4.3.8 
Failure of syringe pumps to accurately deliver doses of intravenous insulin and 
dextrose 
43 
4.3.9 
Risk of improper syringe pump set up ........................................................................ 44 
4.3.10 
Risk of diabetic ketoacidosis (dKA) ............................................................................. 44 
4.3.11 
risk of severe hyperglycemia ........................................................................................ 45 
4.3.12 
risk of hyperosmolar hyperglycemic syndrome ......................................................... 45 
5 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 45 
6 
STUDY DESIGN ........................................................................................................................................... 48 
6.1 
Overall Design .................................................................................................................................... 48 
6.2 
Scientific Rationale for Study Design .............................................................................................. 48 
6.3 
Justification for Dose ......................................................................................................................... 49 
6.4 
End of Study Definition ..................................................................................................................... 49 
7 
STUDY POPULATION ................................................................................................................................ 49 
7.1 
Inclusion Criteria ................................................................................................................................ 49 
7.2 
Exclusion Criteria ............................................................................................................................... 50 
7.3 
Lifestyle Considerations .................................................................................................................... 51 
7.4 
Screen Failures .................................................................................................................................. 51 
7.5 
Strategies for Recruitment and Retention ...................................................................................... 51 
8 
STUDY INTERVENTION ............................................................................................................................ 52 
8.1 
Study Intervention(s) Administration ............................................................................................... 52 
8.1.1 
Study Intervention Description ..................................................................................... 52 
8.1.2 
Dosing and Administration ............................................................................................ 60 

  
8.2 
Preparation/Handling/Storage/Accountability ................................................................................ 60 
8.2.1 
Acquisition and accountability ...................................................................................... 60 
8.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 60 
8.2.3 
Product Storage and Stability ....................................................................................... 61 
8.2.4 
Preparation ...................................................................................................................... 61 
8.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 61 
8.4 
Study Intervention Compliance ........................................................................................................ 61 
8.5 
Concomitant Therapy ........................................................................................................................ 62 
8.5.1 
Rescue Medicine ............................................................................................................ 62 
9 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 62 
9.1 
Discontinuation of Study Intervention on individual subject ........................................................ 63 
9.2 
discontinuation of entire study ......................................................................................................... 63 
9.3 
Participant Discontinuation/Withdrawal from the Study ............................................................... 64 
9.4 
Lost to Follow-Up ............................................................................................................................... 64 
10 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 64 
10.1 
Efficacy Assessments ....................................................................................................................... 64 
10.2 
Safety and Other Assessments ....................................................................................................... 66 
10.2.1 
Safety 
66 
10.2.2 
Physical exam/Labs ....................................................................................................... 66 
10.2.3 
Special assays ................................................................................................................ 67 
10.2.4 
Use of Existing Medical Record Data ......................................................................... 67 
10.3 
Adverse Events and Serious Adverse Events ............................................................................... 67 
10.3.1 
Definition of Adverse Events (AE) ............................................................................... 67 
10.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 67 
10.3.3 
Classification of an Adverse Event .............................................................................. 68 
10.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 69 
10.3.5 
Adverse Event Reporting .............................................................................................. 70 
10.3.6 
Serious Adverse Event Reporting ............................................................................... 70 
10.3.7 
Reporting Events to Participants ................................................................................. 71 
10.3.8 
Events of Special Interest ............................................................................................. 71 
10.3.9 
Reporting of Pregnancy ................................................................................................ 71 
10.4 
Unanticipated Problems .................................................................................................................... 71 
10.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 71 
10.4.2 
Unanticipated Problem Reporting ................................................................................ 72 
10.4.3 
Reporting Unanticipated Problems to Participants ................................................... 72 
11 
STATISTICAL CONSIDERATIONS .......................................................................................................... 72 
11.1 
Statistical Measurements ................................................................................................................. 73 
11.2 
Sample Size Determination .............................................................................................................. 74 
11.3 
Populations for Analyses .................................................................................................................. 74 
11.4 
Statistical Analyses ............................................................................................................................ 75 
11.4.1 
General Approach .......................................................................................................... 75 
11.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 75 
11.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 75 
11.4.4 
Safety Analyses .............................................................................................................. 76 
11.4.5 
Baseline Descriptive Statistics ..................................................................................... 76 
11.4.6 
Planned Interim Analyses ............................................................................................. 76 

  
11.4.7 
Sub-Group Analyses ..................................................................................................... 76 
11.4.8 
Tabulation of Individual participant Data .................................................................... 76 
11.4.9 
Exploratory Analyses ..................................................................................................... 77 
12 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 77 
12.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 77 
12.1.1 
Informed Consent Process ........................................................................................... 77 
12.1.2 
Study Discontinuation and Closure ............................................................................. 78 
12.1.3 
Confidentiality and Privacy ........................................................................................... 78 
12.1.4 
Future Use of Stored Specimens and Data ............................................................... 79 
12.1.5 
Key Roles and Study Governance .............................................................................. 79 
12.1.6 
Safety Oversight ............................................................................................................. 80 
12.1.7 
Clinical Monitoring .......................................................................................................... 80 
12.1.8 
Quality Assurance and Quality Control ....................................................................... 81 
12.1.9 
Data Handling and Record Keeping ............................................................................ 81 
12.1.10 
Protocol Deviations ........................................................................................................ 82 
12.1.11 
Publication and Data Sharing Policy ........................................................................... 83 
12.1.12 
Conflict of Interest Policy .............................................................................................. 84 
12.2 
Additional Considerations ................................................................................................................. 84 
12.2.1 
Data Identification .......................................................................................................... 84 
12.2.2 
Role of ideal medical technologies personnel in study ............................................. 84 
12.3 
Abbreviations ...................................................................................................................................... 85 
12.4 
Protocol Amendment History ........................................................................................................... 88 
13 
REFERENCES ............................................................................................................................................. 89 

DEMONSTRATION OF AN ARTIFICIAL INTELLIGENCE BASED CLOSED LOOP GLUCOSE CONTROL SYSTEM AS A 
THERAPEUTIC MODALITY IN TYPE 1 AND TYPE 2 DIABETIC PATIENTS 
 
Version1.0.7 
Protocol IMT 2022-1                                                           CONFIDENTIAL  
22 August 2022 
 
 
 
1 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonisation (ICH) 
Good Clinical Practice (GCP) and the following:  
 
• 
Applicable standards as set forth by the NIH and/or FDA. 
 
National Institute of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
DEMONSTRATION OF AN ARTIFICIAL INTELLIGENCE BASED CLOSED 
LOOP GLUCOSE CONTROL SYSTEM AS A THERAPEUTIC MODALITY IN 
TYPE 1 AND TYPE 2 DIABETIC PATIENTS 
Study Description: 
Tight glucose control in the Intensive Care Unit (ICU) setting is difficult to 
achieve. We hypothesize that a closed loop glucose control system based 
on artificial intelligence (AI) will improve upon the glucose control 
currently achieved by open loop systems, and may improve the outcomes 
of critically ill patients, including those with COVID-19. This Earl Feasibility 
Study (EFS) will test the ability of a prototype artificial intelligence based 
closed loop glucose control system named FUSION, to provide safe and 
effective glucose control in subjects with type 1 and type 2 diabetes in a 
clinical research center (CRC) setting. Subjects with type 1 diabetes have 
been chosen as they lack native Insulin production, which makes it 

DEMONSTRATION OF AN ARTIFICIAL INTELLIGENCE BASED CLOSED LOOP GLUCOSE CONTROL SYSTEM AS A 
THERAPEUTIC MODALITY IN TYPE 1 AND TYPE 2 DIABETIC PATIENTS 
 
Version1.0.7 
Protocol IMT 2022-1                                                           CONFIDENTIAL  
22 August 2022 
 
 
 
2 
challenging to provide safe and effective glucose control for them. 
Subjects with type 2 diabetes have been chosen as they are insulin 
resistant, which makes their insulin resistance profiles like that of ICU 
patients. As this is a continuation of a first in human study of a new 
medical device, the controlled environment of the CRC is preferable to the 
less controlled environment of an ICU setting. 
 
Objectives: 
 
 
Primary Objectives:   
 
1. The primary safety objective of this first in human study is to test 
the hypothesis that an AI based closed loop glucose control system 
will be able to safely control the blood glucose levels of 
participants with type 1 and type 2 diabetes during a 24 hour stay 
in the CRC setting. 
2. The primary efficacy objective of this first in human study is to test 
the hypothesis that an AI based closed loop glucose control system 
will effectively control the blood glucose levels of participants with 
type 1 and type 2 diabetes during a 24 hour stay in the CRC 
setting. 
 
Secondary Objectives: 
 
The secondary objectives of this study are to test the hypothesis that an AI 
based glucose controller will be effective in minimizing glucose curve 
variations commonly observed in critically ill patients.   
Endpoints: 
Primary Endpoint: 
 
1. The primary safety endpoint will be the percent of all glucose 
values that are within the glucose range of less than < 70 
mg/dL. Time frame will be from start of use of AI controller 
until end of use of AI controller. 
2. The primary efficacy endpoint will be the percent of all glucose 
values that are within the glucose range of 70-180 mg/dL. 

DEMONSTRATION OF AN ARTIFICIAL INTELLIGENCE BASED CLOSED LOOP GLUCOSE CONTROL SYSTEM AS A 
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Time frame will be from start of use of AI controller until end 
of use of AI controller. 
Secondary Endpoints:  
 
• 
Measure the percent of glucose values that are within clinically 
significant hypoglycemic range (glucose <54 mg/dL). 
• 
Measure the percent of glucose values that are within the 
moderate hypoglycemic range of 54-69 mg/dL. 
• 
Number of hypoglycemic events as measured by glucose < 70 
mg/dL. 
• 
Measure the percent of glucose values that are within the desired 
glucose control range of 100-140 mg/dL. 
• 
Measure the percent of glucose values that are within the range of 
70-140 mg/dL. 
• 
Measure the percent of glucose values that are within the 
hyperglycemic range of >140 mg/dL. 
• 
Measure the percent of glucose values that are within the range of 
70-180 mg/dL. 
• 
Measure the percent of glucose values that are within the 
hyperglycemic range of >180 mg/dL. 
• 
Mean glucose level. 
• 
Measure of dispersion – coefficient of variation (CV). 
• 
The study data will be used to determine the percentage of paired 
glucose values (continuous glucose monitor(s) and Reference 
Glucose Value) in each zone using a Clarke error grid analysis.1 
These calculations will be performed for each individual CGM 
system and for the glucose value used by the FUSION system for 
purposes of glucose control (a calculated average of the two CGM 
systems). 
 
Time frame will be from start of the use of AI controller until end of use of 
AI controller. 
Study Population: 
Two participants with type 1 diabetes and six participants with type 2 
diabetes, male and non-pregnant females, ages 18-70 inclusive, admitted 
to a CRC. Participants will eat three standardized meals during their 24-
hour closed loop glucose control study. 

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Phase: 
Early Feasibility Study, First in Human. 
Description of 
Sites/Facilities Enrolling 
Participants: 
Emory University Hospital, a tertiary care facility located in Atlanta, 
Georgia, United States. Single center study, all enrollments within USA.  
Description of Study 
Intervention: 
The medical device to be tested is named FUSION and is a fully functional 
closed loop glucose control system (artificial pancreas). The system 
consists of three main components: 1) Two Dexcom G6 continuous glucose 
monitors (CGM) provide glucose values to the glucose control software, 2) 
Glucose control software that is run by an all in one Medical Computer 
that is mounted on a powered Medical Cart, and which uses an artificial 
intelligence technique to determine, in an iterative fashion, the infusion 
rates of intravenous (IV) insulin and/or dextrose into the type 2 diabetic 
subjects for purposes of controlling their blood glucose into the range of 
100-140 mg/dL, 3) Two syringe pumps that are used to infuse insulin 
and/or dextrose into the study subjects. These syringe pumps are 
connected by serial data cables to the Medical Computer that runs the 
glucose control software, and their infusion rates are controlled by the 
glucose control software. Reference Glucose Values are measured every 
10-60 minutes on the Nova StatStrip Hospital Glucose Meter System point 
of care glucose meter to ensure subject safety. 
Study Duration: 
Six months. 
Participant Duration: 
Thirty-two hours. 
 
 
 

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1.2 
SCHEMA 
 
 
Visit 1: 
Screening 
 
 
 
 
 
 
Visit 2: 
Enrollment 
Time -2 
Weeks to 
-1 Week 
Prior to CRC 
Study 
 
 
 
 
 
 
 
 
 
 
 
Visit 3: 
Time 0 to 
31 hours 
 
 
 
 
 
Total N = 500:  Screen potential participants by inclusion and exclusion criteria. 
Schedule eligible participants for Visit 2 = Enrollment 
 
End of 
study 
Total N = 8: Administer initial study intervention of placement of two Dexcom G6 CGM’s 
in the abdominal position on arrival to the CRC. 
Place two peripheral IV lines for study intervention. 
Once the two Dexcom G6 CGM’s begin to return glucose values to the Dexcom Receivers, 
and the subjects begin to consume their first study meal, commence the 24-hour closed 
loop glucose control session. The first study meal will be lunch, which will be served at 12 
PM
Visit 3 must occur no later than 2 
weeks from Visit 2 
Total N = 16:  Screen potential participants by inclusion and exclusion criteria; obtain 
informed consent.  Obtain history, document. Perform baseline assessments. 
Record height and weight (Kg). Obtain blood work to include: 1) creatinine, 2) alanine 
aminotransferase (ALT), 3) hemoglobin, 4) hemoglobin A1C, 5) C-peptide. For female 
subjects within age range of 18-55 obtain urine pregnancy test. For subjects whose labs 
do not exclude them from the study, proceed to Visit 3 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Visit 1: Screening 
 
Visit 2: Enrollment 
Time -2 weeks to – 1 week 
Visit 3: 
Perform Baseline assessments 
Place Dexcom CGM monitors 
Time 0 to 5 hours 
Visit 3: 
Perform closed loop glucose control session 
Time 5 to 29 hours 
Visit 3: 
Observe subject for two hours after 
completion of the closed loop glucose 
control session 
Time 29 to 32 hours 
Informed consent 
 
X 
 
 
 
Demographics 
X 
X 
 
 
 
Medical history 
X 
X 
X 
 
 
Administer study intervention 
 
 
X 
X 
X 
Concomitant medication review 
 
X 
 
X 
 
 
Physical exam 
 
X 
X 
 
 
Vital signs 
 
 
X 
X 
X 
Height 
 
 
X 
 
 
Weight 
X 
X 
X 
 
 
Hemoglobin and Hemoglobin A1C 
 
X 
 
 
 
Sserum ALT & creatinine 
 
X 
 
 
 
C-Peptide (subjects with type 2 diabetes) 
 
X 
 
 
 
Pregnancy test a 
 
X 
 
 
 
Adverse event (AE) review and evaluation 
 
 
X 
X 
X 
Complete Case Report Forms (CRFs) 
 
X 
X 
X 
X 
a 
Urine pregnancy test (women of childbearing potential). 
 
 
 

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2 
 
INTRODUCTION 
 
 
2.1 
STUDY RATIONALE- GLYCEMIC CONTROL IN THE ICU  
 
In the U.S. there are currently 80,000 adult ICU beds, and 6 million admissions per year of ICU patients 
into these beds.2 The cost to care for these ICU patients is approximately 150 billion dollars per year.3  
At least 75% of ICU patients suffer from dysglycemia – hypoglycemia, hyperglycemia and increased 
glucose variability.4 The hyperglycemia is the result of a relative insulin resistance that is caused by the 
elevation of the stress hormones glucagon, cortisol, growth hormone, epinephrine and norepinephrine 
in these critically ill patients.5 The hypoglycemia and increased glucose variability occur because of the 
ineffectiveness of the current methods of controlling blood glucose levels in these patients. 
 
Poor control as reflected by high rates of hypoglycemia, hyperglycemia, and increased glucose variability 
have been associated with increased morbidity and mortality rates in ICU patients. This deleterious 
effect is caused by impaired function of the infection fighting white blood cells, and by augmentation of 
the bodies’ inflammatory cascades, both of which can impair organ function including the kidneys, bone 
marrow, lungs and heart.5 A large prospective randomized study published in 2001 showed that tight 
glucose control in Intensive Care Unit (ICU) patients decreased their morbidity and mortality rates by 30-
40%.6 Over the past 20 years multiple studies have confirmed the benefits of effective glucose control in 
the ICU setting, with these benefits extending to all patients in the ICU, not just those with diabetes.7-10 
It should be noted these benefits have been seen in medical,11 cardiac,12 and trauma13 ICU settings. 
 
As noted below (Figure 1) mortality rate increases as the degree of hypoglycemia increases. In this study 
of 4,946 ICU patients, the control 
patients had no glucose values less 
than 81 mg/dL, and as a result had an 
overall mortality rate that was 46% 
lower than the group of patients who 
suffered at least one hypoglycemic 
event.14 
Shown below (Figure 2) are the 
deleterious effects of both higher 
average glucose values and increasing 
glucose variability (CV = coefficient of 
variation) in a study of 4,084 ICU 
patients.15 

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Figure 1– Equal number of patients in the TIR hi and TIR lo groups.  LOS 
= Length of stay. TIR = time in range. Krinsley, Critical Care, 2015. 
 
 
 
 
 
 
 
 
Figure 2  – Patients divided into quintiles based on their average ICU glucose levels. Each quintile further divided 
based on the patients CV. CV = Coefficient of Variation. Krinsley, Journal of Diabetes Science and Technology, 
2009. 
As can be deduced from Figure 2, the best patient outcomes would be achieved by maintaining a mean 
blood glucose level in the range of 70-139 mg/dL while at the same time keeping the variability, as 
measured by the coefficient of variation, to less than 15%. 
 
It is also essential to maintain the ICU patient’s glucose level in the clinician prescribed range. Seen 
below (Figure 1) are results from 2,550 non-diabetic ICU patients.16 The prescribed range being used for 
this study was 70 – 140 mg/dL. For purposes of analysis, there were an equal number of patients in the 
high time in range (TIR hi) and low time in range 
(TIR lo) groups. The patients with a high time in 
range (TIR hi) had a median percent time in 
range of 94%, while those with a low time in 
range (TIR lo) had a median value of 61%. The 
overall mortality rate for the patients with a low 
time in range was 86% higher than the high 
time in range group. This study showed that 
mortality rates decrease significantly when the 
glucose time in range 70 – 140 mg/dL exceeds 
90%. Non-diabetic ICU patients are more 
susceptible to the adverse effects of 
dysglycemia than are diabetic patients, and 
overall represent 75% of all ICU patients. 
 
 
 
 
TIR hi 
TIR lo 
   1-2.9  
 
   3+ 

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 Despite the obvious benefits of tight glucose control that are seen in Figures 1-3, almost all studies to 
date have failed to achieve effective tight glucose control, especially when it is defined as time in range 
of 70- 140 mg/dL exceeding 90%, hypoglycemia (< 70 mg/dL) rate of less than 0.1%, and glucose 
variability as measured by a CV of less than 15%. This inability to effectively control blood glucose levels 
in critically ill patients has led to incorrect conclusions from some studies. 
 
In a large randomized prospective tight glucose control study of 6104 patients known as the NICE-
SUGAR study,17 the tight glucose control group (range 81-108 mg/dL) actually had higher mortality rates 
than the control group (glucose < 180 mg/dL) – 27.5 vs 24.9% mortality rates. However, the tight glucose 
control group had a severe hypoglycemia (<= 40 mg/dL) rate of 6.8%, versus 0.5% in the control group. 
This large hypoglycemia rate in the tight glucose control group would have significantly increased the 
mortality rate of this group, as can be seen above (Figure 1). This confounding variable most likely led to 
the higher mortality rate in the tight glucose control group. In a post hoc analysis of their glucose data, 
the NICE-SUGAR investigators noted that there was an association between both moderate (41-70 
mg/dL) and severe (<= 40 mg/dL) hypoglycemia and mortality rates in the patients they studied.18 The 
patient group that did not suffer from any hypoglycemia had a mortality rate of 23.5%, versus 28.5% and 
35.4% in the moderate and severe hypoglycemia groups (p<0.001 for both groups). The odds ratios of 
death were 1.6 and 2.6 in the moderate and severe hypoglycemia groups as compared to the patients 
who did not suffer any hypoglycemia. This confirms the importance of avoiding hypoglycemia while 
attempting to maintain tight glucose control in the ICU setting. 
After it was originally determined that tight glucose control improves ICU patient outcomes, multiple 
methods aimed at achieving tight glucose control in this challenging patient population were developed. 
The original method was paper based intravenous insulin dosing protocols.19 To utilize these, the nurse 
would manually measure the patient’s blood glucose level, then refer to the institutions paper based 
protocol to determine if any adjustment in the current intravenous insulin dose was needed, then go to 
the intravenous pump to make an adjustment to the intravenous insulin infusion rate. This cycle would 
repeat itself every 1-4 hours, and is referred to as open loop control, as there continues to be human 
intervention in the control process. 
The next step in improving glucose control was to utilize two standard engineering control methods. 
Glytec LLC, has created glucose control software based on a Proportional Derivative  technique.20 This 
glucose control software is sold to hospitals as Glucommander, and serves to replace home grown paper 
based protocols, although it is still an open loop method. The nurse still manually measures the patient’s 
blood glucose level, enters the value into the Glucommander software, and then manually enters the 
new insulin dose recommended by the software into the bedside intravenous pump every 1-4 hours. 
Monarch Medical Technologies utilized a Model Predictive Control technique to create its EndoTool 
glucose control software.21 This open loop system works similar to the Glucommander software. 

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While the software-based insulin 
dosing calculators represent an 
improvement over paper-based 
protocols, they still are not capable 
of achieving a time in range (e.g., 
100 – 140 mg/dL) that exceeds 90%, 
while at the same time avoiding any 
significant time in the hypoglycemic 
range and reducing glucose 
variability. In a poster presentation 
presented at the 2016 American 
Diabetes Association meeting, it was 
noted that when Glucommander was 
used in 340 adult ICU patients with 
sepsis, it produced a time in range (70 – 180 mg/dL) of 72%, and a hypoglycemia (< 70 mg/dL) rate of 
0.51%.22 In a study done on 2,398 medical/surgical ICU patients, Glucostabilizer achieved a time in range 
(80-150 mg/dL) of 80.4% and hypoglycemia (<70 mg/dL) rate of 3.5%. In a study done on burn patients, 
Endotool was noted to achieve a time in range (80 – 110 mg/dL) of 47% and a hypoglycemia (<80 mg/dL) 
rate of 4.5%.23 In a multi-center medical ICU study on 508 patients, the Space GlucoseControl system 
time in range (80-150 mg/dL) was 83% and hypoglycemia (<80 mg/dL) rate was 2.3%. These results for 
time in desired control range and hypoglycemia are summarized here (Figure 2, Figure 3). 
It should be noted that the 
standard of care for achieving tight 
glucose control in ICU patients is 
insulin delivery via the intravenous 
route, and that ICU nurses will 
spend 90-120 minutes per patient 
per day attempting to achieve tight 
glucose control with the current 
methodologies.24 
One of the reasons tight glucose 
control is so difficult to achieve is 
that the blood glucose versus time 
curve is highly nonlinear in nature. 
To achieve tight glucose control, a 
control system capable of handling 
a nonlinear state will need to be employed. Most prior attempts to achieve glucose control utilizing 
Figure 2– Although different ranges were reported, none were able to 
achieve > 90% time in range. 
Figure 3– Patient types treated were: Sepsis (Glucommander), 
medical/surgical ICU (GlucoStabilizer), burn ICU (Endotool), medical ICU 
(Space GlucoseControl). Endotool and Space GlucoseControl hypoglycemia 
rates are for < 80 mg/dL. 

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control theory have employed Proportional, Integral, Derivative (PID) controllers.25 These controllers 
were originally developed for linear systems,26 thus they so far have enjoyed limited success in glucose 
control.22 Newer computerized glucose management systems, such as Endotool,27 utilize Model 
Predictive Control (MPC) theory28 and have enjoyed improved success compared to PID controllers in 
keeping blood glucose in the desired range, and limiting the incidence of hypoglycemia. However, these 
systems still focus solely on the glucose lowering effects of insulin and do not consider the glucose 
elevating effects of glycogenolysis/gluconeogenesis – from the liver. This causes them to have 
unacceptably high rates of hypoglycemia and low time in the desired range,29 thus they are not suitable 
in their current format for creating a closed loop glucose control system for use in the ICU setting. The 
failure of PID and MPC based glucose controllers to achieve safe and effective tight glucose control has 
led to the need to consider alternative control techniques. 
 
2.2 
STUDY RATIONALE – COVID-19 
 
 
The current COVID-19 pandemic is 
caused by a Coronavirus that shares 
at least 80% of its RNA with the 
Coronavirus that caused the 2003 
SARS epidemic. During the 2003 
SARS epidemic it was shown that 
admission plasma glucose levels 
were an independent predictor of 
increased mortality rates (Figure 
4).30 
 
In a recently published article on 
over one-thousand U.S. COVID-19 
patients, it was shown that the 
presence of either diabetes or 
uncontrolled hyperglycemia in non-
diabetic patients increased 
mortality rates by more than 400% 
(Figure 5).31 The glucose metrics, 
mortality rates, and length of stay data for the two groups in this study are seen below (Table 1). 
Figure 4 – Patients were divided into terciles based on admission 
fasting plasma glucose (FPG) levels. Survival is correlated with the 
admission fasting plasma glucose (FPG). Low FPG 3.3-5.78 mmol/l, 
Medium FPG 5.78-7.9 mmol/L, High FPG 7.9-29.1 mmol/L. Yang, 
Diabetic Medicine, 2005. 

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No DM/No UH 
(N=671) 
DM/UH 
(N=451) 
p 
Mean admission glucose mg/dL 
114.5 (±20) 
202.4 (±118) 
<0.001 
Mean hospital glucose mg/dL 
116.6 (±25.9) 
178.5 (±71) 
<0.001 
% time in range > 180 mg/dL 
1.4 
39.1 
<0.001 
% time in range 70-180 mg/dL 
97.8 
59.9 
<0.001 
CV 
22.2 
39.8 
Not reported 
Mortality rate (%) 
6.2 
28.8 
<0.001 
Length of stay (days) 
4.3 
5.7 
<0.001 
Table 1 – Summary of data from study noted in Figure 7. DM – Diabetes Mellitus, No DM – No Diabetes Mellitus, 
No UH – No Uncontrolled Hyperglycemia, UH – Uncontrolled Hyperglycemia. Bode, Journal of Diabetes Science 
and Technology, 2020. 
Figure 5- Mortality rates 
among patients with 
diabetes or uncontrolled 
hyperglycemia (n=184), 
versus patients without 
diabetes or hyperglycemia 
(n=386). Diabetes defined as 
HbA1c >= 6.5%. 
Uncontrolled hyperglycemia 
defined as two glucose 
values >180 mg/dL in a 24-
hour period. The n=53 and 
n=24 represent the number 
of patients who died in each 
group. Bode, Journal of 
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In a recent study of 7,336 COVID-19 patients from China, it was demonstrated in a subgroup analysis of 
500 matched type 2 diabetic patients that the group with well controlled glucose levels had a mortality 
hazard ratio of 0.14 (95% CI of 0.03,0.60) and an acute respiratory distress syndrome (ARDS) hazard 
ratio of 0.47 (95% CI of 0.27, 0.83) compared to the group with poorly controlled blood glucose levels 
(Figure 8). These results occurred despite the two groups having similar pulmonary CT findings at the 
time of admission. The Well Controlled glucose group had a median glucose of 6.4 mmol/L (5.2-7.5) 
versus 10.9 mmol/L (7.6-14.3) in the Poorly Controlled glucose group.  For the overall study, the group 
with diabetes had a mortality rate of 7.8% versus 2.7% for the group without diabetes.32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 8 – Each group consisted of 250 matched type 2 diabetic patients with COVID-19 infection. Zhu, Cell 
Metabolism, 2020. 
 
In a single hospital study of 403 consecutively admitted COVID-19 patients, it was shown that 57% of the 
COVID-19 patients developed hyperglycemia (>= 7.78 mmol/L).33 This study noted that hyperglycemia in 
the first 24 and 48 hours of admission increased the mortality odds ratio by factors of 2.15 and 3.31.  
The presence of hyperglycemia showed statistical significance in predicting both ICU admission and the 
development of ARDS. Overall, 51 (12.7%) of the 403 hospitalized COVID-19 patients died in this study.  
In a Spanish study, which used a nationwide registry from 109 hospitals, it was shown in a study of 
11,312 COVID-19 patients that admission hyperglycemia was predictive of mortality in both diabetic and 
non-diabetic patients (Table 2).34  
 
 
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Hazard Ratio
Well Controlled vs Poorly Controlled Glucose
All Cause Mortality
ARDS

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Admission Glucose Level 
< 140 mg/dL 
(N=8,870) 
140-180 mg/dL 
(N=1,340) 
>180 mg/dL 
(N=1,102) 
Mortality Rate (%) 
15.7 
33 
41.1 
Number of Deaths 
1,394 
442 
453 
Table 2 – For the entire group, 61% of all deaths occurred in the group whose admission glucose levels were less 
than 140 mg/dL. Sanchez, Ann of Medicine, 2021. 
This study is the largest COVID-19 study published to date, and while it points out the importance of 
using the admission glucose level to predict mortality rates in hospitalized COVID-19 patients, it should 
be noted that the majority of deaths occurred in the group of patients whose admission glucose levels 
were less than 140 mg/dL. 
This points out the need to remain vigilant for the development of hyperglycemia after admission, in 
COVID-19 patients whose admission blood glucose levels are less than 140 mg/dL, as the previously 
noted study by Matmani demonstrated that the development of hyperglycemia within the first 24 and 
48 hours of hospitalization  has been associated with mortality (odds ratio 2.15 and 3.31, respectively).33 
The study by Matmani also demonstrated that non-diabetic patients admitted with COVID will often go 
on to develop hyperglycemia (e.g., > 140 mg/dL) after the first week of hospitalization (Figure 6), thus 
vigilance for the 
development of 
hyperglycemia may need to 
be extended throughout the 
entirety of their hospital 
stay. 
 
In a study performed in Italy 
it was shown that the 
presence of hyperglycemia 
(>7.7 mmol/L) on admission 
significantly increases 
mortality rates in COVID-19 
patients.35 
 
 
Figure 6 - This graph demonstrates that non-diabetic COVID-19 patients who develop 
hyperglycemia (e.g., > 140 mg/dL = 7.8 mmol/L), will often do so after their 7th day of 
admission (see yellow line above). The patients were divided into four groups based on 
their diabetes status (DM) and hyperglycemia (HG) status. Blue line represents no diabetes 
(DM-) and no hyperglycemia (HG-); yellow line no diabetes (DM-) but the presence of 
hyperglycemia (HG+); green line presence of diabetes (DM+) but no hyperglycemia (DM-); 
and red line presence of diabetes (DM+) and hyperglycemia (HG+). Matmani, MedRxiv, 
2020. 

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In this same study it was shown that in the 
group of 25 patients with hyperglycemia on 
admission, a non-randomized subgroup who 
electively chose to be treated with 
intravenous insulin versus usual care with 
subcutaneous insulin, that the improved 
glucose control produced by use of an 
intravenous insulin infusion significantly 
decreased mortality rates (Figure 7). The 
patients treated with intravenous insulin 
had a target glucose range of 7.77 – 9.99 
mmol/L. The patients treated with 
subcutaneous insulin received usual glucose 
control per their treating physician. The 
group treated with intravenous insulin were 
on the infusion for a mean of 32.7 ± 4.9 hours 
after entering the target glucose range of 7.77 
– 9.99 mmol/L. After cessation of the 
intravenous insulin, this group of treated 
patients received usual glucose control with 
subcutaneous insulin per their treating 
physician. 
 
One explanation for the improved outcomes in the patients treated with an intravenous insulin infusion 
may be a reduction in their inflammatory state and a reduction in their propensity to form blood clots, 
which are two common and most likely related conditions seen in COVID-19 patients.36-38 
 
Previous animal models of lung injury have confirmed that elevated blood glucose levels exacerbate 
lung inflammation, and that lowering of the blood glucose level with insulin effectively minimizes the 
degree of induced lung inflammation and edema based on wet lung weight, lung inflammatory markers, 
and on pathological specimens.39-41 These results have been confirmed in human studies that 
demonstrated the ability of acute hyperglycemia to induce increased cytokine levels.42 Furthermore, 
increased cytokine levels have been implicated in the development of ARDS in COVID-19 patients.43  
 
Finally, a laboratory study showed that when human peripheral monocytes are infected with CoV-2 
(COVID-19), the viral load of the monocytes after 24 hours of incubation in glucose containing medium 
was logarithmically related to the glucose level of the medium the monocytes were incubated in.44  This 
Figure 7 – Non-randomized initiation of insulin infusion in 
hyperglycemic (> 7.7 mmol/L on admission) COVID-19 patients. The 
No insulin infusion group were treated with subcutaneous insulin. 
Approximately 70% of patients in each group had diabetes. Sardu, 
Diabetes Care, 2020. 
Avg Glucose 138 mg/dL 
Avg Glucose 192 mg/dL 

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same laboratory study noted a similar effect on expression of the pro-inflammatory cytokine IL-1𝛽, 
which has been shown to be an important mediator of the cytokine storm seen in COVID-19 patients.45  
Although the optimal glucose control range for critically ill COVID-19 patients is unknown, a recent 
multi-center study demonstrated that average ICU glucose levels greater than 140 mg/dL increased 
COVID-19 mortality rates by almost 100% (Table 3).46 In this same study, a multivariable Cox regression 
analysis was conducted to assess predictors of ICU mortality. Age older than 60 (HR:3.21 [95% CI 1.78, 
5.78]) and hyperglycemia with mean ICU glucose >140 mg/dL (HR:1.79 [95% CI 1.14, 2.82]) were the 
only two predictors of increased ICU mortality. 
 
 
Average ICU glucose 
< 140 mg/dL 
(n=242) 
Average ICU glucose 
>= 140 mg/dL 
(n=253) 
p Value 
Mortality rate (%) 
16.6 
31.4 
< 0.001 
Mechanical 
Ventilation (%) 
37.2 
50.0 
<0.004 
ICU LOS 
3.5 
5.5 
< 0.001 
Table 3 – Diabetes present in 38.5% of entire cohort. For the entire cohort, the mean value of blood glucose at 
the time of admission was 186.6 mg/dL (SD+130.8). Saand, J Diabetes, 2020. 
To date, most attempts to control the glucose level of COVID-19 patients have met with only marginal 
success, as their glucose levels are highly variable and nonlinear, making them difficult to control using 
the current open loop techniques. In a retrospective analysis of 562 ICU admissions at a single medical 
center, the patients with COVID-19 had statistically significant worse glucose control, versus non-COVID-
19 ICU patients, despite attempts to control their glucose levels with the FDA approved GlucoStabilizer 
insulin dosing software program (Table 4).47 

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Table 4 – Table is from retrospective data analysis study comparing glucose control in ICU patients both with 
(n=93) and without (n=469) COVID-19. The ICU patients with COVID-19 had statistically significant lower percent 
time in range 70-150 mg/dL, compared to non-COVID-19 ICU patients. Kapoor, Journal of Clinical Medicine, 
2020. 
A multi-center retrospective analysis of 1,122 hospitalized COVID-19 patients demonstrated the 
importance of attempting to achieve good glucose control in this patient population. The group of 
patients with either diabetes or uncontrolled hyperglycemia had statistically significant worse glucose 
control (Table 5) and higher mortality rates. Inadequate glucose control occurred in the Diabetic and 
Uncontrolled Hyperglycemia group despite use of the FDA approved Glucommander insulin dosing 
software program.31 

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Table 5 – Glucose data from retrospective analysis of 1,122 patients with COVID-19. The group of patients with 
either Diabetes or Uncontrolled Hyperglycemia (two glucose values > 180 mg/dL in any 24-hour period) had 
statistically significant worse glucose control despite use of an FDA approved insulin dosing software program 
(Glucommander). Bode, Journal of Diabetes Science and Technology, 2020. 
In these open loop systems, the nurse manually checks the patient’s blood glucose level every 1-4 hours, 
enters the measured level into the insulin dosing software, and then manually enters the results of the 
insulin dosing software into the insulin infusion pump as depicted below (Figure 11). These systems do 
not utilize a dextrose (D-glucose) component for purposes of control, which makes them prone to 
periods of hypoglycemia. 

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Figure 11 – Depiction of the current process of glucose control in the ICU setting using an open loop method. 
With use of the current open loop glucose control technique ICU patients still experience high rates of 
hypoglycemia, hyperglycemia, low time in the desired glucose range, and large glucose variability.48  
In the U.S., as of June, 2022, there have been more than 88 million cases and over 1 million deaths due 
to COVID-19. Given that the new BA.5 COVID variant is driving a new wave of infections in the U.S., with 
currently more than 30,000 patients hospitalized, and the potential for tight glucose control to lower 
mortality rates in hyperglycemic COVID-19 patients both with and without diabetes, development of a 
safe and effective closed loop glucose control system intended for use in COVID-19 patients is urgently 
needed. 
 
2.3 
STUDY RATIONALE – FUSION AI BASED ARTIFICIAL PANCREAS SYSTEM 
 
The novel glucose control system to be tested in this study is an expert based rule system or Knowledge 
Based System.49,50 This system should be considered a form of artificial intelligence, whose main goal is 
to completely model the natural glucose homeostatic system. The essential elements of the native 

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glucoregulatory system, which were used to create the AI based system under study, have been 
reviewed51 by Dr. Leon DeJournett, who is the developer of the novel AI based glucose controller to be 
tested in this study. If successful, this controller could be utilized in a closed loop glucose control system 
(artificial pancreas) for treatment of dysglycemia in ICU patients. 
 
Through an intensive review of how the native glucose control system functions (e.g., pancreas & liver), 
a knowledge based multiple input multiple output (MIMO) glucose control system has been 
developed.52 The algorithms of this system use the four input variables of absolute glucose, glucose 
rate of change, weight based intravenous insulin dose and weight based intravenous dextrose dose. 
Based on the values of these four input variables and the desired glucose control range, the two output 
variables of continuous intravenous insulin and continuous intravenous dextrose are adjusted. The 
results from the primary knowledge-based controller are also run through additional knowledge based 
controllers. These additional controllers monitor for outlying situations such as rapid falls or rise of 
blood glucose levels. These controllers will modify the two output variables from the primary controller 
if the clinical situation warrants such a change. Through utilization of the proper control techniques and 
frequent adjustment of the insulin and/or dextrose infusion rates (every 5 or 10 minutes), tight control 
of glucose will be achieved. In addition, episodes of clinically significant hypoglycemia will be avoided, 
and glucose variability will be minimized. 
 
The20lucosn for continuing clinical studies at this time is that thorough preclinical studies and a small 
first in human study of this controller have already been completed. The preclinical studies included the 
largest simulation study of a glucose controller published to date,53 and a comparative simulation study 
that showed clear superiority of the AI  based controller over Glucommander and several other ICU 
based glucose controllers.54 In addition, non-Good Laboratory Practice (GLP) animal testing using a 
swine model of stress induced hyperglycemia55 showed that the controller was able to achieve tight 
glucose control with no significant hypoglycemia.56 In a second larger animal study the artificial pancreas 
(AP) system demonstrated its ability to avoid severe hypoglycemia and minimize moderate 
hypoglycemia despite having to deal with an unannounced intravenous insulin injection.57 Finally, in a 
two subject first in human study on type 2 diabetic subjects in a CRC setting, the controller was able to 
maintain a high percent time in range 70-180 mg/dL while avoiding any hypoglycemia (< 70 mg/dL). 
3 
FUSION SYSTEM TESTING BACKGROUND  
 
The testing to date of the AI based glucose controller under study includes two simulation studies, two 
animal studies, and a first in human study on two subjects.  
 
3.1 
SIMULATION STUDIES 

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Both simulation studies used a mathematical model of the ICU patients glucose-insulin system that has 
been clinically validated.58 The two AI controller outputs of insulin and dextrose were incorporated into 
the model, such that the controller’s outputs could attempt to bring control to the modelled system as 
the system experienced time variant changes of its internal parameters, or was perturbed through time 
variant exogenous infusions of intravenous dextrose. 
 
In the first simulation study, ICU “patients” were created through use of time variant changes in their 
insulin sensitivity, volume of distribution and half-life. In addition, variable rates of dextrose infusions 
were used to simulate potential clinical scenarios. The glucose sensor data also had variable degrees of 
accuracy ranging from 5-15%, and bias ranging from ± 0-10 mg/dL. Finally, three different starting 
glucose values and seven different control ranges were used. This led to 126,000 unique simulations, 
each done over a period of five days. This study produced 15 million hours of simulation time and 107 
million glucose values for analysis.53 As can be seen below (Figure 12), when the control range was set to 
100-140 mg/dL and the sensor error was 10%, the time in range of 70-140 mg/dL was 95%, which is 
consistent with the “time in range hi” group noted above (Figure 1).  
 
Figure 12 – SE = sensor error. DeJournett, Journal of Diabetes Science and Technology, 2016.  
The controller also did an exceptional job of avoiding any significant hypoglycemic events with an overall 
rate of hypoglycemia (< 70 mg/dL) of 0.09% with a sensor error of 10% as noted below (Figure 13). By 
adjusting the desired control range, clinicians can easily adjust the hypoglycemia rate towards zero, as 
was seen in the 100-140 mg/dL control range group. For the entire study there were no glucose values 
less than 45 mg/dL. 

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Figure 13 –Hypoglycemia defined as < 70 mg/dL.  SE = sensor error. DeJournett, Journal of Diabetes Science and 
Technology, 2016.  
As seen below (Figure 14), the controller was just as adept at minimizing glucose variability as noted by 
an average CV of 11.1% when the sensor error was 10%. The ability to minimize glucose variability to 
this degree should have a significant impact on ICU mortality rates as evidenced by the clinical results 
shown in  Figure 2 above. 
 
Figure 14 – SE = sensor error. DeJournett, Journal of Diabetes Science and Technology, 2016. 

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In a second simulation study the same mathematical model and time variant changes were used to 
create 80 virtual “patients,” and a novel random walk sensor error method was used that guaranteed an 
overall sensor error of 10%. This study utilized five, time variant exogenous dextrose infusions to 
perturb the model and produced a total of 400 five-day simulations per controller. The AI controller to 
be tested in the current study,52 which is being commercialized by Ideal Medical Technologies (IMT), was 
compared to the Yale protocol (YALE),59 Glucommander (GLUC),60 Wintergerst et al PID controller 
(PID),61 GRIP,62 and the NICE-SUGAR (NICE) study protocol63 in a comparative simulation study.54 Seen 
below (Table 6) is a summary of the results from this study. 
 
Severe 
Hypoglycemia 
Incidence (%) 
Mild 
Hypoglycemia 
(40-69 
mg/dL) 
Control 
range 
(100-140 
mg/dL)* 
Normoglycemia      
(70-140 mg/dL) 
CV 
(%) 
IMT 
0.00 
0.00 
(0.00-0.00) 
92.6 
(89.8-96.2) 
96.7 
(94.6-97.9) 
9.9 
(8.4-11.5) 
Yale 
0.25 
0.81 
(0.00-1.61) 
64.1 
(54.3-72.7) 
71.5 
(63.8-77.7) 
18.3 
(15.1-21.2) 
Glucommander 
4.50 
1.63 
(0.82-3.23) 
67.6 
(57.6-76.4) 
78.0 
(70.7-84.1) 
18.2 
(14.7-21.5) 
PID 
4.50 
0.80 
(0.00-2.43) 
63.8 
(52.5-71.2) 
75.7 
(67.8-81.4) 
19.1 
(15.9-22.3) 
GRIP 
6.25 
1.66 
(0.00-3.01) 
65.1 
(51.3-75.9) 
76.1 
(65.6-83.8) 
19.0 
(14.7-22.0) 
NICE 
2.50 
3.97 
(0.00-6.40) 
42.8* 
(33.6-52.6) 
89.0 
(80.9-95.1) 
20.6 
(17.0-24.2) 
Table 6 – Values are median (25-75) percent of all glucose values in given range and CV., Severe hypoglycemia is 
percent of simulations. *NICE results are for time in range 81-108mg/dL. DeJournett, Journal of Diabetes Science 
and Technology, 2017. 
As can be seen from Table 6 the IMT AI based controller showed clear superiority in this simulation 
study. It is important to note that the IMT controller achieved a time in range 70-140 mg/dL greater 
than 95%, a CV less than 15% and a hypoglycemia rate of 0. Per the previous noted clinical studies, all 
these results will correlate with improved survival of ICU patients, if they carry over to the real world 
setting. 
3.2 
ANIMAL STUDIES 
Although the FDA does accept simulation testing as a sole valid method to accomplish pre-clinical 
testing of glucose controllers,64-66 it was decided to perform two animal tests to assess the performance 
of IMT’s complete closed loop glucose control system in an in vivo setting. In the first small pilot animal 

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study a fully functional closed loop glucose control system, which is essentially the same system to be 
tested in the current proposed study, was utilized to complete a twelve hour closed loop glucose control 
study in a swine model of stress induced hyperglycemia.56 For this study the stressors to the 
anesthetized swine included endotoxin infusion to mimic sepsis,67 lung aspiration of hydrochloric acid to 
mimic acute respiratory distress syndrome,68 and a high dose of Solumedrol to mimic the stress 
hormone response seen in critically ill patients.69 The animals also received dextrose boluses to elevate 
their24lucosee Levels at the start of the experiment, and high rates of dextrose infusions (5-10 
mg/kg/min) to make glucose control difficult to achieve. In one scenario, the animals were under type 1 
diabetes conditions through infusion of Octreotide,70 with C-peptide levels confirming lack of native 
insulin production. 
As noted below (Figure 15), the fully functional artificial pancreas (AP) system was able to maintain the 
blood glucose level in a normal swine range of 40-80 mg/dL in the animals that were rendered type I 
diabetics via an Octreotide infusion56 and simultaneously were in a state of stress induced 
hyperglycemia (SIH). While it is not surprising that the control animal that did not receive any insulin 
died, the important point is that the treated animal was able to achieve effective tight glucose control 
which produced a lower stress state as noted by a normal lactic acid level. 
 
Figure 15 – Dextrose bolus of 0.25 grams/Kg given at time 0, and dextrose infusion of 5 mg/kg/min from time 0-
12 hours. AP = artificial pancreas. Octreotide infusion used to create a type I diabetic state in both animals. 
DeJournett, Diabetes, 2016. 

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As can be seen below (Figure 16), IMT’s AI based glucose control system was just as effective in 
augmenting the animal’s intact endogenous insulin production. Although the control animal was unable 
to bring its glucose level into the normal range throughout the course of the twelve hour experiment, 
IMT’s AI based controller was able to bring the glucose level into the desired range within 4 hours, and 
maintain it within or close to the desired range throughout the rest of the experiment. It should also be 
noted that the untreated animal had elevated lactic acid levels compared to the animal that achieved 
effective tight glucose control with IMT’s AP system. 
 
 
Figure 16 – Dextrose bolus of 0.25 grams/Kg given and time 0, and dextrose infusion of 10 mg/kg/min from time 
0-12 hours. AP = artificial pancreas. Both animals had their endogenous insulin production left intact. 
DeJournett, Diabetes, 2016. 
In the second animal study the safety and performance of the FUSION system was assessed using a 
swine model of unannounced hypo- and hyperglycemia challenges. For this test the FUSION system was 
composed of the EIRUS (Getinge AB) CGM, which is a CE marked CGM designed for use in the ICU 
setting, the FUSION systems artificial intelligence-based (AI-based) glucose control software, and two 
syringe pumps. The study protocol is seen below (Figure 17). 
 
 

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Figure 17 – Protocol format. The ICU physician attempted to control to the range of 4.4 – 9 mmol/L, while the 
FUSION artificial pancreas system attempted to control to the tighter range of 4.4 – 6.6 mmol/L. The protocol 
was designed to induce hypoglycemia with a bolus of 3 units of insulin at time 20 minutes, and unavoidable 
hyperglycemia with a glucose infusion of 17 mg/kg/min from time 110 – 140 minutes as a means to test the 
artificial pancreas systems ability to avoid severe hypoglycemia after an unannounced insulin overdose and 
delayed moderate hypoglycemia secondary to treatment of the induced hyperglycemic state. DeJournett, 
Journal of Clinical Monitoring and Computing, 2020. 
The results from the fully autonomous FUSION system were compared to an ICU physician who had 
access to every 30-minute arterial glucose values and who used Dextrose 20% and NovoRapid to treat 
hypoglycemia and hyperglycemia. Both the control and treated animals had EIRUS CGM’s in place, and 
the glucose values from these CGM’s were used for statistical comparison. Noted below (Figure 18) are 
the median (25-75) glucose values from both groups. As can be seen from this graph the FUSION system, 
acting in a fully autonomous mode, was able to avoid both severe hypoglycemia after the insulin bolus 
and rebound moderate hypoglycemia secondary to treatment of the induced hyperglycemic state. The 
ICU physician, despite having access to every 30-minute arterial blood glucose values, was unable to 
avoid severe and moderate hypoglycemia. 
 

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Figure 18 – Median (25-75) glucose values from both groups. The FUSION artificial pancreas system had an 
improved safety profile despite controlling to the tighter range of 4.4 – 6.6 mmol/L. Treated = FUSION system, 
Control = ICU physician. 
Noted below (Table 7) is the performance of the FUSION system in the hypoglycemic range (<3.5 
mmol/L). It should be noted that none of the “Treated” animals experienced severe hypoglycemia and 
that all other measures related to hypoglycemia were significantly improved by the fully autonomous 
artificial pancreas system, despite the fact it was controlling to a tighter range which should have led to 
a higher rate of hypoglycemia as noted above (Figure 13). This study provides proof that an autonomous 
glucose control system that adjusts the rates of insulin and/or glucose infusions every 5-10 minutes 
should be able to outperform a bedside ICU physician, even when the physician has access to every 30-
minute arterial blood glucose values. 
 

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Table 7 – Hypoglycemia defined to be glucose less than 3.5mmol/L. All continuous data are reported as median 
(25-75).  All glucose data, and not just the data from the induced hypoglycemia episode from time 20min to time 
110min, were considered in these statistics. Statistical significance (p<0.05) indicated by *. A “hypoglycemic 
event” is defined as a sequence of hypoglycemic blood glucose values that is contiguous in time, terminated on 
both ends by a non-hypoglycemic value. † If an animal experienced any values less than 2.22mmol/L, it was 
counted as having experienced severe hypoglycemia – comparison made using the Fisher’s exact test. ††Area 
under the curve (AUC); area accumulated while glucose was less than this threshold. 
 
3.3 
HUMAN STUDY 
The first in human study on two subjects was performed in the clinical research center (CRC) of Emory 
University under the direction of Dr. Francisco Pasquel. This study was performed on subjects with type 
2 diabetes who had no underlying end organ disease, used insulin at home to treat their diabetes, and 
whose HbA1c was in the range of 7-10%. The FUSION system attempted to control their glucose level to 
a range of 100-140 mg/dL for a period of 24 hours. The subjects at three standardized meals during this 
24 hour period, with the first meal consumed being lunch. The subjects were also allowed to eat snacks 
from 2100 to 0600 hours. For safety reasons, the subjects had an independent reference glucose 
checked every 10-60 minutes using either a YSI glucose analyzer or the Nova StatStrip Hospital Glucose 
Hypoglycemia Statistics 
Treated 
(N = 8) 
Control 
(N = 6) 
p value 
Number of animals with severe hypoglycemia† 
0 
5 
<0.003*  
Minimum glucose (mmol/L) 
2.83 (2.75-2.96) 
1.69 (1.68-1.89) 
0.033* 
Total time in hypoglycemia for all events (minutes) 
12.5 (10.5-16.0) 
41.0 (33.5-61.3) 
<0.004* 
Mean of all hypoglycemic glucose values (mmol/L) 
3.20 (3.07-3.24) 
2.80 (2.43-2.87) 
<0.033* 
Longest singular hypoglycemic event (minutes) 
9.5 (8.8-11.3) 
24.5 (20.8-29.8) 
<0.012* 
AUC†† 3.5mmol/L (mmol/L * minutes) 
4.8 (3.1-5.2) 
28.9 (21.1-54.2) 
<0.004* 
AUC†† 2.2mmol/L (mmol/L * minutes) 
0.0 (0.0-0.0) 
3.6 (1.3-5.2) 
<0.004* 

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Meter System point of care glucose meter. The two subject’s demographic data is noted below (Table 
8). 
 
Subject 1 
Subject 2 
Age, years 
37 
40 
Sex, M/F 
F 
F 
Weight, Kg  
149.7 
114.6 
BMI, (kg/m2) 
47.7 
39.6 
Race 
African American 
Caucasian 
Ethnicity  
Non-Hispanic 
Hispanic 
Diabetes duration, years 
4 
20 
Home Diabetes Treatment 
 
 
Total daily insulin, U/day 
155 
54 
Total daily insulin, U/kg 
1.04 
0.47 
Total Basal Insulin, U/day  
80 
28 
Prandial Insulin, U/day 
75 
28 
OAD, y/n 
Y 
Y 
Baseline Labs 
 
 
Glucose, mg/dL 
162 
197 
HbA1c, % 
8.2 
8.2 
Cr, mg/dL 
0.88 
0.55 
GFR, mL/min/1.72m2 
88 
118 
Hb, g/dL  
13.8 
12.3 
ALT, unit/L 
13 
13 
AST, unit/L 
14 
13 
Na, nmol/L 
142 
138 
K, nmol/L 
3.9 
4.0 
Table 8 – Demographic data for the two subjects from the first in human trial of the FUSION system. 
The glucose metrics and weight based infusion rate data from the two subjects are seen below (Table 9). 
 
Subject 1 
Subject 2 
Average (SD) 
% TIR < 70 mg/dL 
0 
0 
0 
% TIR 70-140 mg/dL 
88.7 
76.4 
82.6 (6.2) 
% TIR 100-140 mg/dL 
78.1 
60.6 
69.4 (8.8) 
% TIR 70-180 mg/dL 
100 
94.5 
97.3 (2.7) 
% TIR > 180 mg/dL 
0 
5.5 
2.7 (2.7) 
Coefficient of Variation (%) 
13 
26 
19.7 (10) 
Mean Glucose (mg/dL) 
121 
125 
123 (2) 
Average insulin infusion rate 
(U/Kg/hr) 
0.044 
0.038 
0.041 (0.005) 
Average glucose infusion rate 
(mg/Kg/min) 
0.39 
0.62 
0.50 (0.16) 
Table 9 – Glucose metrics and infusion rate data from first in human study of FUSION system. SD – Standard 
deviation. 

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The 24 hour glucose versus time graphs from the two studies can be seen below (Figure 19). 
Figure 19 – Glucose vs time plots with overlayed weight based insulin and dextrose infusion rates for subjects 1 
and 2. M – Meal or snack. CA – Compression artifact secondary to subject lying directly on Dexcom G6 CGM 
sensor. Gaps in infusion rate data (e.g., Insulin infusion Subject 1 at times 400 & 450 minutes) represent FUSION 
system pauses for syringe changes or CGM calibration. 
M 
M 
M 
M 
M 
M 
M 
M 
CA 
CA 

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The medical device to be tested in this proposed CRC study is a fully functional closed loop glucose 
control system and is pictured below (Figure 20). 
 
 
Figure 20 – Pictured is the prototype of the FUSION device. The FUSION systems AI based glucose control 
software (Controller) is run on an all in one Medical Computer (Teguar) that is mounted on the powered Medical 
Cart (Enovate). This picture shows KDS Legato 950 OEM syringe pumps, but the study will be done with KDS 
Legato 100 syringe pumps. 
A screen shot of the glucose control software is shown below (Figure 21). 
Dexcom G6 Receivers 
KDS Legato 100 syringe pumps 
All in one Medical Computer 
running the FUSION systems AI 
based glucose control software 
Powered Medical Cart with keyboard & 
mouse 

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                  A                 B                                 C         D 
     
 
 
 
 
 
 
 
 
 
         E 
                             F                G                                   H                                                   I 
                               J 
 
 
 
 
 
 
        K 
                                     L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        M 
       N 
 
 
 
 
 
 
 
        O    P      Q 
                                       R 
 S                 T                   U              V 
 
 
 
 
       W 
 
 
 
 
 
 
 
 
 
        X  
 
 
 
         
Figure 21 – Screenshot of active glucose control software. 
 
 
          
A 
Patients weight in kg. 
B 
Unique identification number of study patient. 
C 
Glucose control range used for study in mg/dL. 
D 
Flashing green circle indicating software is functioning normally. 
E 
Note entry button – allows for entry of notes related to use of FUSION system. 
F 
Glucose versus time curve (blue line). 
G 
Dextrose infusion rate curve (green line). See right Y-axis for rate. 
H 
Insulin infusion rate curve (red line). See right Y-axis for rate. 
I 
Coefficient of variation statistic. 
J 
Upper limit of glucose control range (dashed light blue line). 
K 
Percent time in hyperglycemic range (> 140 mg/dL). 
L 
Lower limit of glucose control range (dashed light blue line). 
M 
Percent time in glucose control range (100-140 mg/dL). 
N 
Y axis (Glucose level in mg/dL). 
O 
Dextrose infusion rate (mL/hr). 
P 
Insulin infusion rate (mL/hr). 
Q 
Percent time in hypoglycemic range (< 70 mg/dL). 
R 
X-axis (Time in minutes). 
S 
Insulin infusion rate (U/kg/hr). 
T 
Dextrose infusion rate (mg/kg/min). 
U 
Total time elapsed since start of study (hours:minutes:seconds). 
V 
Next glucose value to be used by controller for purposes of glucose control. 
W 
Pause button to temporarily stop FUSION system. 
X 
Stop button to permanently stop FUSION system. 

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Similar set ups have been previously used in the ICU setting to achieve tight glucose control. In a study 
published in 2013,71 the set up pictured below (Figure 22) was utilized, with the overall form factor 
being very similar to the FUSION system seen above (Figure 20). 
  
Figure 22 – Picture notes set up for fully functional closed loop glucose control system. System consists of a CGM 
placed in the abdominal position, a receiver for the CGM signal (Navigator Companion), a laptop housing the 
glucose control software, and two syringe pumps controlled by the MPC based glucose control software in the 
laptop. Leelarathna, Critical Care, 2013. 
 
For this 48-hour study on 24 ICU patients the control range was 6-8 mmol/L. The closed loop patients 
had Reference Glucose Values measured on a blood gas machine every 30 minutes to 6 hours. The MPC 
based closed loop controller used in this study automatically adjusted the flows of insulin and/or 20% 
dextrose every 5 minutes based on the input from the CGM, the desired control range, and the MPC 

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controller. The control group patients were managed with a local insulin protocol and controlled to the 
same range. The results from this study are noted below (Table 10). 
 
 
Local Protocol 
(N=12) 
Automated closed-loop 
(N=12) 
p 
Primary end point 
 
 
 
Time glucose in target (%) (6.0-8.0 
mM) 
18.5 (0.1-39.9) 
54.3 (44.4-72.8) 
0.001 
Secondary end points 
 
 
 
Starting glucose (mM) 
10.8 (9.9-12.0) 
10.0 (8.9-11.1) 
0.21 
Mean glucose (mM) 
9.1 (8.3-13.0) 
7.9 (7.4-8.2) 
0.001 
Standard deviation of glucose (mM) 
1.9 (0.8) 
1.3 (0.5) 
0.089 
Time spent at glucose levels (%) 
 
 
 
   4.0-10.0 mM 
73.2 (21.2-89.4) 
93.3 (86.5-100.0) 
0.002 
   5.6-10.0 mM 
73.2 (21.2-82.4) 
92.2 (83.4-99.2) 
0.001 
   >8.0 mM 
78.4 (57.6-99.9) 
39.0 (23.5-51.4) 
0.001 
   >10.0 mM 
26.8 (10.5-78.8) 
6.7 (0-13.5) 
0.002 
   <6.0 mM 
0 (0-3.0) 
4.6 (3.1-8.3) 
0.028 
   <5.6 mM 
0 (0-0) 
0.7 (0-2.7) 
0.128 
   <4.0 mM 
0 (0-0) 
0 (0-0) 
NA 
Hypoglycemia 
 
 
 
   Episodes <4.0 mM 
None 
None 
 
   Hypoglycemia treatments 
None 
None 
 
Hyperglycemia 
 
 
 
   Number of subjects ≥ 15 mM 
5 (42%) 
1 (8%) 
 
   Number of subjects ≥ 17 mM 
4 (33.3%) 
1 (8%) 
 
   Episodes ≥ 15 mM 
11 
1 
 
   Episodes ≥ 17 mM 
13 
1 
 
Insulin infusion-data 
 
 
 
   Total units for 24 hours 
40.9 (34.9-101.4) 
57.4 (40.0-112.3) 
0.478 
   Hourly infusion rate 
1.7 (1.5-4.2) 
2.4 (1.7-4.7) 
0.478 
Total dextrose infusion for 48 hours 
(g) 
0.21 (0.0-5.2) 
NA 
NA 
Data shown are mean (SD) or median (interquartile range). 
Table 10 – Data from study utilizing closed loop system shown above (Figure 22). Leelarathna, Critical Care, 
2013. 
  
Although the closed loop system in this study improved upon the results from the local protocol, it was 
only able to achieve a time in range 6-8 mmol/L of 54%, a time in range 3.9-8 mmol/L of 60%, and a CV 
of 16.5%. However, it did avoid any significant hypoglycemia. 
 

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Effective tight glucose control can decrease ICU mortality rates as has been previously reported. In 
addition, significant improvement in morbidity is expected, as demonstrated by the only large 
prospective tight glucose control study ever performed that achieved a high time in range while at the 
same time having no hypoglycemia. In this Japanese study of 447 pancreatic surgical patients,72 the tight 
glucose control group (80-110 mg/dL) had an 86% time in range, while the intermediate control group 
(140-180 mg/dL) had a 97% time in range, with neither group experiencing any hypoglycemia. The tight 
glucose control group had a 58% reduction in the surgical site infection rate as can be seen below 
(Figure 23). 
 
 
Figure 23 – Okabayashi, Diabetes Care, 2014. 
 
A large study done at the John Hopkins Health System estimated that surgical site infections (SSI) cost 
their system around $21,000 per infection, or around $3.3 million annually.73 There are around 150,000 
SSI’s per year in the U.S., thus tight glucose control in these patients has the potential to save around 
$1.8 billion per year.74  
 
This same Japanese closed loop glucose control study also demonstrated a 21% reduction in the length 
of stay in the more tightly controlled group, as noted below (Figure 24). 
 

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Figure 24 – Okabayashi, Diabetes Care, 2014. 
Any intervention that shortens hospital length of stay will have a positive impact on reducing overall 
hospital cost of care, as the latter is directly correlated with length of stay. 
 
To emphasize the size of the problem, in the U.S there are 80,000 ICU beds with 6 million annual 
admissions,2 with the European Union experiencing similar numbers.75 The U.S. spends 150 billion 
dollars caring for these ICU patients.76 Given an average ICU mortality rate of 10%, an effective glucose 
control system that lowers ICU mortality rates by at least 20%  would be expected to save 120,000 lives 
per year in the U.S. In addition, a safe and effective artificial pancreas system that reduces net cost of 
care by at least $1,000 per patient, if used on 50% of ICU patients, would be expected to reduce overall 
U.S. healthcare costs by 3 billion dollars annually. If the European Union were included, these numbers 
would be roughly doubled. 
 
 
4 
RISK/BENEFIT ASSESSMENT   
 
4.1 
KNOWN POTENTIAL RISKS 
 
The main risk associated with tight glucose control studies is hypoglycemia, with hypoglycemia being 
defined as any glucose value less than 70 mg/dL. The rate of hypoglycemia has traditionally been close 
0
5
10
15
20
25
Days
Hospital Length of Stay
80 - 110 mg/dL                                 140 - 180 mg/dL

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to 20% in studies aiming at lower glycemic targets.77,78 In addition, hypoglycemia in tight glucose control 
studies has been associated with increasing mortality rates,14,18 although a causal relationship has not 
been established. The immediate risk of a hypoglycemic event, especially a clinically important one with 
glucose values less than 54 mg/dL, is impaired brain function resulting in a temporary coma, or a 
hypoglycemia induced seizure.79,80 However, there does not appear to be any long term cognitive 
impairment in adults who have experienced hypoglycemic events.81,82 An additional potential risk of 
tight glucose control is the development of hypokalemia, which can lead to a prolonged Qt interval and 
potentially fatal  dysrhythmias. However, this issue has been reviewed and it was found that there was 
no association found between tight glucose control and development of prolonged Qt syndrome.83,84 
 
Hypoglycemia is a risk for any tight glucose control study, however the AI based FUSION glucose control 
system under study was particularly effective at avoiding hypoglycemic events in the simulation and 
animal studies. When the control range was set to 100-140 mg/dL in the simulation studies, no glucose 
values less than 70 mg/dL were recorded in either study. In the two subject first in human study the 
percent time in range less than 70 mg/dL was zero. 
 
The risks of severe hypoglycemia (< 54 mg/dL); moderate hypoglycemia (54 – 69 mg/dL) with associated 
hypoglycemia symptoms of anxiety, irritability, sweating, hunger, shakiness, fatigue, pale skin, lethargy, 
seizures; and symptoms of hypoglycemia at any level due to falling glucose levels (e.g., neuroglycopenia) 
will be mitigated by the following means: 
1. Monitoring of the subject’s glucose level with two Dexcom G6 CGM’s. 
2. Sharing of the Dexcom G6 CGM’s values with study personnel via the Dexcom Follow App on 
two smartphones. 
3. Setting the Dexcom CGM’s to alarm for CGM glucose values less than 85 mg/dL. 
4. Measurement of Reference Glucose Value for any CGM glucose value less than 85 mg/dL. 
5. Measurement of Reference Glucose Values at a minimum frequency of every 1 hour. 
6. Measurement of Reference Glucose Values every 10 minutes if either CGM has a glucose value 
less than 70 mg/dL. 
7. Measurement of Reference Glucose Values every 10 minutes if the most recent Reference 
Glucose Value was less than 70 mg/dL. 
8. Measurement of a Reference Glucose Value at any time if the subject displays any of the above 
noted signs of hypoglycemia. 
9. Terminating the study on subject if the subject has a Reference Glucose Value less than 54 
mg/dL. 
10. Terminating the entire study if two subjects have a Reference Glucose Value less than 54 mg/dL. 
 
For purposes of this document, the term Reference Glucose Value refers to the following: 

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1. A whole blood glucose value in mg/dL measured at the subject’s bedside using the FDA 
approved Nova StatStrip Hospital Glucose Meter System. The whole blood sample should be 
immediately analyzed after it is taken from the subject. 
2. The whole blood sample should be taken from the following two sources, which are listed in 
their order of preference: 
a. Venous blood sample from a retrograde hand vein intravenous catheter using the 
standard blood draw method of Emory University’s CRC. 
b. Capillary blood sample from a fingerstick using the standard fingerstick method of 
Emory University’s CRC. 
 
If the subject experiences severe hypoglycemia as measured by a Reference Glucose Value, moderate 
hypoglycemia as measured by a Reference Glucose Value with hypoglycemia symptoms, or  
neuroglycopenia, they will receive the following treatments to minimize their risks: 
 
1. The subjects will be given free access to snacks and glucose containing juices of sufficient 
quantity to raise their Reference Glucose Value so that it is greater than 70 mg/dL and so that 
they are no longer experiencing any symptoms of hypoglycemia. 
2. The subjects will be given a rescue dose of 15 mL of 50% dextrose in any of the following 
scenarios: 
a. For a Reference Glucose Value less than 54 mg/dL. 
b. For a Reference Glucose Value of 54-69 mg/dL with accompanying symptoms of 
hypoglycemia – anxiety, irritability, sweating, hunger, shakiness, fatigue, pale skin, 
lethargy, seizures. 
c. For any Reference Glucose Value when the subject is experiencing signs of hypoglycemia 
caused by a rapid fall in the subject’s blood glucose level (e.g., neuroglycopenia) and the 
ingestion of snacks or glucose containing juices do not relieve these symptoms within 10 
minutes from the time the snacks/juice is ingested. 
3. If intravenous access is no longer available and the subject has a Reference Glucose Value less 
than 70 mg/dL, or is exhibiting signs of neuroglycopenia, the subject will be given Glucagon 1 mg 
intramuscularly every 15 minutes as needed until their Reference Glucose Value is greater than 
70 mg/dL on two consecutive checks that are separated in time by at least 30 minutes, and 
when their hypoglycemia symptoms have completely resolved. 
 
The other potential risks of participating in this study include severe hyperglycemia, diabetic 
ketoacidosis, hyperosmolar hyperglycemic syndrome, excessive blood removal (lab draws), and fluid 
overload. 

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Given the FUSION systems results in its first in human testing, the current studies proposed control 
range of 100-140 mg/dL, and the above monitoring and risk mitigation strategies, no alternative 
procedures are warranted at this time. 
 
4.2 
KNOWN POTENTIAL BENEFITS  
 
The immediate benefits for participants with diabetes in a brief (31 hour) tight glucose control study in a 
CRC setting are limited. However, development of a closed loop glucose control system designed for use 
in the inpatient setting may have long term benefits for this patient population, as preliminary studies 
have demonstrated improved outcomes through use of automated closed loop glucose control in this 
group in the non-ICU inpatient setting.85,86  
 
With regards to benefits to ICU patients, as has been previously noted, effective tight glucose control 
can lead to decreased morbidity rates, whether it be decreased wound infection rates in post-operative 
patients,72 or decreased renal failure and blood transfusions rates.6 In addition, mortality rates will be 
lower if the subject is able to maintain a high time in the control range,16 while at the same time 
avoiding any hypoglycemia events.14 Finally, safe and effective tight glucose control has the potential to 
lower critical illness related mortality including COVID-19 related mortality .35 
 
Long term potential benefits for the ICU patient population mainly relate to a shorter overall recovery 
period based on decreased complication rates and the potential for a shorter ICU length of stay to 
decrease mortality rates after hospital discharge.87 
 
4.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
 
4.3.1 FAILURE OF DEXCOM G6 CONTINUOUS GLUCOSE MONITOR(S) 
The risk of complete failure of the continuous glucose monitoring system will be mitigated through use 
of two Dexcom G6 CGM systems, which will provide redundancy to this critical component of the 
FUSION artificial pancreas system. In addition, replacement of the Dexcom CGM system – sensor, 
transmitter, or receiver – will be allowed if any of these three components of an individual CGM system 
experiences a failure. To clarify, the FUSION system uses a simple average of the two Dexcom G6 CGM 
values to decide what steps to take to bring the subject’s blood glucose value into the desired control 
range. In order to be averaged, these two Dexcom G6 CGM values must be time stamped within 5 
minutes of each other. The FUSION system will operate for up to four hours with glucose readings from 
only one Dexcom G6 CGM system, and for up to 20 minutes with no values from either Dexcom G6 CGM 

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system. The FUSION system will automatically shut down after four hours if it has only one Dexcom G6 
CGM system available for use. The FUSION system will automatically shut down if it has no Dexcom G6 
CGM systems available for use for a period of time exceeding 20 minutes. 
The Dexcom G6 CGM Sensor/Transmitter pair communicate via Bluetooth, to the Dexcom G6 Receiver. 
IMT has not altered in any way, how the Dexcom G6 CGM system works or handles communications 
between the Transmitter and Receiver.   The Dexcom G6 CGM system sends new glucose values to the 
Receiver every 5 minutes, if they are available, from the Sensor/Transmitter pair attached to the 
subject. The Dexcom G6 CGM manual notes that the Transmitter and Receiver must be within 20 feet of 
each other, with no obstacles between them (e.g., walls) in order to effectively communicate via 
Bluetooth. The FDA is aware of the 20 foot range limitation of the Dexcom G6 CGM system and has 
approved this CGM system for use in artificial pancreas systems. IMT has developed software called a 
Driver, that queries the database of the Dexcom G6 Receiver, every 30 seconds, for new glucose values.   
When the Driver discovers new date/time stamped glucose values in the database of the Receiver, it 
brings these values into a glucose queue within the FUSION system for use by the FUSION system. The 
FUSION system will only average glucose values that are time stamped within 5 minutes of each other. 
The all-in-one Medical Computer running the FUSION systems software is connected to the Dexcom G6 
CGM Receiver via a serial data cable. In our internal testing, each Dexcom G6 CGM Receiver was able to 
receive new glucose values from the Dexcom G6 Transmitter 99.53% of the time within the designed 5 
minute time interval. 
The benefit of using the Dexcom G6 CGM is that the FDA has already approved this system for use as an 
integrated continuous glucose monitor (iCGM) in automated insulin dosing (AID) systems for use in 
treatment of patients with diabetes in the outpatient setting. This study and follow-up studies to be 
performed in the ICU setting will attempt to demonstrate the feasibility of using the Dexcom G6 CGM 
system in an AID system (e.g., FUSION) designed for use in the inpatient setting.  
 
In addition, the study will also demonstrate the ability of the Dexcom G6 transmitter to simultaneously 
transmit its glucose data to one medical device (e.g., the Dexcom G6 Receiver) and the Dexcom G6 
Follow App on a mobile phone placed 15 feet from the subject’s bed. Demonstration of this functionality 
is important, as a mobile phone device will be needed in the ICU setting to provide remote monitoring 
(e.g., outside of the room) of the subject’s continuous glucose measurements. 
 
4.3.2 USE OF INNACURATE CGM GLUCOSE VALUE FOR GLUCOSE CONTROL 
The risk of using an inaccurate CGM value for glucose control will be mitigated by averaging the glucose 
value of the two CGM devices. In addition, independent Reference Glucose Values (Nova StatStrip 
Hospital Glucose Meter System) will be obtained every 10-60 minutes to ensure subject safety.  

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The benefit of using Dexcom’s G6 CGM, which has already been approved as an iCGM, is to determine 
its accuracy in different scenarios/settings (e.g., participants with diabetes in the proposed study; 
COVID-19 patients in ICU in future study). 
 
The benefit of obtaining Reference Glucose Values every 10-60 minutes is to independently monitor for 
hypoglycemia in cases where the CGM systems are providing the FUSION system with false high glucose 
levels that could lead to hypoglycemia, or to monitor for hyperglycemia in cases where the CGM 
systems are providing the FUSION system with false low glucose levels that could lead to hyperglycemia. 
The Reference Glucose Values can be used to administer rescue doses of 50% intravenous dextrose in 
cases of severe hypoglycemia (< 54 mg/dL), moderate hypoglycemia (54-69 mg/dL) with associated 
hypoglycemia symptoms, or in cases of neuroglycopenia. 
 
4.3.3 USE OF FALSE LOW CGM VALUES DUE TO COMPRESSION OF SENSOR SITE 
The risk of using a CGM value that is falsely low due to local compression of the sensor site, due to the 
subject laying on the sensor site, will be mitigated by monitoring of the Dexcom G6 CGM values by the 
study nurse. When the study nurse notes the presence of a compression artifact, which manifests as a 
sudden non-physiologic fall in the glucose value (e.g., < ± 2 mg/dL/min), the study nurse will move the 
subject until they are no longer laying on the sensor site. If one of the two abdominal sensors 
experiences repeated compression artifact values, the study nurse will have the option of placing a new 
CGM sensor on an alternative abdominal site, or on the posterior aspect of the contralateral upper arm 
from the abdominal sensor that continues to function normally (e.g., right side of abdomen and 
posterior aspect of left upper arm). The arm position may decrease the risk of both sensors suffering 
from compression artifacts, which could occur if the subject were to lay on both of their abdominal 
sensors during sleep. 
A recent study involving the Dexcom G7 CGM revealed that positioning the CGM on the back of the 
upper arm was as accurate and reliable as the abdominal position.88 This study, which involved 316 
participants and 77,774 paired (CGM vs YSI) glucose values, demonstrated an overall MARD of 8.2% for 
the arm and 9.1% for the abdomen. Among the 308 sensors worn on the arm, 291 (94.5%) had >80% of 
CGM-YSI matched pairs that met the %20/20 accuracy criterion. Among the 311 sensors worn on the 
abdomen, 272 (87.5%) had >80% of matched pairs that met the %20/20 accuracy criterion. There were 
no serious adverse events in the study population. 
The benefit of using the arm position will be to demonstrate its potential utility in a closed loop glucose 
control system, and to demonstrate its accuracy relative to the abdominal position as measured against 
the Reference Glucose Value. 

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4.3.4 EXCESSIVE VOLUME LOADING FROM FUSION SYSTEM 
In the first in human study performed on two subjects with type 2 diabetes in the CRC, the FUSION 
system infused an average of 26% of the subject’s total daily volume needs during the 24 hour study 
period. The risks to the subjects from this amount of volume include generalized edema in the setting of 
abnormal renal/liver function, or exacerbation of underlying congestive heart failure in the setting of 
underlying congestive heart failure. This risk will be mitigated by selecting subjects who have no 
underlying renal, liver, or cardiac conditions. 
This risk will also be mitigated by further optimizing the FUSION systems glucose control software, based 
on an analysis of the results from the first two subjects studied. These optimization efforts include steps 
to prevent excessive use of insulin during states of hyperglycemia (e.g., > 140 mg/dL), which can lead to 
a rapid fall of elevated glucose values into and through the desired glucose control range of 100-140 
mg/dL. This rapid fall of glucose levels leads the FUSION system to either start a dextrose infusion if one 
is not currently infusing, or to rapidly increase the rate of the current dextrose infusion. The FUSION 
systems glucose control software will also be optimized to decrease the dextrose infusion more quickly 
in states where the glucose level is in the desired control range and is either stable or increasing. These 
efforts to avoid excessive use of dextrose should decrease overall fluid intake, as the dextrose infusion 
accounted for 88% of the total fluid given by the FUSION system. 
Finally, the risk of fluid overload will be minimized through routine monitoring of the subjects for signs 
of fluid overload, throughout the 24-hour closed loop glucose control session. These signs will include 
evidence of peripheral edema (swollen hands, ankles, legs, eyelids), increased respiratory rate, 
shortness of breath, or signs of pulmonary edema on exam such as rales. Excessive volume loading, from 
the FUSION system, will be defined as fluid delivered by the FUSION system (e.g., insulin infusion and 
dextrose infusion ) in excess of 2000 mL during the 24 hour closed loop session. If this fluid delivery 
threshold is exceeded on a subject, the study will be stopped on that subject. 
The benefits of creating a closed loop glucose control system for use in the inpatient setting outweigh 
the risks of excessive fluid intake in this highly monitored CRC study. 
4.3.5 FAILURE OF ABILITY TO OBTAIN A REFERENCE GLUCOSE SAMPLE 
This risk will be minimized through use of two sample sites for Reference Glucose Values. The preferred 
sample site will be a retrograde hand vein intravenous catheter. If the clinical study staff is unable to 
obtain a venous draw from the retrograde hand vein catheter for any reason, they will obtain a capillary 
blood sample from a fingerstick. To be clear, if the retrograde hand vein catheter is no longer available 
as a sample site, the 24-hour closed loop glucose control study may be completed using fingerstick 
capillary samples as a source for Reference Glucose Values. 

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4.3.6 FAILURE OF REFERENCE GLUCOSE ANALYZER 
In cases where there is no Reference Glucose Value available for a period exceeding 60 minutes, the risk 
will be mitigated through termination of the study on that subject. An additional risk of relying on 
reference glucose analyzers is that they may produce inaccurate independent glucose results. This risk 
will be minimized through use of the Nova StatStrip Hospital Glucose Meter System, which the FDA has 
approved for use in the ICU setting. 
 
4.3.7 FAILURE OF CONTROL ALGORITHM TO PERFORM AS EXPECTED 
 
The risk of the control software to not perform as expected has been mitigated through version control 
of the software. In addition, the rules and sequencing of the software have been independently verified 
by the both the designer of the software, and the software developer. Furthermore, the control 
software to be used in this study has been tested in two simulation studies, two animal studies, and a 
first in human study with no instances of software failure, and excellent overall glucose control 
capabilities as demonstrated by the previously mentioned results. Finally, the glucose control software 
has undergone an independent verification and validation process by an outside company (JKI) that 
specializes in working with the LabVIEW engineering software suite used to create the FUSION systems 
glucose control software. This verification and validation testing is repeated with each new version of 
the software, and prior to using the updated software in the clinical setting. The risks of software failure 
will be mitigated through independent monitoring of the subject’s glucose values to prevent the serious 
risk of hypoglycemia. Complete software failure during the study would lead to termination of the study. 
 
The benefit of using closed loop glucose control software is demonstration of the feasibility of using this 
software to create a complete glucose control system and outweighs the noted risks. 
 
4.3.8 FAILURE OF SYRINGE PUMPS TO ACCURATELY DELIVER DOSES OF INTRAVENOUS 
INSULIN AND DEXTROSE 
 
The risk of the syringe pumps to not accurately deliver doses of insulin and dextrose has been mitigated 
through assessment of their accuracy prior to the study using a balance scale technique.89 This testing 
has demonstrated the accuracy of the syringe pumps to be within ± 5% from the prescribed infusion 
rate/volume. In addition, the infusion pump output rates are monitored by the glucose control software 
every 10 seconds to ensure the pump output rates match the prescribed rates from the software. If 
these rate differences are greater than 20%, the study is temporarily stopped until the syringe pump is 
replaced. 
 

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The benefits of using the KDS Legato 100 syringe pumps is that they were designed to work with the 
LabVIEW software that was used to implement the glucose controller, have a demonstrated infusion 
rate accuracy of within ± 5%, and can detect intravenous line occlusion and alert the clinician to this 
condition (e.g., occlusion) if it is detected. 
 
4.3.9 RISK OF IMPROPER SYRINGE PUMP SET UP 
 
The risk of the study personnel to not properly set up and use the syringe pumps will be mitigated 
through pre-study tutorials on their use, in addition to making available a standard operating procedure 
(SOP) as to their original set up and ongoing use. In addition, an IMT representatives will be immediately 
available for consultation throughout the entirety of the 24 hours of closed loop glucose on each 
subject. 
 
The benefit of using the KDS Legato 100 syringe pumps is their highly accurate dosing and their 
compatibility with the LabVIEW software used to develop the FUSION closed loop glucose control 
system being tested in this study. It is expected that the KDS Legato 100 syringe pumps will not be part 
of the final FUSION system for which marketing approval will be sought. 
 
4.3.10 RISK OF DIABETIC KETOACIDOSIS (DKA) 
DKA is a metabolic condition brought on by lack of sufficient insulin supply such that the body can no 
longer use glucose as a fuel source, which leads to excessive breakdown of fat, and abnormal labs 
consisting of elevated blood levels of glucose and beta hydroxybutyrate, with a concomitant lowering of 
the blood pH. The risk of the participants entering the study while they are in DKA will be mitigated by 
screening for ketones at the time they are admitted to the CRC on visit 3. This screening will include a 
capillary blood Reference Glucose Value measured on the Nova StatStrip Hospital Glucose Meter System 
and blood ketone levels measured on the Nova Max Plus ketone meter (Nova Biomedical). 
The risk of the subjects developing DKA while they are in the study will be mitigated by obtaining 
Reference Glucose Values at least every 1 hour. If the subjects CGM or Reference Glucose Value is > 240 
mg/dL, the subjects will have their blood screened for ketones using the Nova Max Plus ketone meter. If 
the subject’s blood ketone level is > 1 mmol/L, they will have venous blood sent for a basic metabolic 
panel, pH, and beta hydroxybutyrate to determine if they are in DKA. Subjects who are found to be in 
DKA, during their stay in the CRC during visit 3, will be removed from the study. 

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The benefit of testing the FUSION system on type 1 and type 2 diabetic subjects, whose blood glucose 
levels are difficult to control, outweighs the risk of the subjects developing DKA, given the information 
on the FUSION systems performance that will be gathered during the course of this study. 
4.3.11 RISK OF SEVERE HYPERGLYCEMIA 
Severe hyperglycemia is defined as a Reference Glucose Value greater than 240 mg/dL. In subjects with 
type 1 or type 2 diabetes, this degree of hyperglycemia may be a sign that the subject is at risk of 
developing DKA or hyperosmolar hyperglycemic syndrome (HHS). The risk of subjects developing 
untreated severe hyperglycemia while they are in the study will be mitigated by monitoring of the 
subject’s Reference Glucose Values at least every 1 hour with the Nova StatStrip Hospital Glucose 
Meter. CGM alarms will be set up to alert the research nurse and study staff for CGM glucose values > 
240 mg/dL for early detection of up trending glucose values. If the subject has a CGM or Reference 
Glucose Value greater than 240 mg/dL, the risk of DKA will be further mitigated by monitoring the 
subjects Reference Glucose Values every 30 minutes until their Reference Glucose Value is less than 240 
mg/dL. The risk of DKA will be mitigated by terminating the study if a subjects’ Reference Glucose Value 
remains > 240 mg/dL for more than 2 hours.  
4.3.12 RISK OF HYPEROSMOLAR HYPERGLYCEMIC SYNDROME 
HHS is defined as a serious complication in subjects with type 2 diabetes, and occasionally in subjects 
with type 1 diabetes, that occurs when the subject experiences severe hyperglycemia (usually >600 
mg/dL) for a prolonged period of time. HHS may produce severe dehydration, altered level of 
consciousness, and coma. The risk of subjects developing HHS while they are in the study is expected to 
be low and will be mitigated close monitoring of the subject’s Reference Glucose Values at least every 1 
hour with the Nova StatStrip Hospital Glucose Meter. If the subject has a CGM value greater than 240 
mg/dL (detected by CGM alarm set for glucose values > 240 mg/dL) or Reference Glucose Value greater 
than 240 mg/dL, the risk will be further mitigated by monitoring the subjects Reference Glucose Value 
every 30 minutes until their Reference Glucose Value is less than 240 mg/dL. Finally, the risk will be 
mitigated by terminating the study if the subjects CGM or Reference Glucose Value remains > 300 mg/dL 
for more than 1 hour. 
The overall risks of the study are outweighed by the potential benefit of demonstrating the safety of the 
FUSION systems AI based glucose control software, which is the first step in testing this software with an 
eventual goal of using it to create a closed loop glucose control system for use in the ICU setting. 
 
 
5 
OBJECTIVES AND ENDPOINTS 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
i. 
Safety 
 
To assess the hypothesis that an AI 
based glucose controller will 
provide safe glucose control in 
participants with type 2 diabetes 
consuming three meals over the 
course of the 24-hour closed loop 
glucose control session.  
 
 
 
 
 
 
 
 
 
2. 
Efficacy 
 
To assess the hypothesis that an AI 
based glucose controller will 
provide effective glucose control in 
participants with type 2 diabetes 
consuming three meals over the 
course of the 24-hour closed loop 
glucose control session.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The percent of all glucose values that 
are in the hypoglycemic range, when 
the latter is defined as glucose 
values less than 70 mg/dL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The percent of all glucose values that 
are within the range of 70-180 
mg/dL. 
 
 
 
 
 
 
Avoidance of 
hypoglycemia during 
tight glucose control 
leads to decreased 
mortality rates, and thus 
measurements of the 
rate of occurrence of 
hypoglycemia can be 
considered an 
assessment of the 
overall safety of the 
glucose control system 
under study. 
 
 
 
 
 
ICU mortality rates 
increase when patients 
experience both 
hypoglycemia (< 70 
mg/dL) and 
hyperglycemia (> 180 
mg/dL). Thus, testing 
the ability of the AI 
based glucose control 
system to maintain the 
study subjects in the 
range of 70-180 mg/dL 
will give an indication of 
its ability to avoid these 
two deleterious 
glycemic states. 
 
Secondary 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
The secondary objectives of the 
study are to assess the controller’s 
ability to minimize glucose curve 
measurements associated with 
increased ICU morbidity/mortality 
rates, and to maximize those 
measurements associated with 
decreased ICU morbidity/mortality 
rates. 
 
 
 
 
 
 
 
1. Measure the percent of glucose 
values that are within the severe 
hypoglycemic range of 0 – < 54 
mg/dL. 
2. Measure the percent of glucose 
values that are within the 
moderate hypoglycemic range of 
54-69 mg/dL.  
3. Number of hypoglycemic (< 70 
mg/dL) events. Each event 
separated by at least one glucose 
value >= 70 mg/dL. 
4. Measure the percent of all 
glucose values that are within the 
desired glucose control range of 
100 – 140 mg/dL.  
5. Measure the percent of glucose 
values that are within the range 
of 70-140 mg/dL.  
6. Measure the percent of glucose 
values that are within the 
hyperglycemic range of > 140 
mg/dL.  
7. Measure the percent of glucose 
values that are within the range 
of 70-180 mg/dL.  
8. Measure the percent of glucose 
values that are within the 
hyperglycemic range of > 180 
mg/dL.  
9.  Mean glucose level (mg/dL). 
10.  Measure of dispersion – 
coefficient of variation. 
11. The study data will be used to 
determine the percentage of the 
Dexcom’s G6 CGM’s glucose 
values in each zone using a Clarke 
error grid analysis.1 This same 
calculation will be performed on 
the average of the two Dexcom 
 
The chosen secondary 
endpoints are routinely 
measured in glucose 
control studies and 
serve to provide a more 
complete picture of the 
AI based glucose control 
systems ability to both 
safely and effectively 
provide glucose control. 
 
 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
G6 CGM systems used by the 
FUSION system for purposes of 
glucose control. 
 
Tertiary/Exploratory  
 
 
None planned 
 
 
 
 
The glucose data for the above statistical analysis will be the glucose data used by the FUSION system 
for purposes of glucose control, unless otherwise specified. 
 
6 
STUDY DESIGN  
 
6.1 
OVERALL DESIGN 
 
Tight glucose control in the ICU setting is difficult to achieve. We hypothesize that a closed loop glucose 
control system based on artificial intelligence will improve upon the glucose control currently achieved 
by open loop systems. This non-randomized Early Feasibility First in Human Study at a single study site 
will test the ability of a prototype closed loop glucose control system to provide safe and effective 
glucose control in participants with type 1 diabetes who lack endogenous insulin production, and type 2 
diabetes who have insulin resistance profiles that match those of ICU patients.58 The study will be 
performed in a CRC setting on two participants with type 1 diabetes and six participants with type 2 
diabetes over a time period of thirty-two hours per subject. The subjects will all consume three 
standardized meals during the 24-hour period their blood glucose levels are being controlled by the 
FUSION system. Study volunteers will be recruited from the adult endocrinology clinics of Emory 
University and/or Grady Hospital in Atlanta. Identified subjects who have been screened and enrolled in 
the study will have the study completed within two weeks of enrollment. An interim data analysis is not 
planned.  
 
6.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
A non-randomized Early Feasibility Study design was chosen as this represents a first in human test of 
this artificial intelligence based closed loop glucose control system. The main goal of the study will be to 
test the safety and efficacy of the FUSION closed loop glucose control system, as measured by the 
percent of glucose values less than 70 mg/dL (safety), and the percent of glucose values in the range of 
70-180 mg/dL (efficacy). Testing in the CRC setting was chosen as it is a highly monitored environment, 
and the subjects can be carefully chosen based on inclusion/exclusion criteria. 

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6.3 
JUSTIFICATION FOR DOSE 
 
 
For safety reasons the maximal allowed insulin dose (e.g., NovoLog) will be 0.5 units/kg/hour and the 
maximal dextrose (D10NS) infusion rate will be 4 mL/kg/hour, except during periods of dextrose 
boluses, when the maximal infusion rate will be 6.25 mL/kg/hour over a 5-minute period. These limits 
are consistent with a similar prior study.71 
 
 
6.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
 
7 
STUDY POPULATION 
 
7.1 
INCLUSION CRITERIA 
 
 
A. Participants with type 1 and type 2 diabetes are eligible to be included in the study only if they 
meet all the following criteria: 
 
1. Are 18-70 years of age, inclusive. 
2. Can understand and sign an informed consent, communicate with the investigator, and 
understand and comply with the protocol requirements. 
3. Have had a diagnosis of type 1 or type 2 diabetes for a period of at least 1 year. 
4. Use insulin injections at home for glucose control and are on a stable insulin regimen without 
more than a 20% change in their total daily insulin dose during the previous 3 months. Their 
total daily insulin dose during the previous 3 months will be confirmed through a review of 
the subject’s electronic health record, insulin prescriptions, and insulin pump settings (if 
applicable). 

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5. Have a hemoglobin A1c (HbA1c) in the range of 7.0 – 10.0%. 
6. Have a hemoglobin in the normal range for sex: 
a. Females: 12-15.5 grams/dL. 
b. Males: 13.5–17.5 grams/dl. 
7. Have adequate venous access sites in upper extremities. 
8. Body weight between 40 – 150 kg. 
 
 
7.2 
EXCLUSION CRITERIA 
 
A. Subjects will be excluded from the study if they meet any of the following criteria: 
1. Have participated in an interventional medical, surgical, or pharmaceutical study within 30 days 
of screening.  
2. Have a known hypersensitivity to any of the components of study treatment. 
3. Have skin disease/injury at Dexcom G6 CGM insertion site(s) that would prevent insertion of the 
CGM. 
4. Currently abuses drugs or alcohol or has a history of abuse that in the investigator’s opinion 
would cause the individual to be noncompliant. 
5. Have a medical condition that in the opinion of the investigator could affect study participation 
and/or personal well-being. 
6. Have a clinically significant history or presence of any of the following conditions: 
a. Hepatic failure or has alanine aminotransferase (ALT) greater than 3 times the upper 
limit of normal. 
b. Has an estimated GFR <60 ml/min/1.73 m2 or End Stage Kidney Disease on renal 
replacement therapy. 
c. Type 2 diabetic subjects who have a C-peptide level less than 0.2 nmol/L (these subjects 
will be referred to their primary care doctor or endocrinologist for further work up). 
d. Have congestive heart failure of class 1 or greater on the NYHA classification system. 
e. Have a history of seizures. 
f. 
Have a history of cerebrovascular accident. 

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g. Have a history of ischemic heart disease. 
7. For female subjects of potential childbearing age (age 18 to 55) they will be excluded if: 
a. Pregnant. 
b. Refuse to agree to a pregnancy test at the time of enrollment. 
c. Have a positive urine pregnancy test at the time of enrollment. 
8. Have a positive COVID-19 test within 14 days of visit 3. 
9. Have any COVID-19 related symptoms in the 14-day period prior to visit 3. 
10. Have a known unprotected COVID-19 exposure in the 14-day period prior to visit 3. 
 
7.3 
LIFESTYLE CONSIDERATIONS 
 
Not applicable. 
 
7.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious adverse 
event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a failure 
to meet all inclusion and exclusion criteria will not be rescreened for participation in the trial. 
 
 
7.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants with type1 and type 2 diabetes will be recruited from the Diabetes Center at Grady Hospital 
and adult endocrinology clinics at Emory Healthcare, located in Atlanta, Georgia.  All adult type 1 and 
type 2 diabetic patients being cared for in these clinics will be screened for inclusion in the study. The 
original screening will include age, weight, length of diagnosis of diabetes, use of insulin in the home 
setting, and their most recent HbA1c level. Potential subjects who pass these criteria will then be 
assessed for exclusion criteria. Potential subjects who pass the exclusion criteria will be approached for 
participation in the study. Willing participants will be scheduled for enrollment during visit 2. Subjects 

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who sign an informed consent during visit 2 will have blood drawn to evaluate their hemoglobin, HbA1c, 
ALT, creatinine, and C-peptide (type 2 diabetic subjects) levels. Female subjects aged 18-55 inclusive 
who have signed an informed consent will also have a urine pregnancy test performed during visit 2.  It 
is anticipated that 500 adult type 1 and type 2 diabetic subjects will need to be screened to yield 8 
subjects for participation in the study. It is expected that the inclusion criteria will eliminate 97% of 
potential enrollees.   It is expected that the exclusion criteria will eliminate another 30% of the 
remaining potential enrollees. Study participants will be compensated for participation in the study.  
 
8 
STUDY INTERVENTION 
 
8.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
8.1.1 STUDY INTERVENTION DESCRIPTION 
 
8.1.1.1 COMPONENTS OF CLOSED LOOP GLUCOSE CONTROL SYSTEM 
 
1. Two complete Dexcom G6 continuous glucose monitoring systems – Glucose sensor, 
Transmitter, and Receiver 
2. Two mobile phones with the Dexcom G6 Follow App 
3. One Medical Computer and associated power cord 
4. One Powered Medical Cart and associated power cord 
5. Two KDS Legato 100 syringe pumps and associated power cords 
6. Two serial data cables to attach syringe pumps to Medical Computer 
7. Two serial data cables to attach Dexcom G6 Receivers to Medical Computer 
 
8.1.1.2 VISIT 1, SCREENING 
This screening visit includes evaluating the medical history, comprising preexisting conditions and 
concomitant medications of type 1 and type 2 diabetic subjects being seen at the Diabetes Center at 
Grady Hospital and the adult endocrinology clinics of Emory Healthcare, located in Atlanta, Georgia. 
Those subjects who meet study inclusion criteria, and who do not meet any study exclusion criteria, will 
be approached for participation in the study. Willing participants will be scheduled for visit 2, for 
purposes of obtaining an informed consent and enrolling them in the study. 
 
8.1.1.3 VISIT 2, ENROLLMENT 

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Subjects who volunteer for the study will have the study thoroughly explained to them during visit 2. 
Subjects who willingly volunteer for the study, after having all their questions answered, will sign an 
informed consent.  Subjects who have signed an informed consent will be assigned a unique 
identification number that will remain the same throughout the study. Those subjects who have signed 
an informed consent and whose lab results obtained during visit 2 do not exclude them from the study, 
will proceed to visit 3, which must occur within 2 weeks of the date of enrollment. The following 
instructions will be given to the subjects in preparation for visit 3: 
 
1. For subjects taking the SGLT-2 inhibitor Ertugliflozin, they will be instructed to stop taking this 
medication four days prior to visit 3. 
2. For subjects taking the SGLT-2 inhibitors Canagliflozin, Dapagliflozin, and Empagliflozin, they will 
be instructed to stop taking these medications three days prior to visit 3. 
3. For subjects taking sulfonylureas or meglitinides, they will be instructed to stop taking these 
medications after their morning doses on the day prior to visit 3 (e.g., if visit 3 starts on a 
Wednesday, the subjects will stop taking these medications after their morning doses on the 
previous day = Tuesday). 
4. If usually taking long-acting insulin in the PM, then on the evening prior to visit 3: 
a) Take half the usual evening dose of long-acting insulin if history of nocturnal hypoglycemia. 
b) Take the full usual dose of insulin if no history of nocturnal hypoglycemia. 
c) Insulin doses may also be adjusted at the discretion of the investigators (endocrinologists: Dr 
Francisco Pasquel and Dr. Georgia Davis).  
5. Subjects to fast after midnight on the evening prior to visit 3. 
6. Subjects to not take any oral anti-hyperglycemic medications on the morning of visit 3. 
7. After admission to the CRC on the morning of visit 3, all Reference Glucose Values and insulin 
administration will be performed by the clinical study staff of the CRC. Insulin dosing will be at 
the recommendation of adult endocrinologists (Drs. Pasquel or Davis) who are the principal 
investigators for this study. The dose of short acting insulin ordered after admission to the CRC 
will be based on the amount of carbohydrates ingested by the subjects for breakfast after their 
CRC admission, their Reference Glucose Value measured just prior to breakfast, and their usual 
home routine. 
8.1.1.4 VISIT 3, TIME 0 TO 5 HOURS (PREPARATION FOR CLOSED LOOP GLUCOSE CONTROL 
STUDY) 
 
1. 
General 
All subjects will be admitted between the hours of 0600 to 0700 to a single patient CRC room large 
enough to hold the subject, study personnel and necessary equipment. The study equipment, at a 

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minimum should include a cardiac monitor, pulse oximeter, intermittent blood pressure capabilities, and 
a resuscitation cart. 
2. 
Screening Prior to Initiation of the Closed Loop Glucose Control Session 
The subjects will be tested for the presence of diabetic ketoacidosis and appropriate Reference Glucose 
Values prior to proceeding to steps 3-6 below. This testing will include: 
i. 
Reference Glucose Value at time of admission to the CRC – If the Reference Glucose 
Value is greater than 300 mg/dL, the subject will be screened for blood ketones using 
the Nova Max Plus (Nova Biomedical) ketone meter. If the Reference Glucose Value is 
less than 70 mg/dL or the subjects are experiencing any symptoms of hypoglycemia, 
regardless of their Reference Glucose Value, the subjects will be offered a snack or 
glucose containing juice. To be clear, the Nova Max Plus ketone meter will be used for 
any blood ketone analysis performed during the time the subjects are in the CRC. 
ii. 
Blood ketones – The study will be cancelled if the blood ketones are > 1 mmol/L. If 
blood ketones are > 1 mmol/L, a venous blood sample will be sent to the central lab at 
Emory University for a basic metabolic panel, venous pH and beta-hydroxybutyrate to 
rule out diabetic ketoacidosis. If diabetic ketoacidosis is confirmed, the subject will be 
stabilized per the usual routine care at Emory Healthcare. 
iii. 
Blood glucose prior to insertion of Dexcom G6 CGM’s and intravenous lines – The 
subjects Reference Glucose Value must be in the range of 70-300 mg/dL prior to 
insertion of the two Dexcom G6 CGM’s and two intravenous lines. 
 
In addition, the closed loop glucose control session of the study will not be initiated if the participant has 
symptoms requiring action (e.g., abdominal pain, vomiting, unable to eat or drink, fever ≥ 101.5), 
regardless of blood glucose or ketone levels. 
 
3. 
Dexcom G6 CGM devices 
The subjects will have two Dexcom G6 CGM devices placed in the abdominal position, approximately 5 
cm to the left or right of the umbilicus (Figure 25). 

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Figure 25 – Green shaded areas denote appropriate areas of the abdominal wall to place the Dexcom G6 CGM’s. 
This figure is  from the Dexcom G6 CGM user manual. 
 
The CGM devices should be placed shortly after arrival to the CRC facility. For the Dexcom G6 CGM labeled 
“#1”, enter the glucose sensors four-digit code and the transmitters six-digit serial number into the 
Dexcom G6 Receiver labeled “#1” and into the Dexcom G6 Follow App on the mobile phone labeled “#1”. 
For the Dexcom G6 CGM labeled “#2”, enter the glucose sensors four-digit code and the transmitters six-
digit serial number into the Dexcom G6 Receiver labeled “#2” and into the Dexcom G6 Follow App on the 
mobile phone labeled “#2”. Position the mobile phones 15-20 feet from the bed the subject will be using 
during the study. 
 
4. 
Peripheral Intravenous Lines 
For purposes of medication infusion, all subjects will have a peripheral IV placed into the antecubital 
vein of one arm. For purposes of blood removal, all subjects will have an IV placed in the contralateral 
hand in a retrograde position. The hand with the retrograde IV will be warmed to 50-55 degrees Celsius 
with a commercial warming box or warming pad for purposes of arterializing the venous blood.90 
5. 
Reference Glucose Value 
After both Dexcom CGM’s have started to return glucose values to the Dexcom Receivers, and prior to 
starting the closed loop glucose control portion of study, a Reference Glucose Value(s) (taken from 
arterialized retrograde hand IV line) will be measured using the Nova StatStrip Hospital Glucose Meter 
System. If the retrograde hand vein is no longer available at any point during visit 3, Reference Glucose 
Values may be obtained from a finger stick (capillary blood), with analysis of this sample being 
performed on the Nova StatStrip Hospital Glucose Meter System. 
 
On July 12, 2018, the FDA cleared the Nova StatStrip Hospital Glucose Meter System for point of care 
capillary blood glucose monitoring for all hospital patients, specifically including those receiving 
intensive medical intervention therapy. According to the FDA’s 510(k) Substantial Equivalence 
Determination Decision Summary Assay and Instrument Combination Template for this product, two 

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studies were performed. In the first study for blood glucose values less than  75 mg/dL, 1 of 1 specimen 
(100%) was compliant, and for blood glucose values greater than or equal to 75 mg/dL, 484/567 (85.4%) 
specimens were compliant. In the second study for blood glucose values less than 75 mg/dL, 1614/1894 
(85.2%) specimens were compliant, and for blood glucose values greater than or equal to 75 mg/dL, 
12799/14884 (86.0%) specimens were compliant.91 
 
The Nova StatStrip Hospital Glucose Meter System has been cleared for use on arterial, venous, and 
capillary whole blood samples, and is currently used to guide intravenous insulin infusion rates in the 
ICU setting. 
 
6. 
Calibration of Dexcom G6 CGM’s 
The Dexcom G6 CGM’s will be calibrated under the following scenarios: 
 
1. The Dexcom G6 CGM value(s) do not meet CGM Validation Criteria 
If one or both of the Dexcom G6 CGM’s are more than 20 mg/dL different from the Reference 
Glucose Value for CGM values less than 100 mg/dL, or are more than 20% different from the 
Reference Glucose Value for CGM values greater than or equal to 100 mg/dL at any time during 
visit 3, they will be recalibrated against the result from the Reference Glucose Value (using the 
Dexcom G6 receiver(s)). This calibration must occur within 5 minutes of obtaining the Reference 
Glucose Value sample. If the Dexcom G6 Receivers are recalibrated, the matching mobile 
phone’s Dexcom App must also be recalibrated at the same time (e.g., if Dexcom Receiver #1 is 
recalibrated, also recalibrate the Dexcom G6 Follow App in mobile phone #1). If a Dexcom G6 
sensor is recalibrated, a follow up CGM one hour after the recalibration must be within 20 
mg/dL of the Reference Glucose Value for CGM values less than 100 mg/dL, or within ± 20% of 
the Reference Glucose Value for CGM values greater than or equal to 100 mg/dL. If a CGM is felt 
to be inaccurate – cannot be calibrated to meet the aforementioned CGM Validation Criteria – it 
may be replaced according to the CGM Replacement Criteria. 
2. The Dexcom G6 CGM’s are greater than 20% different than their averaged value. If the averaged 
glucose value of the two Dexcom G6 CGM’s is greater than 20% different than the CGM values, a 
Reference Glucose Value will be obtained and both CGM’s will be re-calibrated against the result 
of the Reference Glucose Value using the Dexcom G6 receivers. This recalibration must occur 
within 5 minutes of obtaining the Reference Glucose Value sample. In this scenario, the FUSION 
system will automatically alert the clinical study staff of the need to recalibrate both Dexcom G6 
CGM’s. If the Dexcom G6 Receivers are recalibrated, the matching mobile phone’s Dexcom 
Follow Apps must also be recalibrated at the same time. If a Dexcom G6 CGM is recalibrated, the 
CGM value one hour after recalibration must be within 20 mg/dL of the Reference Glucose 
Value for CGM values less than 100 mg/dL, or within ± 20% of the Reference Glucose Value for 
CGM values greater than or equal to 100 mg/dL. 

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Prior to starting the closed loop glucose control session, a Reference Glucose Value will be obtained 
immediately after the time when the CGM sensors begin to return glucose readings. Reference Glucose 
Values will be subsequently checked every 30 minutes until the CGM sensor values meet the following 
CGM Validation Criteria: 
 
1. CGM’s must be within 20 mg/dL of the Reference Glucose Value for CGM values less than 100 
mg/dL, or within ± 20% of the Reference Glucose Value for CGM values greater than or equal to 
100 mg/dL. 
 
Closed-loop therapy will begin after two consecutive averages of CGM values meet the above CGM 
Validation Criteria. The above CGM Validation Criteria will be used throughout the entirety of visit 3. 
 
Blood for independent glucose analysis will be drawn from the retrograde venous line in the warmed 
hand. The drawn blood will be immediately analyzed for glucose using the Nova StatStrip Hospital 
Glucose Meter System. These blood glucose values will be known as the Reference Glucose Values. If 
the arterialized venous line stops working, it may be replaced. If an arterialized venous line is no longer 
available, fingerstick capillary blood may be used for Reference Glucose Values. Fingerstick capillary 
blood will be analyzed using the Nova StatStrip Hospital Glucose Meter System. 
 
All Reference Glucose Values will be manually recorded on the studies case report form, however, they 
will not be used by the FUSION system for purposes of glucose control (except to calibrate the Dexcom 
G6 CGM’s, as necessary). 
 
All subjects will be allowed to drink water throughout the course of the study. No glucose containing 
drinks will be allowed during the closed loop portion of the study, unless the subjects glucose level 
(CGM or Reference Glucose Value) is < 70 mg/dL, or the subject is experiencing symptoms of 
neuroglycopenia. Subjects will remain confined to either the bed or a bedside chair throughout the 
course of the study. Subjects will use a bedside commode for bathroom breaks in order to prevent any 
interruption to their closed loop glucose control session. 
 
The following supplies will be needed to complete the study: 1) four 4-way stopcocks, 2)  two IV tubing 
(non-microbore) of 6-12 foot length for purpose of attaching the glucose controllers syringe pumps to 
the subject, 3) Forty 50 mL BD syringes filled with D10NS (study site research pharmacy to fill these 50 
mL syringes using their standard sterile technique), 4) Six 50 mL BD syringes filled with NovoLog insulin 
mixed in normal saline to a concentration of 1 unit/mL (study site research pharmacy to fill these 50 mL 
syringes using their standard sterile technique). The FUSION system (Figure 20) will be supplied by the 
study sponsor. 

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8.1.1.5 VISIT 3, TIME 5 TO 29 HOURS (CLOSED LOOP GLUCOSE CONTROL SESSION) 
 
The closed loop glucose control session will not begin until the following criteria has been met: 
1. Both Dexcom G6 CGM’s are returning glucose values and have been calibrated – if necessary; or 
replaced – if necessary. 
 
Please refer to the below standard operating procedure (SOP) document for the calibration procedure 
for the Dexcom G6 CGM’s, setting up the FUSION system, and initiating it’s software: 
 
FUSION System SOP 
 
To better simulate how the FUSION system will be used in the ICU setting, no run-in period will be 
performed prior to the subject consuming the first meal. During the 24-hour closed loop glucose control 
study (time 5 to 29 hours), blood glucose control will be performed autonomously by Ideal Medical 
Technologies FUSION glucose control system.  For safety reasons, the subjects will have a Reference 
Glucose Value independently measured every 10-60 minutes on the Nova StatStrip Hospital Glucose 
Meter System. These independent Reference Glucose Values will not be used by the FUSION system for 
glucose control. After 2-3 hours of confirmed CGM accuracy (e.g., from 0900 to 1200), the closed loop 
glucose control session will begin. The first meal consumed during the closed loop glucose control 
session will be lunch.  
 
Lunch will consist of 60 grams of carbohydrate (45-60% of total meal Kcal’s) and be consumed beginning 
at   ̴1200 hours (the beginning of the closed loop glucose control session). Dinner will consist of 75 grams 
of carbohydrates (45-60% of total meal Kcal’s) and be consumed beginning at 1800 hours (6 hours after 
beginning of closed loop glucose control session). Breakfast will consist of 50 grams of carbohydrate (45-
60% of total meal Kcal’s) and be consumed beginning at 0800 hours on day 2 of the closed loop session 
began (20 hours after the beginning of the closed loop glucose control session). 
 
Subjects will be allowed to have snacks between the hours of 2100 on day 1 and 0600 hours on day 2 of 
their CRC study, or at any time for CGM or Reference Glucose Values less than 70 mg/dL or for 
symptoms of neuroglycopenia. Subjects will preselect their breakfast, lunch, and dinner meal choices 
from the CRC menu prior to the study. These meals will be unannounced to the FUSION system. Once 
the closed loop glucose control period has ended after 24 hours of glucose control, the control software 
will be stopped, and the subject will be disconnected from all intravenous infusions. 
 

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If the subjects are removed from the study due to the occurrence of a severe hypoglycemic event (< 54 
mg/dL), the subjects will have their glucose values measured with a Reference Glucose Analyzer (e.g., 
Nova StatStrip Hospital Glucose Meter System) every 10 minutes, until their Reference Glucose Values 
are greater than 70 mg/dL. They will then have additional Reference Glucose Values drawn every 30 
minutes, until they have consistent Reference Glucose Values in the range of 80-250 mg/dL for a period 
of at least two hours. See Recovery Period (Pages 107-108) for details with regards to subcutaneous 
insulin doses to be received prior to discharge from the Clinical Research Center. 
 
The insulin and dextrose 50 mL medication syringes may not be used for more than 24 hours. Although 
the study should be terminated after a period of 24 hours (e.g., may not go longer than 24 hours), if for 
any reason the study period is longer than 24 hours (e.g., on orders from the principal investigator), the 
insulin and dextrose medication syringes must be exchanged for new medication syringes. To be clear, 
the insulin and dextrose medication syringes may not be used for a period of time exceeding 24 hours. 
 
8.1.1.6 VISIT 3, TIME 29 TO 32 HOURS (OBSERVATION AFTER CLOSED LOOP GLUCOSE 
CONTROL SESSION) 
 
At the end of the subjects 24 hour closed loop glucose control session, they will be fed lunch consisting 
of 60 grams of carbohydrate (45-60% of total meal Kcal’s). The subjects will resume control of their 
blood glucose per the protocol instructions (see IMT2022-1-P2) once the closed loop glucose control 
period has ended. After finishing their lunch, the subjects will continue to have Reference Glucose 
Values measured every 30 minutes using the Nova StatStrip Hospital Glucose Meter System. When the 
subjects Reference Glucose Value is in the range of 80-250 mg/dL for a period of at least two hours after 
the end of their closed loop glucose control session and their most recent glucose rate of change is less 
than ± 2 mg/dL/min, their intravenous catheters will be removed, and they will be discharged from the 
CRC. If their blood Reference Glucose Value is less than 80 mg/dL, they will be given additional snacks 
until their Reference Glucose Value is greater than 80 mg/dL. If the subjects require additional snacks, 
they will continue to have Reference Glucose Values measured every 30 minutes using the Nova 
StatStrip Hospital Glucose Meter System until their Reference Glucose Value has been stable in the 
range of 80-250 mg/dL on four consecutive values and their most recent glucose rate of change is less 
than ± 2 mg/dL/min, after which time their intravenous catheters will be removed, and they will be 
discharged from the CRC unit. If their Reference Glucose Value is greater than 250 mg/dl the study’s 
principal investigators (Dr. Pasquel or Dr. Davis) will order a dose of short acting insulin, which will be 
administered by the clinical study nurse, and their Reference Glucose Value will be monitored every 30 
minutes until it is less than 250 mg/dL and their most recent glucose rate of change is less than ± 2 
mg/dL/min, at which time they may be discharged from the CRC unit. 
 

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8.1.1.7 OTHER 
Refer to Protocol 1 (IMT2022-1-P1) for other materials needed to complete the study. 
Refer to Protocol 2 (IMT2022-1-P2) for meal challenge in diabetic subjects. 
 
8.1.2 DOSING AND ADMINISTRATION 
 
The dosing of intravenous insulin and intravenous dextrose will be determined by the glucose values 
measured by the Dexcom G6 continuous glucose monitors, the difference between this measurement 
and the desired glucose range of 100-140 mg/dL, the glucose rate of change, the current weight based 
doses of intravenous insulin and/or dextrose that are under the control of the FUSION system, and the 
rules of Ideal Medical Technologies FUSION glucose control system. 
 
8.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
8.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Ideal Medical Technologies FUSION closed loop glucose control system that is to be utilized in this study 
will be hand delivered by a representative of Ideal Medical Technologies to the Emory University Clinical 
Research Center at least two weeks prior to the initiation of the study. This will allow for adequate in-
servicing of the principal investigator and all pertinent study personnel as to the use of the complete 
closed loop glucose control system. The study site will store this system in a secure location so that only 
study personnel who will be participating in the study will have access to it. After the study has either 
been completed or cancelled, all equipment supplied to the study site by Ideal Medical Technologies will 
be immediately returned to Ideal Medical Technologies (at Ideal Medical Technologies expense). 
 
8.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Medical Device Labeling 
 
The medical device under study in this Early Feasibility Study protocol will be labeled as follows: 
 
“Ideal Medical Technologies 
18 North Kensington Rd 

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Asheville, NC 28804 
1-828-337-9960 
leondej@idealmedtech.com 
Storage & Operating temperature of 41-95 F 
CAUTION  Investigational device. Limited by Federal (or United States) law to 
investigational use” 
 
 
8.2.3 PRODUCT STORAGE AND STABILITY 
 
Store and operate all components of medical device under study at room temperatures in range of 41-
95 degrees Fahrenheit. 
 
 
8.2.4 PREPARATION 
 
Not applicable. 
 
8.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Not applicable. 
 
 
8.4 
STUDY INTERVENTION COMPLIANCE 
 
Adherence to the study protocol will be determined through monitoring by Ideal Medical Technologies 
personnel. In addition, any deviations from the study protocol will be documented on the CRF. Ideal 
Medical Technologies will review the CRF forms after each study session to ensure adherence to the 
studies inclusion criteria, exclusion criteria, and for the presence of a signed informed consent 
document. Please refer to the following document for the studies monitoring plan: 
 
001_IMT_CRC_T1DM_T2DM_Clinical Monitoring Plan 
 
 

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8.5 
CONCOMITANT THERAPY 
 
Not applicable. 
 
8.5.1 RESCUE MEDICINE 
 
The study site will supply rescue medication that will be obtained locally. The following rescue 
medications may be used: 
 
1. 15 mL of 50% Dextrose for intravenous delivery (IV push), every 10 minutes as needed. 
2. Glucagon (1 mg/mL) for Intramuscular or intravenous delivery. May give repeat dose 15 minutes 
after first dose. 
 
 The 50% dextrose and Glucagon rescue medications will be used to treat the following conditions: 
 
1) Severe hypoglycemia, which is defined as a Reference Glucose Value less than 54 mg/dL. 
2) Moderate hypoglycemia (Reference Glucose Value in the range of 54-69 mg/d) that is accompanied 
by any of the following neurological signs of hypoglycemia: Anxiety, irritability, sweating, hunger, 
shakiness, fatigue, pale skin, lethargy, seizures. 
3) Neuroglycopenia, which is defined as hypoglycemia of sufficient duration and degree to interfere with 
normal brain metabolism and function. Neuroglycopenia may occur at Reference Glucose Values greater 
than or equal to 70 mg/dL. If the subject has signs of hypoglycemia such as anxiety, irritability, sweating, 
hunger, shakiness, fatigue, pale skin, lethargy, or seizures, they will be treated with 15 mL of 50% 
Dextrose.” 
 
These medications will be hand pushed into the subject’s intravenous line by the study nurse or given by 
intramuscular injection in the case of Glucagon. The date and time of rescue medication administration 
as well as the name and dosage regimen of the rescue medication will be recorded on the case report 
forms. 
 
In addition to the above rescue medications, in cases of severe hypoglycemia, moderate hypoglycemia 
with hypoglycemia symptoms, or neuroglycopenia, the subjects will also be offered snacks and glucose 
containing juices to treat their hypoglycemia and related symptoms. 
 
 
9 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 

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9.1 
DISCONTINUATION OF STUDY INTERVENTION ON INDIVIDUAL SUBJECT 
In the context of this study, termination is defined as the act of bringing either the study on one subject, 
or the entire study to a permanent end. 
On each subject the study will be immediately terminated for any of the following reasons: 
A. Termination Criteria for individual subjects: 
The study will be terminated on individual subjects if any of the following criteria are met: 
1. Subject or their legal authorized representative requests withdrawal from the study for any 
reason. 
2. The clinical study nurses are unable to insert two working Dexcom G6 CGM’s prior to beginning 
the closed loop glucose control session. 
3. Subject has a Reference Glucose Value less than 54 mg/dL. 
4. Subject has signs of prolonged severe hyperglycemia, as defined by Reference Glucose Value > 
240 mg/dL for more than 2 hours. 
5. Subject has signs of DKA, as defined by a Reference Glucose Value > 240 mg/dL and  blood ketones 
> 1 mmol/L. 
6. CGM or Reference Glucose Value remains > 300 mg/dL for more than 1 hour. 
7. FUSION system has only one Dexcom G6 CGM available for use for more than 4 hours. 
8. FUSION system has no Dexcom G6 CGM’s available for use for more than 20 minutes. 
9. There are no Reference Glucose Values for a period of time greater than 60 minutes. 
10. The FUSION system experiences any unanticipated adverse device effect (UADE). 
11. The subject has had more than 2% of their estimated total blood volume drawn during visit 3. 
12. The FUSION system delivers more than 2000 mL (insulin and dextrose infusions) during the 24-
hour closed loop glucose control session. 
 
9.2 
DISCONTINUATION OF ENTIRE STUDY 
 
A. Termination Criteria for the entire study: 
The entire study will be terminated if any of the following criteria are met: 
1. Two subjects experience an episode of severe hypoglycemia (Reference Glucose Value < 54 
mg/dL) during the time period the FUSION system is in use. 
2. Two subjects experience an episode of severe hyperglycemia, as defined by a Reference Glucose 
Value > 240 mg/dL for more than 2 hours. 
3. One subject experiences an episode of DKA after starting the closed loop glucose control session. 
4. One subject experiences an episode of HHS after starting the closed loop glucose control session. 
5. The FUSION system delivers more than 2000 mL (insulin and dextrose infusions) during the 24-
hour closed loop glucose control session in two subjects. 
6. The FUSION system experiences any unanticipated adverse device effect (UADE). 
7. The study’s principal investigator determines that the safety of the studies subjects is being 
compromised through use of the FUSION system. 
 

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If subjects are removed from the study due to hypoglycemia or the development of diabetic 
ketoacidosis, they will have ongoing monitoring and care in the CRC as noted in Recovery Period (pages 
107-108). If a subject signs an informed consent but does not receive closed loop glucose control, they 
may be replaced. If a subject begins the closed loop glucose control portion of the study, they may not 
be replaced. 
 
If the study has been terminated on only one subject for a reason other than an unanticipated adverse 
device effect, the study may continue. If the entire study has been terminated, it may not be resumed 
until the study’s sponsor has submitted study results to the FDA, the study sponsor has presented plans 
to mitigate the risks that led to the study’s termination, and the FDA has approved resumption of the 
study. 
 
9.3 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
The reason for subject withdrawal or involuntary removal from the study will be recorded on the CRF. If 
subjects withdraw themselves from the study after starting the closed loop glucose control session, they 
will be discharged from the CRC after meeting all of the discharge criteria noted in Recovery_Period on 
page 106. If a subject signs an informed consent but does not receive closed-loop glucose control, they 
may be replaced. If a subject begins the closed loop glucose control portion of the study, they may not 
be replaced. 
 
As the study is limited to 32 hours of glucose control/monitoring, no long term follow up will done for 
the subjects who either complete the study, or for those who are withdrawn for any reason, except as 
required to record and monitor any adverse events or unanticipated problems. 
 
9.4 
LOST TO FOLLOW-UP 
 
Not applicable. 
 
10 STUDY ASSESSMENTS AND PROCEDURES 
 
10.1 EFFICACY ASSESSMENTS  
 
The following procedures/evaluations will be performed on the subjects: 

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1. Review of medical history and inclusion/exclusion criteria to determine eligibility for the study. 
This may be performed by any qualified study personnel. 
2. Obtain informed consent. This may be performed by any qualified study personnel. 
3. Draw blood for creatinine, alanine aminotransferase, hemoglobin, HbA1c, and C-peptide. These 
labs will be analyzed in the hospital’s central laboratory. For women of childbearing age of 18-55 
years inclusive, obtain a urine pregnancy test. Blood draw will be performed by any qualified 
personnel. If these results have already been obtained as part of the subject’s routine laboratory 
studies, the already obtained results may be used to assess the subject for inclusion/exclusion 
criteria. 
4. For subjects who have signed an informed consent and whose lab results do not exclude them 
from the study, an appointment for visit 3 will be set. This appointment must occur within 2 
weeks of the date the informed consent was signed.  
5. During visit 3, the subject will undergo closed loop control of their blood glucose level from time 
5 to 29 hours utilizing Ideal Medical Technologies FUSION closed loop glucose control system. 
Refer to the SOP for set up, initiation and use of this system. To initialize the glucose control 
software the study RN will enter the patient’s weight (Kg), study identification number, and 
initial Reference Glucose Value. The glucose control range of 100-140 mg/dL will be 
automatically defaulted to by the glucose control software. On initiation of the closed loop 
glucose control session the study RN will obtain a blood sample for glucose analysis from the 
arterialized retrograde intravenous line every 30 minutes. This blood sample will be immediately 
analyzed for a Reference Glucose Value on the Nova StatStrip Hospital Glucose Meter System. 
Results from this test will be entered into the appropriate case report form as soon as it 
becomes available. The frequency of checking Reference Glucose Values is outlined in the study 
protocol on pages 102-103. The study RN will be responsible for making sure the insulin and 
dextrose syringes in the syringe pumps being used for glucose control remain at least 20% full 
(at least 10 mL volume remaining in 50 mL BD syringe) throughout the course of the closed loop 
glucose control study. 
6. A total of approximately 60 blood draws for glucose analysis will be obtained during the study. 
The blood volume removed with each blood draw will be 0.5 mL, for a total blood loss of no 
more than 40 mL’s. This is in addition to the 10 mL removed previously for lab analysis to verify 
eligibility for the study. The total volume of blood removed from the subject for purposes of 
completing this study should be less than 80 mL’s over a period of 2 weeks. 
7. At the conclusion of the study the two Dexcom G6 CGM’s and the two intravenous lines will be 
removed from the subject by the study clinical nurse. The subjects will be discharged from the 
CRC when they have met the discharge criteria noted in the study protocol (IMT2022-1-P2). 
 
 

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The subjects who have participated in the study will be given the following information after conclusion 
of the study: 
 
1. Their average glucose value over the period of closed loop glucose control. 
2. Their CV value over the period of closed loop glucose control. 
3. Their percent time in range < 70 mg/dL over the period of closed loop glucose control. 
4. Their percent time in range 70-180 mg/dL over the period of closed loop glucose control. 
5. Their percent time in range > 180 mg/dL over the period of closed loop glucose control. 
 
 
10.2 SAFETY AND OTHER ASSESSMENTS 
 
10.2.1 SAFETY 
 
The exclusion criteria which are used to screen for potential subjects eliminates those with hepatic 
failure, signs of significant hepatic disease as defined by an alanine aminotransferase greater than three 
times the upper limit of normal, any signs of renal failure, subjects with any history of congestive heart 
failure, subjects with a history of ischemic heart disease/cerebrovascular accident/seizures and 
eliminates all females who are pregnant. The purpose of these exclusion criteria is to avoid first in 
human trials on subjects with severe organ compromise, and exposure of a fetus to an untested medical 
device. 
 
Independently monitoring Reference Glucose Values every 10-60 minutes will ensure subject safety 
should they experience hypoglycemia that the closed loop glucose control system is either unaware of 
or is unable to effectively treat. This monitoring will allow for early intervention in case the subjects 
experience severe hypoglycemia (Reference Glucose Value < 54 mg/dL) or moderate hypoglycemia 
(Reference Glucose Value 54-69 mg/dL) with clinical signs of hypoglycemia. 
   
10.2.2 PHYSICAL EXAM/LABS 
 
The visit 1 physical exam will be limited to recording the subject’s weight. No vital signs will be recorded. 
During the closed loop glucose control portion of the study the subject’s vital signs will be monitored 
with a frequency of at least every 1 hour. 
 
No EKG’s will be needed for purposes of completing this study. No radiologic studies will be needed for 
purposes of completing this study. 

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The screening labs which are part of the exclusion criteria will be performed in the central laboratory. 
The blood for these labs will be stored as per institution specific guidelines as the study itself does not 
require that the blood used for these studies be stored for any length of time. The overall blood volume 
needed for purposes of completing the study is estimated to be approximately 50 mL but may be as 
much as 80 mL. 
 
10.2.3 SPECIAL ASSAYS 
 
The Reference Glucose Values to be done at the bedside will be performed on a Nova StatStrip Hospital 
Glucose Meter System. The study personnel will require specialized training on use of the Nova StatStrip 
Hospital Glucose Meter System, if they have not previously been trained on its use. 
10.2.4 USE OF EXISTING MEDICAL RECORD DATA 
 
For purposes of performing the screening criteria the existing medical records available at the time of 
the subject’s routine visit to the adult endocrinology clinic will be used whenever possible. In addition to 
medical history and physical exam information, this may also include use of necessary lab work to 
include creatinine, alanine aminotransferase, hemoglobin, HbA1c, C-peptide, and urine pregnancy test.  
 
10.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
10.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related. 
 
 
10.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
 
An adverse event (AE) or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, a persistent or significant incapacity, or substantial disruption of the ability to conduct normal life 
functions. Important medical events that may not result in death or be life-threatening may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the 

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participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  
 
 
10.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
10.3.3.1 SEVERITY OF EVENT 
 
For adverse events (Aes) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity:  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’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 participant’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 to “serious”. For 
purposes of this study, the following will be considered severe adverse events: 
 
1. Death 
2. A life threatening experience 
3. Persistent or significant disability/incapacity 
4. Seizure secondary to hypoglycemia 
5. Myocardial infarction that is temporally related to a hypoglycemic (< 70 mg/dL) event 
6. Cardiac dysrhythmia that that is temporally related to a hypoglycemic (< 70 mg/dL) event 
7. Reference Glucose Value < 54 mg/dL 
8. Diabetic Ketoacidosis: meeting all criteria: symptoms such as polyuria, polydipsia, nausea, or 
vomiting, serum ketones > 1.5 mmol/L, either arterial blood pH < 7.30 or venous pH < 7.24, or 
serum bicarbonate < 15. DKA is suspected as either the primary or a contributing cause for these 
findings. 
9. Considered severe for any other reason. 

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Study site personnel must alert Ideal Medical Technologies Inc. or its designee of any severe adverse 
event (SAE) within 48 hours of investigator awareness of the event via an agreed upon method. Alerts 
issued via telephone are to be immediately followed with official notification on study-specific SAE 
forms. See attachment IMT2022-1-A1 for serious adverse event form. 
 
 
10.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (Aes) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial of a 
medical device, the medical device under study must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
10.3.3.3 EXPECTEDNESS  
 
The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
 
10.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or severe adverse event (SAE) may come to the attention of 
study personnel during study visits or upon review by a study monitor. 
 
All Aes including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report CRF. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to medical device under study (assessed only by those 

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with the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All Aes occurring while on study must be documented appropriately regardless of relationship. All Aes 
will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Aes characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The Principal Investigator or his designee will record all reportable events with start dates occurring any 
time after informed consent is obtained until 1 (for non-serious Aes) or 3 days (for SAEs) after the last 
day of study participation.  At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution or 
stabilization. 
 
Unsolicited adverse events are not applicable to this study. 
 
 
10.3.5 ADVERSE EVENT REPORTING  
 
Adverse events will be reported by the Principal Investigator to the Institutional Review Board and study 
sponsor if in the opinion of the Principal Investigator the adverse event was caused by or related to use 
of the medical device under study. 
 
10.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
If during the course of this study a serious adverse event occurs, the Principal Investigator shall 
complete an Unanticipated Adverse Device Effect Form and submit to the study sponsor and to the 
reviewing Institutional Review Board (IRB) as soon as possible, but in no event later than 10 working 
days after the investigator first learns of the effect.  The study sponsor is responsible for conducting an 
evaluation of an unanticipated adverse device effect and shall report the results of such evaluation to 
the Food and Drug Administration (FDA), the IRB and the Principal Investigator within 10 working days 
after the sponsor first receives notice of the effect. Thereafter, the sponsor shall submit such additional 
reports concerning the effect as FDA requests. 
 

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10.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Adverse Events and Serious Adverse Events will be reported to the participants of this study if in the 
opinion of the Principal Investigator they are related to the medical device under study. 
 
10.3.8 EVENTS OF SPECIAL INTEREST  
 
Any medical device malfunction that either impedes or prevents the carrying out of this study will be 
reported to the sponsor, IRB, and regulatory agencies. 
 
10.3.9 REPORTING OF PREGNANCY  
 
If during the course of this study, a subject has signed an informed consent and is found to be pregnant 
prior to the treatment phase of the study, this subject will be informed of the positive pregnancy test 
and the fact that this excluded them from the treatment phase of the study. 
 
 
10.4 UNANTICIPATED PROBLEMS 
 
10.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Unanticipated problems will be considered those that involve risks to participants or others to include, 
in general, any incident, experience, or outcome that meets all the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 

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This definition could include an unanticipated adverse device effect, 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. 
 
10.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The Principal Investigator will report unanticipated problems (Ups) to the sponsor and the reviewing 
Institutional Review Board (IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
This report shall be submitted as soon as possible, but in no event later than 10 working days after the 
investigator first learns of the effect. A sponsor who conducts an evaluation of an unanticipated adverse 
device effect shall report the results of such evaluation to the FDA, the reviewing IRB, and to the  
Principal Investigator within 10 working days after the sponsor first receives notice of the effect. 
Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests.    
 
 
10.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable. 
 
11 STATISTICAL CONSIDERATIONS  
 
A formal Statistical Analysis Plan (SAP) will not be developed for this study, thus formal null and 
alternative hypothesis will not be stated. 
 
 

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11.1 STATISTICAL MEASUREMENTS 
 
Primary Safety and Efficacy Endpoints:  
 
1. 
Safety 
The safety of the FUSION system will be determined by its ability to avoid hypoglycemia in adult type 1 
and type 2 diabetic patients consuming three meals over a period of 24 hours. Safety will be measured 
by calculating the percent of all glucose values that are within the hypoglycemic range of less than 70 
mg/dL. 
 
Statistics – No statistical comparison will be made for this measurement. 
 
2. 
Efficacy 
The efficacy of the FUSION system will be determined by its ability to maintain glucose in the normal 
range in adult type 1 and type 2 diabetic patients consuming three meals over a period of 24 hours. 
Efficacy will be measured by calculating the percent of all glucose values that are within the normal 
glucose range of 70-180 mg/dL. 
 
Statistics – No statistical comparison will be made for this measurement. 
 
 
Secondary Efficacy Endpoints: 
 
The secondary objectives of the study are to assess the controller’s ability to minimize glucose curve 
measurements associated with increased ICU morbidity/mortality rates, and to maximize those 
measurements associated with decreased ICU morbidity/mortality rates. 
1. 
Measure the percent of glucose values that are within the severe hypoglycemic range of 0- <54 
mg/dL.  
Statistics – No statistical comparison will be made for this measurement. 
2. 
Measure the percent of glucose values that are within the moderate hypoglycemic range of 54-
69 mg/dL. 
Statistics – No statistical comparison will be made for this measurement. 
3. 
Measure the number of hypoglycemic (< 70 mg/dL) events. 
Statistics – No statistical comparison will be made for this measurement. 

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4. 
Measure the percent of all glucose values that are within the desired glucose control range of 
100-140 mg/dL.  
Statistics – No statistical comparison will be made for this measurement. 
5. 
Measure the percent of glucose values that are within the range of 70-140 mg/dL. 
Statistics – No statistical comparison will be made for this measurement. 
6. 
Measure the percent of glucose values that are within the hyperglycemic range of > 140 mg/dL. 
Statistics – No statistical comparison will be made for this measurement. 
7. 
Measure the percent of glucose values that are within the range of 70-180 mg/dL. 
Statistics – No statistical comparison will be made for this measurement. 
8. 
Measure the percent of glucose values that are within the hyperglycemic range of > 180 mg/dL. 
Statistics – No statistical comparison will be made for this measurement. 
9. 
Measure the mean glucose value in mg/dL. 
Statistics – No statistical comparison will be made for this measurement. 
10. 
Measure of dispersion – coefficient of variation. 
Statistics – No statistical comparison will be made for this measurement. 
11. 
The study data will be used to determine the percentage of paired glucose values (continuous 
glucose monitors and the average of the two continuous glucose monitors versus the Nova StatStrip 
Hospital Glucose Meter System Reference glucose) in each zone using a Clarke error grid analysis.1 No 
statistical comparison will be made for this measurement. 
 
The glucose data for the above statistical analysis will be the glucose data used by the FUSION system 
for purposes of glucose control, unless otherwise specified. 
 
11.2 SAMPLE SIZE DETERMINATION 
 
As this is a first in human study of a medical device a statistically determined sample size was not used. 
Rather, the subject number of eight was chosen as it is consistent with the FDA’s recommended number 
of 6-10 subjects for a first in human study of a medical device. 
 
The anticipated dropout rate after subjects have begun closed loop glucose control is less than 10%, 
which should not significantly affect the study results. No interim analysis is planned. Given the small 
sample size no subgroup analysis is planned.  
 
11.3 POPULATIONS FOR ANALYSES 

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Not applicable. All subjects who begin closed loop glucose control will be used for analysis. 
 
11.4 STATISTICAL ANALYSES 
 
11.4.1 GENERAL APPROACH 
 
The data will be presented as median and interquartile range (25-75), except for the Clarke error grid 
analysis which will be presented as percent of values in zones A, B, C, D and E.  
 
11.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
1. To determine percent time in range < 70 mg/dL for each subject, the calculation is as follows: 
 
(# of glucose values in range < 70 mg/dL/total number of all glucose values) * 100 
 
This result will be presented as median and interquartile range (25-75). 
 
2. To determine percent time in range 70-180 mg/dL for each subject, the calculation is as follows: 
 
(# of glucose values in range 70-180 mg/dL/total number of all glucose values) * 100 
 
This result will be presented as median and interquartile range (25-75). 
 
 
 
11.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
For the secondary endpoints that measure percent time in range, the values will be calculated as noted 
above in 9.4.2. These results will be presented as median and interquartile range (25-75).  
 
The number of hypoglycemic events less than 70 mg/dL will be presented as median and interquartile 
range (25-75).  
 
The mean glucose level will be presented as mean ± SD. 
 
The coefficient of variation will be presented as median and interquartile range (25-75). 

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The Clarke error grid analysis will be presented as a graph of the Clarke error grid. The Reference 
Glucose Value (Nova StatStrip Hospital Glucose Meter System) and Dexcom G6 data will be analyzed to 
determine the percent of all values that are in zones A, B, C, D and E. 
 
 
11.4.4 SAFETY ANALYSES 
 
For the safety primary endpoint of percent time in range < 70 mg/dL, the calculation is as follows: 
 
(# of glucose values in range < 70 mg/dL/total number of all glucose values) * 100 
 
This result will be presented as median and interquartile range (25-75).  
 
Each AE or SAE will be independently reported as percent of patients experiencing the event. SAE’s that 
require stopping the study prematurely will be separately reported in a table. If the principal 
investigator feels the AE or SAE’s are secondary to the intervention this will be reported in the final 
study summary. Any rescue medicine that is used per 8.5.1 will be separately reported as percent of 
subjects requiring rescue medicine. 
 
11.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
The following baseline characteristics will be recorded at the start of the study, 1) age, 2) sex, 3) 
duration of diabetes (years), 4) diabetes therapy at time of CRC study [e.g., insulin, oral anti-
hyperglycemic + insulin], 5) HbA1c level, 6) C-Peptide level, 7) Height (cm), 8) Body weight (Kg), 9) body 
mass index [BMI], 10) starting blood glucose (mg/dL), 11) Estimated Total Blood Volume. 
 
11.4.6 PLANNED INTERIM ANALYSES  
 
Planned interim analysis- None. 
 
 
11.4.7 SUB-GROUP ANALYSES 
 
Not applicable. 
 
11.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 

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Not applicable. 
 
11.4.9 EXPLORATORY ANALYSES 
 
None planned. 
 
12 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
12.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
12.1.1 INFORMED CONSENT PROCESS 
 
12.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol: 
 
IMT2022_1_Informed Consent Form_CRC_8 Subjects 
 
12.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 

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informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
For subjects who are not native English speakers, a study site provided medical translator will be made 
available for purposes of reviewing the informed consent document and answering any questions the 
subject has with regards to the study or the informed consent document. Family members will not be 
allowed to serve as translators. 
 
12.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, the Institutional Review Board, 
the Investigational Device Exemption (IDE)/study sponsor and regulatory authorities.  If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension.   
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or FDA. 
 
 
12.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 

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biological samples in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or medical device company supplying the medical device may 
inspect all documents and records required to be maintained by the Principal Investigator, including but 
not limited to, medical records (office, clinic, or hospital) and pharmacy records that are pertinent to the 
study, for the participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored for internal use during the study. At 
the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Emory University Healthcare. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by Emory University Healthcare research staff will be secured, and password protected. At 
the end of the study, all study databases will be de-identified and archived at Emory University 
Healthcare. 
 
 
12.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Not applicable. 
 
12.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
Francisco J Pasquel, MD, MPH 
Associate Professor of Medicine 
Dr. Leon DeJournett 
Chief Medical Officer 

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Division of Endocrinology, Metabolism, and 
Lipids 
Emory University School of Medicine 
Ideal Medical Technologies 
Emory University School of Medicine 
Division of Endocrinology, Metabolism, and 
Lipids 
69 Jesse Hill Jr Drive SE 
Atlanta, GA 30303 
 
Ideal Medical Technologies 
18 N Kensington Rd 
Asheville, NC 28804 
404-778-1695 
  
828-337-9960 
fpasque@emory.edu 
leondej@idealmedtech.com 
 
 
 
12.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of an Independent Safety Monitor (ISM) who will be a nurse 
with relevant expertise, whose primary responsibility is to provide independent safety monitoring in a 
timely fashion. This is accomplished by review of adverse events, immediately after they occur or are 
reported, with follow-up through resolution. The ISM evaluates individual and cumulative participant 
data when making recommendations regarding the safe continuation of the study. The ISM will provide 
input to both the Principal Investigator and the IRB. The ISM will be an employee of Emory University. 
 
 
12.1.7 CLINICAL MONITORING 
 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, and with 
applicable regulatory requirement(s).  
 
• 
Ideal Medical Technologies will provide an in-service to study personnel in order to ensure safe 
use of its FUSION closed loop glucose control system. IMT personnel will be immediately 

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available to answer any questions pertaining to the study protocol or the FUSION system. If IMT 
personnel are present on site during the 24 hour closed loop glucose control session, they will 
not interact with participants or their identifiable data. All study records will undergo a 
comprehensive review (100% data verification) by an Ideal Medical Technologies representative 
after completion of each study session to verify ongoing adherence to the study protocol. This 
review may occur remotely and must be completed prior to continuing with the subsequent 
study sessions. This review will include a monitoring report that will be sent to the PI via email 
prior to continuing with the study. Any issues raised during this review process must be 
addressed by the PI prior to continuing with the study. 
• 
Independent audits will not be conducted.  
 
The formal monitoring plan can be seen in the following document: 
 
IMT2022_1_CRC_T1DM_T2DM_Clinical Monitoring Plan 
 
12.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.  An individualized quality management plan will 
be developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted, and data are 
generated and biological specimens are collected, documented (recorded), and reported in compliance 
with the protocol, ICH GCP, and applicable regulatory requirements (e.g., GLP, Good Manufacturing 
Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
12.1.9 DATA HANDLING AND RECORD KEEPING  
 
12.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  

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Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
Principal Investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (Aes), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a FDA compliant data capture system 
provided by Emory University Healthcare. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
 
12.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Council on Harminosation (ICH) region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the IDE/study sponsor. It is the responsibility of the IDE/study sponsor to 
inform the investigator when these documents no longer need to be retained. 
 
 
12.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly.  

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These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation.  All deviations must be 
addressed in study source documents and reported to the study sponsor.  Protocol deviations must be 
sent to the reviewing Institutional Review Board (IRB) per their policies. The Principal Investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. The protocol deviations will 
also be reported to the FDA as required. 
 
 
12.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. 
This study will be registered with ClinicalTrials.gov. 
 
For any peer reviewed articles submitted for publication that arise out of the results of this study, the 
Principal Investigator or the Principal Investigators designated co-investigator will serve as lead author. 
In addition, the following two Ideal Medical Technologies (sponsor) employees will also be named 
authors of any and all publications that arise out of the results of this study: 
 
1. Jeremy DeJournett 
2. Leon DeJournett 
 
 

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12.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the medical device 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership has established policies and procedures for all study group members to disclose all conflicts 
of interest and will establish a mechanism for the management of all reported dualities of interest. 
 
Conflicts of interest: 
 
Leon DeJournett – Owns stock in Ideal Medical Technologies. 
 
Jeremy DeJournett – Owns stock in Ideal Medical Technologies. 
 
12.2 ADDITIONAL CONSIDERATIONS 
This section should include a description of any additional considerations not currently covered in this 
protocol template, such as particular institutional or IRB-related requirements.  
 
12.2.1 DATA IDENTIFICATION 
Subjects who have signed an informed consent will be assigned a unique identification number that will 
remain the same throughout the study. This identification number will be used to identify the subject, 
for purposes of initiating the FUSION system at the start of the study. This number will be visible on the 
FUSION systems graphical user interface throughout the 24 hour closed loop glucose control session and 
will be the only subject identifier displayed on the FUSION systems graphical user interface. The FUSION 
systems graphical user interface will not display any information that could be used to directly identify 
the subject (e.g., name, date of birth, social security number). This study will use only de-identified data. 
12.2.2 ROLE OF IDEAL MEDICAL TECHNOLOGIES PERSONNEL IN STUDY 
Ideal Medical Technologies personnel will be available throughout the 24 hour closed loop glucose 
control session to assist the study personnel with use of the FUSION system. This assistance will be 
limited to the following: 

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1. Explanation of the components of the FUSION system including the connecting cables and 
power cords 
2. Explanation of the powering up process of the FUSION system 
3. Explanation of how to use the two syringe pumps that are part of the FUSION system 
4. Explanation of how to load the insulin and dextrose medication syringes into the two syringe 
pumps 
5. Explanation of how to change the medication syringes used in the syringe pumps 
6. Explanation of the proper set up of the medication (e.g., insulin and dextrose) and carrier 
solution (e.g., ½ NS) intravenous lines 
7. Explanation of how to enter the data needed to initiate the FUSION system (e.g., unique 
identification number and weight in kg) 
8. Explanation of how to start the closed loop glucose control session 
9. Explanation of how to pause the closed loop glucose control session 
10. Explanation of how to end the closed loop glucose control session 
11. Explanation of how to extract study data from the FUSION system at the end of the closed loop 
glucose control session 
12. Explanation of how to power down the FUSION system 
13. Explanation of how to properly store the FUSION system 
 
Ideal Medical Technologies personnel will not attempt to interact with the study subjects in any way. 
Ideal Medical Technologies personnel will provide no medical care for the study subjects. Ideal Medical 
Technologies personnel will not personally extract the study data from the FUSION system. Ideal 
Medical Technologies personnel will not analyze the study data (this analysis will be performed by 
Emory University study personnel). 
 
12.3 ABBREVIATIONS 
 
AE 
Adverse Event 
AI 
Artificial Intelligence 
ALT 
Alanine Aminotransferase 
AP 
Artificial Pancreas 
BD 
Becton Dickinson 
BMI 
Body Mass Index 
CGM 
Continuous Glucose Monitor 
CM 
Centimeter 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
CT 
Computerized Tomography 

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CV 
Coefficient of Variation 
dL 
Deciliter 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EFS 
Early Feasibility Study 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HbA1c 
Hemoglobin A1c (glycosylated hemoglobin) 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
iCGM 
Integrated continuous glucose monitor 
ICH 
International Council on Harmonisation  
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IMT 
Ideal Medical Technologies 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
IV 
Intravenous 
KBS 
Knowledge Based System 
KDS 
KD Scientific 
Kg 
Kilogram 
L 
Liter 
LOS 
Length of Stay 
mg 
Milligrams 
mg/dL 
Milligrams/deciliter 
MIMO 
Multiple Input Multiple Output 
min 
Minute 
mL 
Milliliter 
mL/kg/hour 
Milliliters/kilogram/hour 
mM 
Millimole 
mmol 
Millimole 
mmol/L 
Millimole/Liter 
MOP 
Manual of Procedures 
MPC 
Model Predictive Control 
n 
Number 
NA 
Not Applicable 
NIH  
National Institutes of Health 
NYHA 
New York Heart Association 
P 
Probability 
PD 
Proportional Derivative 
PI 
Principal Investigator 
PID 
Proportional Integral Derivative 

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QA 
Quality Assurance 
QC 
Quality Control 
RN 
Registered Nurse 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Sensor Error 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
STAT 
Immediately 
TIR hi 
Time In Range high 
TIR lo 
Time In Range low 
units/kg/hour 
Units/Kilogram/hour 
unit/mL 
Unit/Milliliter 
UP 
Unanticipated Problem 
USA 
United States 
YSI 
Yellow Springs Instrument 
% 
Percent 

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12.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Okabayashi T, Shima Y, Sumiyoshi T, et al. Intensive versus intermediate glucose control in surgical 
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Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe 
sepsis. N Engl J Med 2008;358:125-39. 
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Cryer PE. Hypoglycemia, functional brain failure, and brain death. J Clin Invest 2007;117:868-70. 
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Hulkower RD, Pollack RM, Zonszein J. Understanding hypoglycemia in hospitalized patients. Diabetes 
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Uijtendaal EV, Zwart-van Rijkom JE, de Lange DW, Lalmohamed A, van Solinge WW, Egberts TC. Influence 
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84. 
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Thabit H, Hartnell S, Allen JM, et al. Closed-loop insulin delivery in inpatients with type 2 diabetes: a 
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Takahashi G, Sato N, Matsumoto N, et al. Preliminary study on glucose control with an artificial pancreas 
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Williams TA, Ho KM, Dobb GJ, et al. Effect of length of stay in intensive care unit on hospital and long-term 
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91. 
Klonoff DC, Umpierrez GE, Rice MJ. A Milestone in Point of Care Capillary Blood Glucose Monitoring of 
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92. 
Goldberg PA, Kedves A, Walter K, Groszmann A, Belous A, Inzucchi SE. "Waste not, want not": determining 
the optimal priming volume for intravenous insulin infusions. Diabetes Technol Ther 2006;8:598-601. 
93. 
Liu D, Moberg E, Kollind M, Lins PE, Adamson U, Macdonald IA. Arterial, arterialized venous, venous and 
capillary blood glucose measurements in normal man during hyperinsulinaemic euglycaemia and hypoglycaemia. 
Diabetologia 1992;35:287-90. 
 

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Protocol 1 – Preparation of Subject for Visit 3 
(IMT2022-1-P1) 
 
ii. Study Materials (Visit 3) 
The following materials will be available in the subject’s CRC room for purposes of performing the closed 
loop glucose control study. 
A) 
Six 50 mL BD syringes filled with NovoLog insulin mixed in normal saline to a concentration of 1 
unit/mL (study site research pharmacy to fill these 50 mL syringes using their standard sterile 
technique). Must be available by 1200 hours on day of CRC study. 
B) 
Forty 50 mL BD syringes filled with D10 normal saline (study site research pharmacy to fill these 
50 mL syringes using their standard sterile technique). Must be available by 1200 hours on day 
of CRC study. 
C) 
One 500 mL bags of normal saline and one 500 mL bag of one-half normal saline and associated 
intravenous tubing needed to infuse via an intravenous pump. 
D) 
Two intravenous pumps (these are in addition to the IMT supplied syringe pumps used by the 
FUSION system). 
E) 
One hundred TB syringes for purposes of withdrawing blood from the arterialized hand vein. 
F) 
Nova StatStrip Hospital Glucose Meter System Glucose Hospital Meter System, including at least 
100 glucose test strips. 
G) 
Nova Max Plus ketone meter (Nova Biomedical) and associated ketone test strips. 
H) 
FUSION glucose control system (20) to be provided by the studies sponsor at least 2 weeks prior 
to the studies onset. 
I)  
Four 6-12 foot lengths of non-microbore intravenous tubing for purposes of infusing solutions 
(e.g., insulin, D10NS, ½ NS, NS) into the subject. 
 

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1.2 
Continuous Intravenous Infusion Set Up 
A) 
Run one-half normal saline at 10 mL/hour via the peripheral IV that will be used to infuse the 
insulin and/or D10NS from the FUSION system. Refer to below diagram (Figure 26) for the setup 
of the ½NS, insulin, and dextrose lines. The intravenous tubing used for the insulin infusion 
should be flushed with 50 mL of insulin solution prior to being connected to the peripheral IV.92 
Run normal saline at 10 mL/hour via the retrograde peripheral IV to maintain patency between 
blood draws. 
 
 
 
 
D10NS - FUSION 
½ Normal Saline 
Insulin - FUSION 
Figure 26 – Illustration of set up of insulin, dextrose, and normal saline infusions for the FUSION closed loop 
glucose control system. 

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Protocol 2 – Meal Challenge in Type 1 and Type 2 
Diabetic Subjects 
(IMT2022-1-P2) 
MEAL CHALLENGE PROTOCOL 
Type 1 and Type 2 diabetic subjects will be admitted to the CRC between 0600 to 0700 hours after an 
overnight fast. 
Methods Overview: 
After admission to the CRC and confirming the subjects are eligible to continue with the closed loop 
glucose control session on visit 3 (see pages 53-54), catheters will be placed in one antecubital vein for 
purpose of insulin and or D10NS infusion, and in a contralateral arm vein in a retrograde fashion for 
purposes of blood draws. 
Precaution to Avoid Electrostatic Discharge from Affecting FUSION System 
Touching the FUSION system when your body has a build-up of static electricity may cause an 
electrostatic discharge (e.g., flow of electricity) into the FUSION system. It is unknown if this would 
adversely affect the performance of the FUSION system. In order to mitigate against the risk of study 
personnel introducing an electrostatic discharge into the FUSION system, the following precaution must 
always be taken prior to touching the FUSION system: 
1. Touch a metal table that is positioned near the FUSION system but is not in contact with 
the subject or the FUSION system. This procedure must be performed prior to each 
interaction (e.g., touching) with the FUSION system. 
Meal Challenge Protocol: 
The meal challenge protocol is outlined in detail below. 
Potential Problems. 
Severe hypoglycemia (< 54 mg/dL) may be associated with adrenergic response symptoms (tachycardia, 
sweating, palpitations) and neuroglycopenia symptoms (impaired cognition, coma, seizures).  Based 
upon previous studies, patients can sustain hypoglycemia for approximately 30 min to an hour. 
 

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To avoid risk to our human subjects, vital signs will be monitored closely. Frequent independent glucose 
measurements will be performed (every 10-60 minutes) to minimize the risk of severe hypoglycemia (< 
54 mg/dL) or moderate hypoglycemia (54-69 mg/dL) with the above noted hypoglycemia symptoms. The 
protocol calls for rescue doses of 15 mL of 50% dextrose for severe hypoglycemia, moderate 
hypoglycemia with hypoglycemia symptoms, or neuroglycopenia. In addition, the study on any one 
subject will be terminated if they experience a severe hypoglycemia event (< 54 mg/dL). The overall 
study will be terminated if two subjects experience a severe hypoglycemia event (< 54 mg/dL).  
 
Patients with a history of liver failure, renal failure, cerebrovascular accident, seizure disorder, 
congestive heart failure, and ischemic heart disease will not be recruited for this study. 
During the time period when the FUSION system is operational and active, if a participant’s CGM or 
Reference Glucose Value is >240 mg/dL for over 1 hour or ≥ 300 mg/dL at any point after starting the 
FUSION system, the following steps will be taken: Ketones will be assessed at the discretion of the 
principal investigator(s) for any concern about possible ketosis or DKA by checking a blood ketone level 
at the bedside. If the blood ketone level is greater than 1 mmol/L, a venous blood sample from the 
subject will be sent to the central laboratory of Emory Healthcare for a basic metabolic panel, blood pH, 
and beta hydroxybutyrate level. If the subject is found to be in DKA, the subject will be stabilized per the 
usual routine care at Emory Healthcare. 
When a hyperglycemia/ketotic event meets the above reporting requirements, an Adverse Event Form 
will be completed. Events meeting DKA criteria should be considered serious adverse events with 
respect to reporting requirements. Hyperglycemia events not meeting criteria for DKA generally will not 
be considered as serious adverse events unless one of the severe adverse event criteria is met.  
 
 

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Meal Challenge Protocol Detailed 
 
 
 
Figure 27 – Carbohydrates should represent 45-60% of total Kcal’s for each meal. The total carbohydrates 
consumed at breakfast, lunch and dinner will be 50, 60 and 75 grams. 
 
1.  Admit to Study Site on (specify date) ______________________ between 06:00-07:00AM. 
 
2.  Informed Consent       ___   Signed and in the Medical Chart. 
                                       ___   Must be signed upon Admission prior to any procedure. 
 
3.  Ad Lib water prior to Closed Loop Glucose Control 
 
Instruct subject to void. Subject may have ad lib water throughout their entire stay in the CRC. 
4.  Voiding during the CRC visit (time 0-32 hours) 
The subject may use the bathroom for voiding prior to the onset of the closed loop glucose control 
session (time 0-5 hours), and after conclusion of the closed loop glucose control session (time 29-
32 hours). If subject needs to void during the closed loop glucose control session (time 5-29 hours), 
a bedpan/urinal must be provided, in order to make sure the subjects blood glucose level remains 
under the control of the FUSION system. 
5.  Diet before study onset (time -7 to 1 hours):  
Fast between 00:00 hours (e.g., midnight) on day of closed loop study and time of breakfast at 0800 
hours on day 1. 
6.  Research staff to calibrate and Quality Control the Nova StatStrip Hospital Glucose Meter System 
0
10
20
30
40
50
60
70
80
Breakfast
Lunch
Dinner
(Grams)
Carbohydrate Intake Per Meal

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7.  Screening prior to initiation of the closed loop glucose control session (time 0-1 hours) 
The subjects will be tested for the presence of diabetic ketoacidosis and appropriate Reference 
Glucose Values prior to proceeding with the closed loop glucose control session. This testing will 
include: 
i. 
Reference Glucose Value at time of admission to the CRC – If the Reference 
Glucose Value is greater than 300 mg/dL, the subject will be screened for blood 
ketones using the Nova Max Plus (Nova Biomedical) ketone meter. If the 
Reference Glucose Value is less than 70 mg/dL or the subjects are experiencing 
any symptoms of hypoglycemia, regardless of their blood Reference Glucose 
Value, the subjects will be offered a snack or glucose containing juice. To be clear, 
the Nova Max Plus ketone meter will be used for any blood ketone analysis 
performed during the time the subjects are in the CRC. 
ii. 
Blood ketones – The study will be cancelled if the blood ketones are > 1 mmol/L. 
If blood ketones are > 1 mmol/L, a venous blood sample will be sent to the central 
lab at Emory University for a basic metabolic panel, venous pH and beta-
hydroxybutyrate to rule out diabetic ketoacidosis. If diabetic ketoacidosis is 
confirmed, the participant will be stabilized per the usual routine care at Emory 
Healthcare. 
iii. 
Blood glucose prior to insertion of Dexcom G6 CGM’s and intravenous lines – The 
subjects Reference Glucose Value must be in the range of 70-300 mg/dL prior to 
insertion of the two Dexcom G6 CGM’s and two intravenous lines. 
In addition, the closed loop glucose control session will not be initiated if the participant has 
symptoms requiring action (e.g., abdominal pain, vomiting, unable to eat or drink, fever ≥ 101.5), 
regardless of blood glucose or ketone levels. 
8.  Diet before onset of closed loop glucose control session (time 0-5 hours): 
Subject to be offered breakfast with 50 grams of carbohydrate at time 1 hours ( ̴ 0800 hours on day 
1), after admission to the CRC unit.  After consuming breakfast, the subject is to remain NPO until 
lunch offered at the time of initiation of the closed loop glucose control session at time 5 hours ( ̴ 
1200 on day 1). After admission to the CRC, if the subject has a Reference Glucose Value less than  
70 mg/dL or is experiencing signs of neuroglycopenia (hypoglycemia of sufficient duration and 
degree to interfere with normal brain metabolism and function) at any Reference Glucose Value, 
they will be offered snacks and/or glucose containing juice. 
9.  Insulin Dosing Prior to Study Onset (time 0-5 hours): 
The study’s principal investigators (Dr. Pasquel or Dr. Davis) will determine the short acting insulin 
dose required to cover the breakfast that is consumed at approximately 0800 hours on Day 1, based 
on the subject’s medical history, pre-prandial Reference Glucose Value that is measured by the 
Nova StatStrip Hospital Glucose Meter System from a fingerstick capillary sample, and carbohydrate 
load in the meal. All insulin doses given during the CRC stay (visit 3)  will be administered by a 

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research nurse and will be documented in the subjects Electronic Health Record. The Emory Clinical 
Research Center will provide all insulin that is administered to the subjects throughout visit 3 (e.g., 
the subject may not use their own insulin during visit 3). 
 
10.  Body Measurements: Weight:  __________ kg   Height:  __________ cm 
 
 
11.  Two IV Catheters placements: 
- 
One antecubital intravenous line (for infusion of insulin and dextrose) with an 18-20 gauge 
catheter with two 3-way gang stopcock (insulin from FUSION system in first stopcock, 
dextrose from FUSION system in second stopcock). First stopcock closest to subject, second 
stopcock furthest from subject. 
- 
One IV (18-20 gauge catheter) in contralateral hand (from antecubital IV) placed in a 
retrograde fashion for purposes of blood draws. This hand to be warmed as noted below. 
- 
Study nurse to inspect IV sites on an hourly basis, or whenever subject complains of pain at 
IV site. 
- 
  
A. Run ½ normal saline at 10 mL/hr using a standard IV pump through the IV line used to 
infuse insulin and/or dextrose from the FUSION system. 
B. Run normal saline at 10 mL/hr using a standard IV pump through the retrograde hand IV 
line used for blood draws. 
12.  Warming of retrograde hand vein to 50-55 °C 
 
Arm with retrograde hand IV that is to be used for blood sampling will be kept warm by use of a 
heating pad or similar device to increase blood flow in order to achieve “arterialized” samples.93  
 
13.  Monitoring Activities: 
A. Vital signs (Every 4 hours throughout the entire CRC stay):  
Temp _______          RR _______          HR   ________     Time of collection: _____:_____ 
 
BP ______ / ______          Time of collection: _____:_____ 
Document the vital signs on the case report form. 
B. Assessment of IV sites (Every 1 hour during closed loop glucose control session): 
Assess for signs of infiltration as evidenced by local swelling or pain at IV insertion site. 
Assess for signs of bleeding. Document these assessments on the case report form. 
C. Assessment for fluid overload (Every 2 hours during closed loop glucose control session): 
Assess for signs of fluid overload that will be manifested as peripheral edema (swelling of 
hands, feet, legs, or eyelids), shortness of breath, and rales on auscultation of lungs. 
Document these assessments on the case report form. 
D. Assessment of CGM insertion sites (Every 4 hours from time 4 to 32 hours): 
Assess for local signs of skin irritation, bleeding, or infection. 
E. Assessment for development of DKA, Severe Hyperglycemia, or HHS 

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Assess for the development of DKA, severe hyperglycemia (> 240 mg/dL), or HHS by 
obtaining Reference Glucose Values at least every 1 hour. The study will have termination 
criteria (see below) that will terminate the study on the subject if they are showing signs of 
DKA, severe hyperglycemia, or HHS. 
 
14.  Termination Criteria 
A. Termination Criteria for individual subjects: 
The study will be terminated on individual subjects if any of the following criteria are met: 
1. Subject requests withdrawal from the study for any reason. 
2. The clinical study nurses are unable to insert two working Dexcom G6 CGM’s prior to 
beginning the closed loop glucose control session. 
3. Subject has a Reference Glucose Value less than 54 mg/dL. 
4. Subject has signs of prolonged severe hyperglycemia, as defined by Reference Glucose 
Value > 240 mg/dL for more than 2 hours. 
5. Subject has signs of DKA, as defined by a Reference Glucose Value > 240 mg/dL and  blood 
ketones > 1 mmol/L. 
6. Subject has signs of HHS, as defined by a Reference Glucose Value > 300 mg/dL for more 
than 1 hour. 
7. FUSION system has only one Dexcom G6 CGM available for use for more than 4 hours. 
8. FUSION system has no Dexcom G6 CGM’s available for use for more than 20 minutes. 
9. There are no Reference Glucose Values for a period of time greater than 60 minutes. 
10. The FUSION system suffers any unanticipated adverse device effect (UADE). 
11. The subject has had more than 2% of their estimated total blood volume drawn during 
visit 3. 
12. The FUSION system delivers more than 2000 mL (insulin and dextrose infusions) during the 
24-hour closed loop glucose control session. 
 
B. Termination Criteria for the entire study: 
The entire study will be terminated if the following criteria are met: 
1. Two subjects experience Reference Glucose Values < 54 mg/dL during the time period the 
FUSION system is in use. 
2. Two subjects experience an episode of severe hyperglycemia, as defined by a Reference 
Glucose Value > 240 mg/dL for more than 2 hours. 
3. One subject experiences an episode of DKA after starting the closed loop glucose control 
session. 
4. One subject experiences an episode of HHS after starting the closed loop glucose control 
session. 
5. The FUSION system delivers more than 2000 mL (insulin and dextrose infusions) during the 
24-hour closed loop glucose control session in two subjects. 
6. The FUSION system experiences any unanticipated adverse device effect (UADE). 
7. The study’s principal investigator determines that the safety of the studies subjects is being 
compromised through use of the FUSION system. 

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15.  Obtain Reference Glucose Values using the Nova StatStrip Hospital Glucose Meter System every 
10-60 minutes from time 4 to 32 hours according to the following guidelines: 
 
A. Every 10 minutes: 
Monitor the subject’s Reference Glucose Values every 10 minutes whenever either of the 
following occur: 
I. 
Either of the Dexcom G6 CGM’s is less than 70 mg/dL. 
II. 
When the most recent Reference Glucose Value is less than 70 mg/dL. 
 
Discontinue every 10 minute Reference Glucose Value monitoring when both of the 
following have occurred: 
I. 
Both Dexcom G6 CGM’s are greater than 70 mg/dL. 
II. 
The subjects have two consecutive Reference Glucose Values greater than 70 
mg/dL. These Reference Glucose Values will be measured by the Nova StatStrip 
Hospital Glucose Meter System on either a venous or capillary blood sample. 
B. Every 30 minutes: 
Monitor the subject’s Reference Glucose Values every 30 minutes when the following 
occur: 
I. 
After both Dexcom G6 CGM’s begin to return glucose readings after their original 
insertion and prior to the onset of the closed loop glucose control session, for 
purposes of verifying the accuracy of the CGM’s. This monitoring prior to the onset 
of the closed loop glucose control session may be discontinued once both CGM’s 
have met the following CGM Validation Criteria on two consecutive Reference 
Glucose Values: 
 
CGM readings must be within ± 20 mg/dL of the Reference Glucose Value for CGM 
readings < 100 mg/dL or CGM readings must be within ± 20% of Reference Glucose 
Values for CGM readings >= 100 mg/dL on two consecutive Reference Glucose 
Values. 
 
II. 
During the first 2 hours of the closed loop glucose control session (time 5-7 hours). 
III. 
When either Dexcom G6 CGM has a glucose reading less than 85 mg/dL displayed 
on either the Dexcom G6 Receiver of the Dexcom G6 Follow App. 
IV. 
During periods of severe hyperglycemia, which is defined as a CGM or Reference 
Glucose Value greater than 240 mg/dL. 
V. 
When only one Dexcom G6 CGM is available for use by the FUSION system for 
glucose control. 
VI. 
After a CGM has been replaced, and until the replaced CGM has met the  above 
noted CGM Validation Criteria. 
VII. 
When the subject experiences any signs of neuroglycopenia, regardless of the 
glucose level displayed by the CGM’s. 
VIII. 
From time 29-32 hours, which is the 3 hour time period after conclusion of the 
closed loop glucose control session. 

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C. Every 60 minutes: 
Monitor the subject’s Reference Glucose Value every 60 minutes when the following 
occur: 
i. 
During the last 22 hours of the closed loop glucose control session (time 7-29 
hours), if the following occur: 
a) Both CGM’s are in the range of 85-240 mg/dL and the subject is not 
experiencing any signs of neuroglycopenia. 
 
Result: _____ mg/dL, Time: _________ (24 hour clock) 
Note: Notify study team if the CGM or Reference Glucose Value is < 70 mg/dl or > 300 mg/dl. 
 
16.  Dexcom G6 CGM Placement, Calibration and Replacement 
 
 Visit 3 (Time 0 to 5 hours): 
Place two Dexcom G6 CGM’s in the abdomen 5 cm to the right and left of the umbilicus (Figure 28). 
 
 
 
Figure 28 – Green shaded areas denote appropriate areas of the abdominal wall to place the Dexcom G6 
CGM’s. This figure is  from the Dexcom G6 CGM user manual. 

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Make sure the Dexcom G6 Transmitters are labeled “#1” and “#2”. These labels should be in a 
clearly visible position after the Transmitters have been attached to the Dexcom G6 glucose 
sensors. Once both Dexcom CGM’s begin to return glucose values, obtain a Reference Glucose 
Value using the Nova StatStrip Hospital Glucose Meter 
System. If either of the Dexcom CGM’s do not meet CGM 
Validation Criteria, they may be calibrated. The Dexcom G6 
CGM’s must meet the following CGM Validation Criteria 
throughout the CRC study session (visit 3), otherwise they 
will be calibrated as often as is necessary: 
 
1. CGM readings must be within ± 20 mg/dL of the 
Reference Glucose Value for CGM readings < 100 
mg/dL or CGM readings must be within ± 20% of 
Reference Glucose Values for CGM readings >= 100 
mg/dL on two consecutive Reference Glucose 
Values. 
 
Calibrations should only be attempted when the glucose rate 
of change is less than ± 2 mg/dL/min on the Dexcom G6 CGM 
(see figure 29). 
 
If after two calibration attempts prior to beginning the closed 
loop glucose control session (time 0-5 hours) the CGM(s) still do not meet CGM Validation Criteria, 
they may be replaced. The closed loop glucose control session may not begin until there are two 
working Dexcom G6 CGM’s in place, and both CGM’s have met the above noted CGM Validation 
Criteria. 
 
Closed Loop Glucose Control Session (Time 5 to 29 hours): 
Inspect the CGM sites (see Monitoring Activities) and ensure proper performance and 
communication to the two Dexcom G6 Receivers that are labeled “#1” and “#2”, and that are part 
of the FUSION system (Figure 20); ensure communication with the Dexcom G6 Follow APP on the 
two mobile phones labeled “#1” and “#2”. The CGM’s may be replaced during the closed loop 
glucose control session for any of the following reasons: 
1. The CGM(s) do not meet the above noted CGM Validation Criteria and are unable to be 
calibrated after two attempts over a two-hour period of time. 
2. If the CGM measurement is > 180 mg/dL and the simultaneous (e.g., within 5 minutes) 
Reference Glucose Value is < 100 mg/dL, the CGM may be replaced as this scenario may 
lead to inadvertent insulin administration by the FUSION system, which may result in 
hypoglycemia (< 70 mg/dL). 
3. If the CGM measurement is < 100 mg/dL and the simultaneous (e.g., within 5 minutes) 
Reference Glucose Value is > 180 mg/dL, the CGM may be replaced as this scenario may 
lead to a delay in the treatment of hyperglycemia, which will increase the risk for DKA in 
type I diabetic subjects. 
Figure 29 – Glucose rate of change, 
as noted by the Dexcom G6 CGM 
trend arrows. 

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4. The CGM(s) experience repeated compression artifact that is unable to be relieved through 
repositioning of the subject. Compression artifact is a sudden non-physiologic fall in one of 
the CGM glucose levels (e.g., < ± 2 mg/dL/min), when the second CGM does not experience 
this same degree of fall in its glucose level. The FUSION system monitors for compression 
artifact and will display an alarm alerting the clinical study nurse of its occurrence, and the 
need to reposition the subject so that they are not directly laying on the transmitter/sensor 
pair. 
5. The subject is experiencing significant bleeding, pain, or signs of infection at the CGM 
insertion site. 
6. The CGM transmitter/sensor pair stops working for any reason. 
 
If the Dexcom G6 CGM’s need to be replaced during visit 3, the preferred replacement site is 
another abdominal position (see Figure 28). If another abdominal site is used, place the new CGM 
at least 10 cm away from the other abdominal CGM that is still working properly. As an alternative, 
and only if another abdominal site is not available or may result in further compression artifacts, a 
replacement CGM may be placed in the posterior upper arm position, on the contralateral side 
from the remaining CGM (e.g., if remaining CGM is on the right side of the abdomen, place the 
replacement CGM on the posterior aspect of the left upper arm). In the event a replacement CGM 
is used, it must be calibrated until it meets the above noted CGM Validation Criteria. The position 
of the CGM’s and all calibration attempts will be noted on the Case Report Form. 
 
17.  Frequency of CGM Calibration 
The CGM’s may be recalibrated as often as necessary during the closed loop glucose control session 
(time 5-29 hours) if they do not meet the following CGM Validation Criteria: 
 
1. CGM’s glucose readings must be within ± 20 mg/dL of Reference Glucose Values for CGM 
readings less than 100 mg/dL or must be within ± 20% of Reference Glucose Values for CGM 
readings greater than 100 mg/dL. 
 
 
Only CGM’s not meeting the above noted CGM Validation Criteria will be calibrated, thus either 
one or both CGM’s may be calibrated at any point in time, depending on the circumstances. 
 
In addition, the FUSION system monitors the CGM’s for signs of significant deviation (e.g., > 20%) 
from the average glucose value used by the FUSION system for glucose control. If the FUSION 
system detects CGM deviation of > 20% from the average glucose value used by the FUSION system 
(e.g., CGM #1 = 70 mg/dL, CGM #2 = 130 mg/dL, and average glucose value used by the FUSION 
system = 100 mg/dL) it will display an alarm alerting the clinical study nurse of this occurrence, and 
request that both CGM’s be recalibrated against a Reference Glucose Value. 
 
To be clear, if the CGM’s meet the above noted CGM Validation Criteria throughout their time of 
use in visit 3, and the FUSION system does not automatically call for a CGM calibration, it is possible 
to complete visit 3 with no calibration of either CGM. 

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18.  Standard Blood Collection Protocol per CRC guidelines 
 
RN: Draw blood glucose sample from retrograde intravenous line: Draw 0.5 mL of whole blood to 
measure glucose levels using the Nova StatStrip Hospital Glucose Meter System every 10-60 
minutes (time 4 to 32 hours). 
 
19.  Meal Challenge Protocol 
Time 5 hours ( ̴1200 on day 1): Subject to consume lunch with 60 grams of carbohydrate. 
Time 11 hours ( ̴ 1800 on day 1): Subject to consume dinner with 75 grams of carbohydrate. 
Time 25 hours ( ̴0800 on day 2): Subject to consume breakfast with 50 grams of carbohydrate. 
 
Carbohydrates should make up 45-60% of the total Kcal’s of each meal. 
 
Time 5 to 29 hours: Closed loop control of blood glucose with FUSION system (Figure 20), to control 
range of 100-140 mg/dL. 
 
Throughout the entirety of the subjects stay in the CRC (e.g., time 0 to 32 hours), if the subject has 
a Reference Glucose Value less than 70 mg/dL or is experiencing signs of neuroglycopenia 
(hypoglycemia of sufficient duration and degree to interfere with normal brain metabolism and 
function) at any Reference Glucose Value, they will be offered snacks and/or glucose containing 
juice. 
 
 
 
20.  RECOVERY PERIOD (Time 29 to 32 hours) 
1. Type 1 Diabetic Subjects: 
Type 1 diabetic subjects will be required to have four consecutive Reference Glucose Values 
within the range of 80-250 mg/dL, with the most recent rate of change being less than ± 2 
mg/dL/min, which is equal to either a single sideways arrow or a single up or down arrow as 
noted in the illustration above (Figure 29), which was taken from Dexcom G6 CGM manual. 
The glucose sample source can be either from a venous catheter sample, or from a capillary 
fingerstick. The Nova StatStrip Hospital Glucose Meter System will be used to analyze the sample 
for glucose. 
 
Following standard practice, subjects with type 1 diabetes will receive a dose of basal insulin dose 
two hours before discontinuation of the FUSION systems continuous insulin infusion (CII), as it is 
expected that basal insulin levels will slowly reach a therapeutic level after administration. An 
endocrinologist (Dr. Pasquel or Dr. Davis) will determine the dose of the basal insulin before CII 
discontinuation for subjects with type 1 diabetes. The next dose of basal insulin (at home) and 
transition to the participants home regimen will be determined by Dr. Pasquel or Dr. Davis.  

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The study’s principal investigators (Dr. Pasquel or Dr. Davis) will determine the short acting insulin 
dose to cover the lunch (60 grams of carbs) that is consumed at approximately 1200 hours on Day 
2, based on the participant’s medical history, pre-prandial Reference Glucose Value that is 
measured by the Nova StatStrip Hospital Glucose Meter System, and carbohydrate load in the meal. 
 
Subjects using insulin pumps will start continuous subcutaneous insulin therapy with rapid acting 
insulin immediately after stopping the FUSION systems CII. Dr. Pasquel or Dr. Davis may adjust the 
settings of the subject’s insulin pump prior to discharge from the CRC to minimize the risk of 
hypoglycemia or DKA. 
 
2. Type 2 Diabetic Subjects: 
 
Type 2 diabetic subjects will be required to have four consecutive Reference Glucose Values 
within the range of 80-250 mg/dL, with the most recent rate of change being less than ± 2 
mg/dL/min, which is equal to either a single sideways arrow or a single up or down arrow as noted 
in the above illustration (Figure 29). 
 
The glucose sample source can be either from a venous catheter sample, or from a capillary 
fingerstick. The Nova StatStrip Hospital Glucose Meter System will be used to analyze the sample 
for glucose. 
 
 
 
Recovery Period (Time 29 to 32 hours) – Subject to resume subcutaneous insulin injections: 
i. 
Subjects routinely injecting long acting insulin only in the morning will take a dose of long 
acting insulin at 2/3 of their normal dose. ___ units given at __ __  : __ __ (24 hour clock). 
 
i. 
Subjects routinely injecting long acting insulin morning and evening will take a 
dose of long acting insulin at ½ their normal morning dose and be instructed to 
take their evening dose as usual. ___ units given at __ __:__ __ (24 hour clock). 
 
ii. 
Subjects routinely injecting long acting insulin only in the evening will take a dose 
of long acting insulin at 1/3 of their normal dose and be instructed to take their 
evening dose as usual. 
___ units given at __ __:__ __ (24 hour clock). 
 
iii. 
The study’s principal investigators (Dr. Pasquel or Dr. Davis) will determine the 
short acting insulin dose to cover the lunch (60 grams of carbs) that is consumed at 
approximately 1200 hours on Day 2, based on the participant’s medical history, 
pre-prandial Reference Glucose Value that is measured by the Nova StatStrip 
Hospital Glucose Meter System, and carbohydrate load in the meal. 

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Both type 1 and type 2 diabetic subjects will consume a lunch consisting of 60 grams of 
carbohydrates beginning at 1200 hours on day 2. 
 
The study nurse will check Reference Glucose Values every 30 minutes with the Nova StatStrip 
Hospital Glucose Meter System – Times 29, 29.5, 30, 30.5, 31, 31.5, and 32 hours, etc., until the 
subjects Reference Glucose Values are in the range of 80-250 mg/dL for a period of at least two 
hours after the completion of the closed loop glucose control session, and the most recent 
glucose rate of change is less than ± 2 mg/dL/min. 
 
If the subject is removed from the study early due to the presence of hypoglycemia (e.g., < 54 
mg/dL or < 70 mg/dL with neuroglycopenic symptoms) or for any other reason, they will have 
ongoing monitoring in the CRC until they have had glucose values in the range of 80-250 mg/dL 
for a period of at least two hours, and until their most recent glucose rate of change is less than ± 
2 mg/dL/min. In the event the subject is removed from the study early, any short or long acting 
insulin dosing needed from the time the subject is removed from the study until the time the 
subject is discharged from the CRC, will be per the orders of the study’s principal investigators (Dr. 
Pasquel or Dr. Davis). 
 
If the subjects CGM or Reference Glucose Values are less than 70 mg/dL at the time they are 
removed from the study, they will have Reference Glucose Values measured every 10 minutes 
until such time as their glucose values are greater than 70 mg/dL. If the subject develops signs of 
diabetic ketoacidosis (e.g., Reference Glucose Value > 240 mg/dL and blood ketones > 1 mmol/L), 
they will have a basic metabolic panel, venous pH, and beta hydroxybutyrate drawn. If the subject 
develops diabetic ketoacidosis, they will be stabilized and have ongoing care per the usual routine 
of Emory Healthcare. 
 
21.  Intravenous Catheter Removal: 
Remove both IV catheters once the subjects Reference Glucose Value is in the range of 80-250 
mg/dL for a period of at least two hours after the completion of the closed loop glucose control 
session, and when the most recent glucose rate of change is less than ± 2 mg/dL/min. This criterion 
will not be met prior to time 32 hours ( ̴ 1500 hours of 2nd day in the CRC). The subject may be 
discharged from the CRC unit once this criterion has been met. 
22.  Discharge Criteria 
 
The subjects Reference Glucose Value must be between 80-250 mg/dL  for a period of 2 hours 
before discharge, and their most recent glucose rate of change must be less than ± 2 mg/dL/min. 
For subjects who have been placed back on their usual continuous subcutaneous insulin infusion 
pump, they may be discharged once their Reference Glucose Value is between 80-250 mg/dL  for 
a period of 2 hours, and their most recent glucose rate of change must be less than ± 2 
mg/dL/min. 
 

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All subjects must be observed for a minimum of 3 hours after the conclusion of the closed loop 
glucose control session and for at least 60 minutes after their most recent subcutaneous insulin 
injection (subjects on MDI insulin therapy), before being discharged from the CRC. 
 
End of Study Reference Glucose Value, BG: ____ mg/dL, Time: _________ (24 hour clock) 
 
23.  After the subjects have been discharged from the CRC, they will be instructed to check their blood 
glucose levels at home using their blood glucose meter at the following times: 
1. On arrival at home. 
2. Before dinner. 
3. At 9 P.M. 
4. On awakening the next morning. 
 
Subject to call study coordinator with concerns they have about their glucose levels or any other 
issue. 
 
 
 
 
 
 
 
 
 
 
 

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Attachment 1 
Serious Adverse Event Report Form 
IMT2022-1-A1 
 
Serious Adverse Event 
An adverse event is any untoward medical event associated with use of a drug or drug delivery system in 
humans, whether or not it is considered related to a drug or drug delivery system. For purposes of this 
study, a Serious Adverse Event (SAE) is any adverse event from this study that results in one of the 
following outcomes: 
 
• 
Death 
• 
A life threatening experience 
• 
Persistent or significant disability/incapacity 
• 
Seizure secondary to hypoglycemia 
• 
Myocardial infarction that is temporally related to a hypoglycemic (<70 mg/dL) event 
• 
Cardiac dysrhythmia that that is temporally related to a hypoglycemic (<70 mg/dL) event 
• 
Any other complication related to hypoglycemia 
• 
Reference Glucose Value less than 54 mg/dL 
• 
Considered significant for any other reason 
 
 
 
 
 

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THERAPEUTIC MODALITY IN TYPE 1 AND TYPE 2 DIABETIC PATIENTS 
 
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Serious Adverse Event (SAE) Report Form 
DEMONSTRATION OF AN ARTIFICIAL INTELLIGENCE BASED 
CLOSED LOOP GLUCOSE CONTROL SYSTEM AS A 
THERAPEUTIC MODALITY IN TYPE 1 AND TYPE 2 DIABETIC 
PATIENTS 
 
Protocol Number: 
IMT2022-1 
Site:  _____________________________________ 
Pt ID: ________________________ 
 
 
1. 
SAE Onset Date:  _______________ (dd/mm/yyyy) 
2. 
SAE Stop Date: _________________(dd/mm/yyyy) 
 
3. 
Location of serious adverse event: _________________________________ 
 
4. 
Was this an unexpected adverse event?        Yes        No   
 
5. 
Brief description of participant(s) with no personal identifiers:  
Sex:   F    M      Age: ______    
 
Diagnosis for study participation: _____________________ 
 
6. 
Brief description of the nature of the serious adverse event (attach description if more space needed): 
___________________________________________________________________ 
__________________________________________________________________________ 
 
7. 
Category of the serious adverse event:   
o Death – date __/___/___  (dd/mm/yyyy)  
 
    

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o Complication from severe hypoglycemia 
o Life-threatening 
 
  
         
 
 
  
o Hospitalization- prolonged 
  
 
 
 
  
 
o Disability / incapacity 
 
o Required intervention to prevent permanent impairment 
Other:________________________________________ 
8. 
Intervention type:   
 
 Medication or Nutritional Supplement: specify___________ 
 Device: Specify: ________________________ 
 Surgery: Specify: ________________________ 
 Behavioral/Life Style: Specify: _____________________ 
 
 
9. 
Relationship of event to intervention: 
 
o  Related - The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
 
o Not related - There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
10. 
Was study intervention discontinued due to event?   Yes    
No 
 
11. 
What medications or other steps were taken to treat serious adverse event?  
   

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12. 
List any relevant tests, laboratory data, history, including preexisting medical conditions 
 
 
 
 
13. 
 Type of report: 
 
  Initial   
  Follow-up 
  
  Final 
 
 
Signature of Principal Investigator: _______________________ Date: _______