Automated Insulin Delivery for INpatients With DysGlycemia (AIDING) Feasibility Study
Phase: NA
Conditions: Diabetes Mellitus
Sponsor: Emory University

Protocol 
 
Title: Automated Insulin Delivery for INpatients with DysGlycemia 
(AIDING) Feasibility Study  
 
NCT Number: NCT04714216 
 
 
Protocol Date: November 23, 2020 
 

Automated Insulin Delivery for INpatients with DysGlycemia (AIDING) Feasibility Study 
 
 
Signature Page 
Automated Insulin Delivery for INpatients with DysGlycemia (AIDING) Feasibility Study  
IDE Sponsor: Francisco J. Pasquel, MD, MPH  
Version Number: 2.2 
23 NOV 2020 
 
Study supporter  
Insulet Corporation 
Name, degree 
Trang Ly, MBBS, FRACP, PhD 
Signature/Date 
 
 
Clinical Lead Investigator 
 
Name, degree 
Francisco J Pasquel, MD, MPH 
Signature/Date 
 
 
Medical Monitor 
 
Name, degree 
Roy W. Beck, MD, PhD 
Signature/Date 
 

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Automated Insulin Delivery for INpatients with DysGlycemia (AIDING) Feasibility Study  
 
IDE Sponsor: Francisco J Pasquel, MD, MPH 
Funded by: Insulet Corporation 
 
Version Number: 2.2 
23 NOV 2020 
 

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KEY ROLES 
 
Principal Investigator, 
Coordinating Site 
 
Name, degree 
Francisco J Pasquel, MD, MPH 
Title 
Assistant Professor  
Institution Name 
Emory University School of Medicine 
 
Medical Monitor 
 
Name, degree 
Roy W. Beck, MD, PhD 
Title 
Executive Director 
Institution Name 
Jaeb Center for Health Research 
 
Study supporter 
 
Name, degree 
Trang Ly, MBBS, FRACP, PhD 
Title 
SVP, Clinical and Medical Director 
Institution Name 
Insulet Corporation 
 
Site Principal Investigator 
 
Name, degree 
Bruce Buckingham, MD 
Title 
Professor 
Institution Name 
Stanford University School of Medicine 
 
 
Site Principal Investigator 
 
Name, degree 
Sue A. Brown, MD 
Title 
Associate Professor 
Institution Name 
University of Virginia School of Medicine 

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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ......................................................................................... 15 
1.1 Introduction .................................................................................................................................. 15 
1.2 Rationale ...................................................................................................................................... 16 
1.2.1 Inpatient diabetes management and glycemic control targets ................................................... 16 
1.2.2 Hybrid closed-loop insulin therapy ......................................................................................... 18 
1.3 Preliminary Data .......................................................................................................................... 22 
1.4 Potential Risks and Benefits of the [Investigational Device] .......................................................... 25 
1.4.1 Known Potential Risks ........................................................................................................... 25 
1.4.1.1 Hyperglycemia and Hypoglycemia Risks ........................................................................ 25 
1.4.1.2 Other risks ...................................................................................................................... 26 
1.4.2 Known Potential Benefits ....................................................................................................... 26 
1.4.3 Risk Assessment ..................................................................................................................... 26 
1.5 General Considerations ................................................................................................................. 27 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING ........................................................................... 28 
2.1 Participant Recruitment and Enrollment ........................................................................................ 28 
2.2 Informed Consent and Authorization Procedures .......................................................................... 28 
2.3 Participant Eligibility.................................................................................................................... 29 
2.3.1 Inclusion Criteria .................................................................................................................... 29 
2.3.2 Participant Exclusion Criteria ................................................................................................. 29 
2.4 Screening Procedures ................................................................................................................... 29 
2.5 Data Collection and Testing .......................................................................................................... 30 
2.5.1 Daily data recording ............................................................................................................... 30 
CHAPTER 3: STUDY PROCEDURES ....................................................................................................... 30 
3.1 Omnipod 5/Horizon automated insulin delivery system ................................................................ 30 
3.1.1 Dexcom CGM validation ........................................................................................................ 32 
3.1.2 Ongoing glucose monitoring ................................................................................................... 33 
3.1.3 Insulin Delivery ...................................................................................................................... 33 
3.2 Unit-based monitoring .................................................................................................................. 34 
3.3 Remote monitoring by research staff............................................................................................. 34 
3.4 Interruption of HCL Therapy ........................................................................................................ 35 
3.5 Discontinuation of HCL/AID ........................................................................................................ 36 
CHAPTER 4: STUDY DEVICES ............................................................................................................... 37 
4.1 Description of the Investigational Device...................................................................................... 37 
4.1.1 Omnipod5/Horizon™ automated insulin delivery system ........................................................ 39 

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4.1.2 Continuous Glucose Monitoring ............................................................................................. 40 
4.1.3 Horizon Data Portal ................................................................................................................ 40 
4.1.4 Blood Glucose Meter and Strips ............................................................................................. 40 
4.1.5 Study Device Accountability Procedures ................................................................................ 41 
4.2 Safety Measures ........................................................................................................................... 41 
4.2.1 CGM verification of validation ............................................................................................... 41 
4.2.2 Pump Failure .......................................................................................................................... 41 
4.2.3 Hypoglycemia Threshold Alarm and Safety Protocol .............................................................. 41 
4.2.4 Hyperglycemia Threshold Alarm and Safety Protocol ............................................................. 41 
CHAPTER 5: TESTING PROCEDURES AND QUESTIONNAIRES ............................................................... 42 
5.1 Laboratory Testing ....................................................................................................................... 42 
5.2 Surveys and Questionnaires .......................................................................................................... 42 
CHAPTER 6: UNANTICIPATED PROBLEM, ADVERSE EVENT, AND DEVICE ISSUE REPORTING ............ 43 
6.1 Unanticipated Problems ................................................................................................................ 43 
6.2 Adverse Events ............................................................................................................................ 43 
6.2.1 Definitions.............................................................................................................................. 43 
6.2.2 Reportable Adverse Events ..................................................................................................... 44 
6.2.3 Hypoglycemic Events ............................................................................................................. 45 
6.2.4 Hyperglycemic/Ketotic Events................................................................................................ 45 
6.2.5 Relationship of Adverse Event to Study Investigational Device .............................................. 45 
6.2.6 Severity (Intensity) of Adverse Events .................................................................................... 46 
6.2.7 Expectedness .......................................................................................................................... 46 
6.2.8 Coding of Adverse Events ...................................................................................................... 46 
6.2.9 Outcome of Adverse Events.................................................................................................... 47 
6.3 Reportable Device Issues .............................................................................................................. 47 
6.4 Timing of Event Reporting ........................................................................................................... 48 
6.5 Safety Oversight ........................................................................................................................... 48 
6.6 Stopping Criteria .......................................................................................................................... 49 
6.6.1 Participant Discontinuation of Study Device ........................................................................... 49 
6.6.2 Criteria for Suspending or Stopping Overall Study .................................................................. 50 
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS ............................................................................... 51 
7.1 Drugs Used as Part of the Protocol................................................................................................ 51 
7.2 Collection of Medical Conditions and Medications ....................................................................... 51 
7.3 Prohibited Medications, Devices, Treatments, and Procedures ...................................................... 51 
7.4 Precautionary Medications, Treatments, and Procedures ............................................................... 52 

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7.5 Prophylactic Medications, Treatments, and Procedures ................................................................. 52 
7.6 Rescue Medications, Treatments, and Procedures ......................................................................... 52 
7.7 Pregnancy Reporting .................................................................................................................... 52 
7.8 Participant Compensation ............................................................................................................. 52 
7.9 Participant Withdrawal ................................................................................................................. 52 
7.10 Confidentiality............................................................................................................................ 52 
CHAPTER 8: STATISTICAL CONSIDERATIONS ...................................................................................... 53 
8.1 Statistical and Analytical Plans ..................................................................................................... 53 
8.2 Statistical Hypotheses ................................................................................................................... 53 
8.3 Sample Size.................................................................................................................................. 53 
8.4 Outcome Measures ....................................................................................................................... 53 
8.5 Analysis Dataset ........................................................................................................................... 54 
8.6 Analysis of the Primary Efficacy Endpoint(s) ............................................................................... 54 
The primary purpose of this pilot study is to assess the feasibility HCL use in the inpatient setting; 
therefore, no formal power calculations were performed. The main objectives of this study are to 
improve the quality and efficiency of the main study. In addition, it is conducted in order increase the 
investigators’ experience with the technology in a different setting. We will list values for each patient 
as well as provide summary statistics appropriate to the distribution. To determine the operability of 
AID in the hospital (Aim 1) we will calculate the proportion of time spent in HCL after CGM sensor 
values meet validation criteria [sensor glucose values are within ±20% of POC values for glucose levels 
≥70 mg/dL or ±20 mg/dL for POC glucose values <70 mg/dL]. To evaluate glycemic control (Aim 2) 
we will determine the percentage of time sensor glucose values are within target glucose range [time-in-
range (TIR); 70-180 mg/dL], during closed-loop insulin delivery. ...................................................... 54 
8.7 Analysis of the Secondary Endpoints ............................................................................................ 54 
8.8 Safety Analyses ............................................................................................................................ 54 
8.9 Intervention Adherence ................................................................................................................ 55 
8.10 Protocol Adherence and Retention .............................................................................................. 55 
8.11 Baseline Descriptive Statistics .................................................................................................... 55 
8.12 Device Issues.............................................................................................................................. 56 
8.13 Planned Interim Analyses ........................................................................................................... 56 
8.14 Sub-Group Analyses ................................................................................................................... 56 
8.15 Multiple Comparison/Multiplicity............................................................................................... 56 
8.16 Exploratory Analyses ................................................................................................................. 56 
8.17 Additional Tabulations and Analyses .......................................................................................... 56 
CHAPTER 9: DATA COLLECTION AND MONITORING ........................................................................... 57 
9.1 Case Report Forms and Other Data Collection .............................................................................. 57 
9.2 Study Records Retention .............................................................................................................. 57 

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9.3 Quality Assurance and Monitoring ............................................................................................... 57 
9.4 Protocol Deviations ...................................................................................................................... 58 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ......................................................... 59 
10.1 Ethical Standard ......................................................................................................................... 59 
10.2 Institutional Review Boards ........................................................................................................ 59 
10.3 Informed Consent Process .......................................................................................................... 59 
10.3.1 Consent Procedures and Documentation ............................................................................... 59 
10.3.2 Participant and Data Confidentiality...................................................................................... 59 
10.3.3 Future Use of Stored Specimens and Data ............................................................................. 60 
CHAPTER 11: REFERENCES .................................................................................................................. 61 
 
 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ACE 
Alternate Controller Enabled 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AID 
Automated Insulin Delivery 
ARD 
Absolute Relative Difference 
BG 
Blood Glucose 
BMI 
Body Mass Index 
CEG 
Clarke Error Grid 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
COVID-19 
Coronavirus-2019 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CV 
Coefficient of Variation 
DIC 
Disseminated Intravascular Coagulation 
DKA 
Diabetic Ketoacidosis 
DM 
Diabetes Mellitus 
eGFR 
Estimated Glomerular Filtration Rate 
EGV 
Estimated Glucose Value 
EHR 
Electronic Health Record 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GV 
Glycemic Variability 
HbA1c 
Hemoglobin A1c 
HCW 
Healthcare Worker 
HDP 
Horizon Data Portal 
ICR 
Insulin-to-Carbohydrate Ratio 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IL-6 
Interleukin-6 
IRB 
Institutional Review Board 
ISF 
Insulin Sensitivity Factor 
IV 
Intravenous 
MARD 
Mean Absolute Relative Difference 
MPC 
Model Predictive Control 
PDM 
Personal Diabetes Manager 
POC 
Point-of-Care 
PPE 
Personal Protective Equipment 
PUI 
Person Under Investigation 
QA 
Quality Assurance 
QC 
Quality Control 

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ABBREVIATION 
DEFINITION 
RBM 
Risk-Based Monitoring 
RCT 
Randomized Controlled/Clinical Trial 
SAE 
Severe Adverse Event 
SD 
Standard Deviation 
T1 
Type 1 
T2 
Type 2 
TAR 
Time Above Range 
TBI 
Total Basal Insulin 
TBR 
Time Below Range 
TDD 
Total Daily Dose 
TDI 
Total Daily Insulin 
TIR 
Time In Range 
UADE 
Unanticipated Adverse Device Effect 
 
 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: Automated Insulin Delivery for Inpatients with Dysglycemia (AIDING) 
Feasibility Study 
Protocol Version/Date: v. 2.2 / 11/23/2020 
I have read the protocol specified above.  In my formal capacity as a Site Principal Investigator, 
my duties include ensuring the safety of the study participants enrolled under my supervision and 
providing the Sponsor with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential and that 
this confidentiality requirement applies to all study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
required by the following (use applicable regulations depending on study location and sponsor 
requirements; examples follow): United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 
312, and/or 21 CFR Part 812). 
For the foreign sites, the trial will be carried out in accordance with ICH E6 Good Clinical 
Practice (GCP), the Declaration of Helsinki, and specific regulations applicable to the countries 
in which the trial will be conducted. 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training.  
Further, I agree to ensure that all staff members involved in the conduct of this study are 
informed about their obligations in meeting the above commitments. 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
 
dd 
mmm yyyy 
Investigator’s Name: ____________________________________ 
Site Name/Number: _____________________________________ 
 

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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
Automated Insulin Delivery for Inpatients with Dysglycemia (AIDING) 
Feasibility Study 
Précis 
This single-arm stepwise feasibility study will test initial deployment of 
hybrid closed-loop (HCL) automated insulin delivery (AID) using the 
Omnipod 5/Horizon HCL system with remote monitoring and device 
operation capabilities to hospitalized patients admitted to the general 
medical/surgical floorwith diabetes (type 1 or type 2) requiring insulin 
therapy. All enrolled participants will be placed on HCL insulin therapy 
for 10 days or until hospital discharge (if less than 10 days) to 
determine functional operability of the system and its effect on 
glycemic control in the hospital setting. This study will generate 
preliminary data to inform the design of a large multi-institution 
randomized controlled trial to assess superiority of HCL compared to 
standard inpatient insulin therapy. 
Investigational Device 
The Omnipod 5/Horizon HCL system, consists of a disposable insulin 
infusion pump (or “pod”), a built-in model predictive control (MPC) 
insulin dosing algorithm, and a remote Personal Diabetes Manager 
(PDM) interface, that interact with a Dexcom G6 continuous glucose 
monitor (CGM) to automatically control insulin delivery based upon 
real-time glucose values. The PDM component also enables remote 
interaction with the system, including glucose monitoring as well as 
insulin dosing management and adjustments. 
Objectives 
Primary objective:  
To investigate functional operability and implementation of the 
Omnipod 5/Horizon HCL system in the hospital setting. 
Secondary objectives:  
To describe glycemic control, device settings and insulin delivery 
parameters, and explore staff and patient perceptions associated with 
early use of the Omnipod 5/Horizon HCL system in the hospital setting. 
Study Design 
Pilot and Feasibility 
Number of Sites 
3 
Endpoint 
Primary Endpoints: 
Aim 1 (Operability): Proportion of time spent in HCL after CGM sensor 
meets initial validation criteria [sensor glucose value is within ±20% of 
POC values (for glucose levels ≥70 mg/dL) or ±20 mg/dL for POC 
glucose values <70 mg/dL]. 
Aim 2 (Glycemic control): Percentage of time sensor glucose is within 
target glucose range [time-in-range (TIR)], defined as 70-180 mg/dL. 
Key Secondary Endpoints: 
Aim 1.1 Operability (System function):  

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PARTICIPANT AREA 
DESCRIPTION 
- 
Time from enrollment to start of HCL therapy (after initial CGM 
validation) 
- 
Percentage of time with CGM readings 
- 
Percentage of CGM values meeting accuracy criteria for 
bolus/correction insulin dosing 
- 
Number of CGM readings within %15/15 of POC readings and 
within %20/20 of POC readings with the cut point at 70 mg/dL 
Aim 1.2 Perception (qualitative analyses): 
- 
Patient and Providers: Open-ended feedback 
- 
Patient and Providers: Survey questionnaire results 
Aim 2.1. Glycemic control: 
- 
Number of hypoglycemic (<70 mg/dL) and clinically important 
hypoglycemic (<54 mg/dL) episodes per patient and per patient-
day 
- 
Percent time below range (TBR, <70mg/dL) 
- 
Percent time below range (<54 mg/dL) 
- 
Percent time above range (TAR, >180 mg/dL) 
- 
Percent time in severe hyperglycemia (>250 mg/dL) 
- 
Coefficient of variation (CV), standard deviation (SD) 
Aim 2.2 HCL Settings: 
- 
Frequency of setting adjustments for clinically-important 
hypoglycemia (<54 mg/dL): Overall, to basal rate, to insulin 
carb ratio (ICR), to insulin sensitivity factor (ISF) 
- 
Frequency of setting adjustments for prolonged hyperglycemia 
(>250 mg/dL for >1 hour): Overall, to basal rate, to ICR, to ISF 
- 
Insulin requirements: Total daily insulin (TDI), Total daily basal 
insulin (TBI), Total daily bolus (meal and correction). 
Key Safety Outcomes:  
- 
Reportable hypoglycemia: defined as an event that required 
assistance of another person due to altered consciousness to 
actively administer carbohydrate, glucagon, or other 
resuscitative actions.  This means that the participant was 
impaired cognitively to the point that the participant was unable 
to treat his or herself, was unable to verbalize his or her needs, 
was incoherent, disoriented, and/or combative, or experienced 
seizure or coma.  
- 
Diabetic ketoacidosis 
 
Population 
Key Inclusion Criteria: 

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PARTICIPANT AREA 
DESCRIPTION 
- 
Patients ≥18 years of age with insulin-treated T1 or T2DM 
admitted to general (non-intensive care) medical-surgical 
hospital service requiring inpatient insulin therapy. 
Key Exclusion Criteria: 
- 
Patients admitted the ICU or anticipated to require ICU transfer 
- 
Anticipated length of hospital stay <48 hours. 
- 
Evidence of hyperglycemic crises (diabetic ketoacidosis or 
hyperosmolar hyperglycemic state) at enrollment  
- 
Severely impaired renal function (eGFR < 30 ml/min/1.73m2) or 
clinically significant liver failure 
- 
Severe anemia with hemoglobin <7 g/dL 
- 
Evidence of hemodynamic instability 
- 
Hypoxia (SpO2 <95% on supplemental oxygen) 
- 
Pre-admission or inpatient total daily insulin dose >100 units  
- 
Mental condition rendering the participant unable to consent or 
answer questionnaires 
- 
Pregnant or breast-feeding at time of enrollment 
- 
Unable or unwilling to use rapid-acting insulin analogs 
(Humalog, Admelog, Novolog or Apidra) during the study 
- 
Use of hydroxyurea or high-dose ascorbic acid (>1g/day)  
- 
 COVID-19 infection or person under investigation (PUI) on 
isolation precautions   
Sample Size 
18 patients  
Phase 
Pilot, Feasibility 
Treatment Groups 
All enrolled participants will be placed on HCL insulin therapy for up to 
10 days or until hospital discharge. 
Participant Duration 
Up to 10 days during inpatient stay 
 

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OVERVIEW OF STUDY DESIGN 
This multicenter study testing the feasibility of AID (Omnipod 5/Horizon HCL system) in the 
hospital will be conducted across three sites [Emory, Stanford, University of Virginia (UVA)]. 
To ensure safety of participants with this new impatient glycemic control approach we will 
employ a stepwise enrollment plan with two phases (Figure 1). We will enroll patients ≥18 years 
of age with insulin-treated type 1 (T1) or type 2 (T2) DM requiring insulin therapy during 
hospitalization admitted to the general medical/surgical floor (non-ICU). To have 9 subjects in 
each phase cohort who have used the system for at least 48 hours, we will enroll up to a total of 
30 participants. All participants will be placed on AID for inpatient glucose management.  
The first phase of the study will combine automated insulin delivery (AID) with intensified POC 
glucose monitoring (minimum of 6 POC glucose tests per day; n=9 subjects). During phase 2, 
AID will continue with less frequent POC glucose monitoring (approximately 4 times per day, 
standard-of-care; n=9 subjects) (Figure 1). IRB-approved informed consent will be obtained by 
study personnel designated at each site. Exclusion criteria include: 1) patients requiring total 
daily insulin dose >100 units, 2) patients admitted to ICU, 3) patients anticipated to require <48 
hours of admission, 4) patients with evidence of hyperglycemic crises (diabetic ketoacidosis or 
hyperosmolar hyperglycemic state), 5) patients with severely impaired renal function (eGFR < 
30 ml/min/1.73m2), 6) clinically significant liver failure, 7) severe anemia (hemoglobin <7 g/dL), 
8) hypoxia (SpO2 <95% on supplemental oxygen), 9) evidence of hemodynamic instability, 10) 
active or suspected COVID-19 infection, 11) a mental condition rendering the participant unable 
to consent or answer questionnaires, 12) pregnancy or breast feeding at time of enrollment, or 
13) use of hydroxyurea or high-dose ascorbic acid.  
 
 
Figure 1. AIDING Feasibility Study Stepwise Enrollment Design. IRB: Institutional Review Board; POC: point-of-care 
testing; AC: Before meals; HS: bedtime; MN: midnight. 

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Chapter 1: Background Information 
1 
1.1 Introduction 
2 
The purpose of this study is to assess the safety and efficacy of using the Omnipod 5/Horizon 
3 
automated insulin delivery (AID) system in improving glycemic control for hospitalized patients 
4 
requiring subcutaneous insulin therapy.  This is the first automated insulin delivery system which 
5 
is well-suited for the hospital environment given its remote management capabilities with 
6 
disposable components.  
7 
The coronavirus disease 2019 (COVID-19) pandemic has highlighted how accelerated use of 
8 
technologies [e.g., telemedicine, e-consults, and remote monitoring] has helped healthcare 
9 
systems adapt care delivery while minimizing exposure risk. The pandemic has also shed light 
10 
on the bedside care burden associated with inpatient diabetes management in its current state. As 
11 
more patients are admitted with COVID-19 infection, there is continued concern surrounding 
12 
resource limitations, including PPE. These concerns have led to transformations in clinical care 
13 
that focus on the preservation of scarce resources while continuing to provide the highest level of 
14 
clinical care. Inpatient diabetes (DM) management is one realm of clinical care that has seen 
15 
major changes in the setting of COVID-19, mostly due to the time- and labor-intensive efforts 
16 
required to care for hospitalized patients with DM.1 In the United States, it is estimated that 
17 
about one in five patients with COVID-19 admitted to the hospital has DM.2 The increasing 
18 
proportion of hospitalized patients with DM and concurrent COVID-19 infection continues to 
19 
highlight the importance of advancing inpatient diabetes care to balance the competing demands 
20 
of frequent glucose monitoring and timely insulin administration with the bedside contact 
21 
required for these efforts when PPE is scarce.  
22 
In Atlanta, a diagnosis of diabetes is associated with a threefold increase in the odds of 
23 
hospitalizations.3 Among those patients with COVID-19 hospitalized in Georgia (primarily 
24 
metropolitan Atlanta) beginning in February, DM was documented in 39.7% of hospitalized with 
25 
COVID-19,4 and a recent report showed about 46% of critically ill patients had DM in COVID 
26 
units in the Emory healthcare system.5 Over 3500 cases of COVID-19 have been documented at 
27 
Emory until the end of July 2020, including 883 patients with diabetes, of whom 114 expired 
28 
(14%). At Stanford, of 2345 patients hospitalized with COVID-19 from March 1 to June 30, 
29 
2020, 25% (580) had diabetes. Among these 19% were intubated, and 2.6% of these patients 
30 
died. At UVA, a sample of 141 patients hospitalized with COVID-19 showed 52% required 
31 
treatment with insulin.  We estimate at least 30% of patients with COVID-19 will have DM at 
32 
the three centers. 
33 
The use of AID systems continues to grow in the outpatient setting among patients with both 
34 
type 1 and type 2 diabetes. Preliminary data from AID trials with a single non-commercial 
35 
European system (using an insulin pump with tubing) has shown significant improvements in 
36 
glycemic control in diverse populations, without increasing the risk of hypoglycemia.6-8 There is, 
37 
however, no clinical trial data with the use of AID in the hospital in the US.  
38 

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Automated Insulin Delivery for INpatients with DysGlycemia (AIDING) Feasibility Study 
 
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Consideration has been made as to whether strict glucose control can improve outcomes 
83 
specifically in hospitalized patients with COVID-19. A multi-center retrospective analysis of 
84 
7,337 patients with COVID-19 in Hubei Province, China18 reported an increased incidence of 
85 
acute respiratory distress syndrome (ARDS), acute kidney injury, acute cardiac injury, 
86 
disseminated intravascular coagulation (DIC), and all-cause in-hospital mortality among patients 
87 
with pre-existing DM. As expected, these patients also had higher levels of acute inflammatory 
88 
markers [C-reactive protein (CRP), procalcitonin, and D-dimer]. Yet, a sub-analysis of the cohort 
89 
with DM revealed that in those with well-controlled glucose values (70-180 mg/dL), these 
90 
endpoints and laboratory findings were all significantly reduced.18 Similar findings were also 
91 
reported by Sardu et al.19 in a 28-day prospective study to assess the effect of intensive glycemic 
92 
control on progression to severe COVID-19 disease (ICU admission, mechanical ventilation, or 
93 
death). In this study of 59 patients admitted with moderate COVID-19 pneumonia, two 
94 
subgroups were characterized based on the admission glucose >140 mg/dL (hyperglycemic), or 
95 
<140 mg/dL. Of the hyperglycemic patients, 72% had a diagnosis of DM prior to admission. All 
96 
25 patients with hyperglycemia were asked to consent to intravenous (IV) insulin infusion if their 
97 
glucose exceeded 180 mg/dL. Fifteen patients consented and were given IV insulin to target a 
98 
glucose of 140-180 mg/dL, while the other 10 patients received standard basal-bolus 
99 
subcutaneous insulin injections. The mean glucose during hospitalization for those receiving IV 
100 
insulin therapy was 138 ± 33 mg/dL, and 192 ± 15 mg/dL for those not receiving IV insulin. 
101 
Hyperglycemia and higher baseline levels of interleukin 6 (IL-6) and D-dimer were associated 
102 
with progression to severe disease. However, of those who opted for IV insulin, only 33% 
103 
progressed to severe disease, compared to 80% of those who did not. Additionally, those 
104 
receiving IV insulin demonstrated much larger reductions in IL-6 and D-dimer levels at one- and 
105 
two-week time points. These early studies suggest that improved glucose control may promote 
106 
better clinical outcomes among patients with COVID-19. 
107 
However, use of continuous IV insulin infusion requires hourly interventions and significant 
108 
oversight by healthcare providers. In non-ICU patients, basal-bolus insulin regimens continue to 
109 
be the mainstay of therapy for patients with hyperglycemia in the hospital, relying heavily on the 
110 
ability of healthcare workers (HCW) to perform frequent blood glucose monitoring and timely 
111 
administration of multiple insulin injections to achieve glycemic control.20 During COVID-19, 
112 
related shortages in PPE and the healthcare workforce will undoubtedly have a negative impact 
113 
on inpatient glycemic control and outcomes for these patients. Additionally, inpatient 
114 
hyperglycemia itself may become increasingly challenging to mitigate, as rapidly evolving data 
115 
has directed attention towards the use of high-dose steroids in the treatment of COVID-19.21 
116 
Recent preliminary results from the “Randomised Evaluation of COVID-19 Therapy” 
117 
(RECOVERY) trial showed a significant reduction in 28-day mortality among patients requiring 
118 
supplemental oxygen (including non-invasive ventilation) or invasive mechanical ventilation 
119 
treated with high-dose dexamethasone (6 mg daily).22 Therefore, in light of the baseline 
120 
prevalence and prognostic implications of pre-existing DM, early reports suggesting an 
121 
association between glucose control and improved outcomes, and the now probable forthcoming 
122 
increase in steroid usage among patients with COVID-19, maintaining glycemic control has 
123 
become an integral part of inpatient COVID-19 management. 
124 
Advances in diabetes technology have changed the face of diabetes care in the outpatient setting 
125 
through the use of CGM, insulin pump therapy and the integration of these two technologies to 
126 

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provide AID.23 Recent efforts have focused on moving these technologies to the inpatient setting 
127 
to improve hospital diabetes management.24 Our interest in this concept predates the pandemic, 
128 
and we have previously reported our experience using CGM in the inpatient setting, including 
129 
the implementation of a glucose telemetry system (NCT03877068).25-28 Recently, this progress 
130 
has been accelerated and has become available for more widespread clinical implementation 
131 
during the COVID-19 pandemic. During the beginning of the pandemic, the US Food and Drug 
132 
Administration (FDA) allowed for the use of CGM in the inpatient setting, with many hospitals 
133 
rapidly implementing CGM with little guidance in a desperate effort to preserve PPE and glucose 
134 
monitoring abillities.25,29 Already, this has shown some potential for the intended ancillary 
135 
benefits, as one report of CGM with remote monitoring in four patients with COVID-19 in Israel 
136 
showed a 50% decrease in the number of required bedside glucose measurements, as well as a 
137 
decrease in the risk of staff exposure and care burden.30 The feasibility of remote real-time CGM 
138 
use during COVID-19 was also recently reported by Reutrakul and colleagues.31 In addition, a 
139 
reduction in hypoglycemia has also been demonstrated using inpatient remote real-time CGM in 
140 
a recent trial at the Baltimore VA Medical Center.32 In this study, patients with T2DM on basal-
141 
bolus insulin who were considered at-risk for hypoglycemia were randomized to Dexcom G6 
142 
CGM with data continuously available to nursing staff in a similar telemetry-like set-up vs. 
143 
standard inpatient capillary BG checks (approximately four times daily) with a blinded CGM. 
144 
Among those in the actively monitored CGM group, total per-patient glycemic events <70mg/dL 
145 
and <54 mg/dL were reduced by 60% (p=0.024) and 89% (p=0.003) respectively compared to 
146 
standard of care. Reductions were also seen in percent of time spent below <70 mg/dL (0.40% 
147 
vs. 1.88%, p=0.002) and below <54 mg/dL (0.05% vs. 0.82%, p=0.017). Furthermore, another 
148 
recent RCT using real-time CGM (G6) showed a modest reduction of time spent in 
149 
hyperglycemia >250 mg/dL (-11.41%) with a similar approach but including alarms, the TIR 
150 
(70-180 mg/dl) was 25% for the intervention group and 19.9% in the control group.33 With a 
151 
standard protocol using basal-bolus, the TIR (70-180) was ~55% with two different basal 
152 
insulins.27  
153 
1.2.2 Hybrid closed-loop insulin therapy 
154 
Hybrid closed-loop (HCL) or automated insulin delivery (AID) systems are one of the newest 
155 
available technologies for diabetes management, designed to make algorithm-based adjustments 
156 
to insulin infusion using CGM sensor glucose values and trends to maximize time in target 
157 
glucose range [time in range (TIR), 70-180 mg/dL]. An insulin delivery device (pump) interacts 
158 
directly with the CGM to adjust insulin continuously according to need in real-time. The use of 
159 
HCL therapy is being rapidly incorporated into ambulatory DM management and has been 
160 
shown to be safe and effective in diverse populations and settings.34-37 The proposed 
161 
Omnipod5/Horizon AID system, employing a personalized MPC algorithm, is a novel device 
162 
that has been evaluated for safety in children and adults with T1DM, performing well under 
163 
supervised free-living conditions.35 It has also been shown to cope effectively with common 
164 
glycemic control challenges in the outpatient setting, including daily physical activity and 
165 
unrestricted meals in adults with T1DM.35,36 This system has demonstrated remarkable 
166 
achievement of glycemic targets in children, adolescents, and adults with T1DM,35 including in 
167 
those at the highest risk of hypoglycemia.36 For example, use of the Omnipod Horizon HCL 
168 
system resulted in a very low risk of hypoglycemia with a median of 0.9% ± 1.3% of glucose 
169 
readings <70 mg/dL and 0.09% ± 0.25% <54 mg/dL in adults with T1DM treated as 
170 

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outpatients.38 They achieved 72.5% TIR (70-180 mg/dL), a mean glucose of 154 ± 15 mg/dL and 
171 
a coefficient of variation (CV) of 30 ± 6%.38  
172 
The system provides a low rate of hypoglycemia with <2% of sensor glucose readings <70 
173 
mg/dL, while achieving over 70% TIR.38 The pediatric subjects in the Omnipod 5 pivotal study 
174 
entered the study with a mean glucose of 185 ± 23 mg/dL with 51 ± 13.3% TIR.38  Other initial 
175 
trials of this AID system showed percentage of TIR above 70% in different age groups with 
176 
various challenges applied to the AID system (Table 1).  
177 
 
178 
While some recent efforts have been made to move these new technologies to the inpatient 
179 
setting to improve hospital diabetes management,23,24 inpatient data for HCL/AID use is limited. 
180 
Several studies from the United Kingdom have shown promising results in glycemic control 
181 
parameters in specific hospitalized populations.6-8 For example, an inpatient trial by Bally et al. 
182 
enrolling non-ICU patients with DM showed those assigned to closed-loop therapy achieved 
183 
65% TIR compared to 41% with usual care (P<0.001) without an associated increase in 
184 
hypoglycemia.6 Two recent studies reporting data on glycemic control using real-time CGM in 
185 
the inpatient setting showed lower percent TIR achieved in this setting for patients on 
186 
subcutaneous insulin regimens [median TIR 25.31% (11.78-42.97)33; mean TIR 56.6 ± 25.6% 
187 
and 57.5 ± 25.1%27]. 
188 
The Omnipod5/Horizon AID system has not been tested in hospitalized adults; however, among 
189 
available options, we believe it is uniquely fashioned toward assimilation and optimal 
190 
performance in the inpatient setting. The system provides significant hypoglycemia protection, 
191 
with an automated “hypoglycemia protect” feature which simultaneously raises the algorithm’s 
192 
glucose target to 150 mg/dL, decreases basal insulin delivery by 50%, and decreases the 
193 
Table 1. Initial studies of the Omnipod5/Horizon AID system. 
IDE 
G160169 
G160169 
G170012 
G170012 
G170143 
Omnipod 5 
Omnipod 5 
S003 
S003 
S001 
S001 
S002 
Pivotal – first 
4-9 weeks 
Pivotal – first 
4-9 weeks 
Age group 
(years) 
Adults 
Adolescents 
Adults 
Adults 
Adults 
Adults   
(14-70) 
Pediatrics 
(6-14) 
Challenge 
100% 
meal bolus 
100%  
meal bolus 
Meals 
Exercise 
Free-living 
Free-living 
Free-living 
Sample size (n) 
10 
12 
12 
12 
11 
18 
18 
Study duration 
36 hours 
36 hours 
54 hours 
54 hours 
96 hours 
4-9 weeks 
4-9 weeks 
Mean age (yrs) 
41.7±18.1 
14.6±1.5 
35.4±14.2 
36.6±14.4 
28.3±7.5 
35±11 
10.6±1.8 
DM duration (yrs) 
23.7±15.3 
4.6±3.3 
16.5±9.3 
21.6±15.7 
13.4±6.0 
17±12 
5±3 
A1C (%) 
7.4±0.8 
8.2±0.9 
7.7±0.9 
7.6±1.1 
7.4±1.1 
7.1±0.8 
7.8±0.9 
Mean glucose 
155.0±14.8 
153.4±21.6 
153.4±15.3 
136.0±14.3 
149.7±11.3 
155 ± 15 
158 ± 10 
Sensor Glucose (% 
time) 
 
 
 
 
 
 
 
70-180 mg/dL 
73.0±15.0 
72.6±15.5 
76.1±8.0 
85.1±9.3 
73.7±7.5 
73.8 ± 9.1 
70.1 ± 5.2 
< 50 mg/dL 
0.0 ± 0.1 
0.2 ± 0.3 
0.0 ± 0.1 
0.1 ± 0.2 
0.1±0.2 
0.1 (0.0, 0.2) 
0.2 (0.0, 0.5) 
< 70 mg/dL 
0.7±1.2 
2.0±2.4 
0.6±0.9 
1.4±1.3 
1.9±1.3 
0.9 (0.5, 1.3) 
1.2 (0.9, 2.2) 
> 180 mg/dL 
26.3±14.4 
25.4±16.1 
23.3±8.5 
13.5±9.5 
24.5±7.7 
25.0 ± 9.1 
28.3 ± 5.2 
≥ 250 mg/dL 
3.6±3.7 
4.9±6.3 
4.5±3.6 
1.8±2.4 
4.5±4.2 
5.6 ± 6.1 
8.6 ± 4.1 

Automated Insulin Delivery for INpatients with DysGlycemia (AIDING) Feasibility Study 
 
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aggressiveness of any insulin delivery in response to increasing glucose levels. Glucose rate of 
194 
change information is also accounted for at the time of boluses, such that a reverse correction is 
195 
calculated and instituted to prevent hypoglycemia when glucose levels are below the target at the 
196 
time of a bolus insulin dose. As described previously, in the outpatient setting, these have 
197 
resulted in extremely low rates of hypoglycemia,38 and will be both practical and valuable in 
198 
managing patients with variable insulin requirements. Automated features are supplemented by 
199 
patient-specific physician input, as providers also have control over the insulin-to-carbohydrate 
200 
ratios (ICR) and correction/sensitivity factors (ISF) for manual dose calculations.  
201 
Another key aspect of this system that makes it particularly attractive for inpatient use lies in its 
202 
remote operation capability. Most HCL/AID insulin delivery systems require a physical 
203 
connection between patient and device wherein the insulin pump is attached to the infusion site 
204 
cannula by variable lengths of plastic tubing. However, the Omnipod is the only commercially 
205 
available insulin pump that does not employ any tubing to connect the subcutaneous insulin 
206 
infusion site to the insulin reservoir; both are contained within the disposable “Pod” worn by the 
207 
patient. Additionally, the Omnipod5/Horizon AID system employs a physically independent 
208 
controller (PDM smartphone) that is used to monitor CGM values and HCL functional status, 
209 
perform infusion site (pod) changes, and manually control insulin infusion when required 
210 
(“open-loop” setting), while also allowing closed-loop/automated insulin delivery to continue in 
211 
the physical absence of the controller.35 This will enable HCW to interact with the pump, 
212 
including delivering insulin and changing delivery settings from outside the patient’s room. As 
213 
such, this device independence offers a unique opportunity for insulin delivery in the 
214 
hospital to improve glycemic control with remote management capabilities. 
215 
A third key aspect of the Omnipod5/Horizon AID system is that all of the components are 
216 
intended for single-person use and have relatively low start-up costs compared to other available 
217 
insulin pumps. The Omnipod5/Horizon AID system (PDM, pod) costs much less than other 
218 
available closed-loop systems. Pumps used by these other systems can cost on the order of 
219 
$4,000 to $8,000 and are intended to be used for at least four years before replacement.  This 
220 
makes it possible to use the Omnipod5/Horizon AID system in the hospital without needing to 
221 
own any component of the system prior to admission, including the insulin pump (PDM).  This is 
222 
especially relevant for patients requiring isolation. 
223 

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PAGE 21 OF 63 
Our overarching central hypothesis is that with the Omnipod 5/Horizon AID system, AID 
224 
therapy is feasible and safe in the hospital, achieves superior glycemic control compared to the 
225 
current standard of care, and reduces the frequency of patient-staff encounters associated with 
226 
PPE use. This protocol is an initial implementation trial to assess feasibility of and barriers to 
227 
larger-scale inpatient deployment of this system (Aim 1) and to describe early experience with its 
228 
use and glycemic control in the hospital (Aim 2). Results generated from this trial will serve as 
229 
preliminary data in the creation of a large multi-institution randomized controlled trial (RCT) to 
230 
assess superiority compared to standard of care insulin therapy, including the potential for future 
231 
use in those with COVID-19 infection or other conditions requiring isolation precautions. 
232 
Aim 1: To test the functional operability and applied use of the Omnipod 5/Horizon AID 
233 
system in patients with DM admitted to the hospital (Figure 3). We will test deployment of 
234 
the HCL system in each of the three institutions that plan to participate in the eventual RCT. 
235 
Eighteen patients with pre-existing insulin-treated DM admitted to a non-ICU medical-surgical 
236 
floor will receive HCL insulin therapy. Glucose monitoring will transition from intensified POC 
237 
testing (phase 1, n=9) to standard of care POC testing (phase 2, n=9). To investigate operability 
238 
(Aim 1.1), we will specifically examine the proportion of time spent in HCL settings after initial 
239 
CGM validation, percentage of time with CGM readings, and percentage of bolus or corrective 
240 
insulin doses given based on CGM values. We will also assess proportion of CGM values within 
241 
±15 and 20% of POC reference values for glucose levels >70 mg/dL and ±15 or 20 mg/dL for 
242 
POC glucose levels ≤100 mg/dL (%15/15, %20/20). To assess perception and identify additional 
243 
unforeseen barriers to implementation (Aim 1.2), patients and hospital staff will be asked to 
244 
Figure 3. Schematic for Omnipod5/Horizon AID and Dexcom G6 CGM remote monitoring in the hospital. 

Automated Insulin Delivery for INpatients with DysGlycemia (AIDING) Feasibility Study 
 
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provide intermittent open-ended feedback and structured surveys regarding the use of the AID 
245 
system. 
246 
Hypothesis 1: Inpatient HCL therapy with the Omnipod 5/Horizon AID system functions 
247 
well/consistently in the hospital and is supported by patients and staff. 
248 
Aim 2: To assess glycemic control with the Omnipod 5/Horizon AID system in the inpatient 
249 
setting. To describe glucometric data associated with inpatient HCL use (Aim 2.1), we will 
250 
analyze and report CGM data including percent time in target glucose range (TIR, 70-180 
251 
mg/dL), number of hypoglycemic (<70 mg/dL) and clinically-important hypoglycemic (<54 
252 
mg/dL) episodes per patient and per patient-day, percent time below range (TBR, <70mg/dL), 
253 
percent time in clinically-important hypoglycemia range (<54 mg/dL), percent time above range 
254 
(TAR, >180 mg/dL), percent time in severe hyperglycemia (>250 mg/dL), coefficient of 
255 
variation (CV) and standard deviation (SD). To assess HCL initiation settings and the need for 
256 
setting adjustments in hospitalized patients (Aim 2.2), we will evaluate the frequency of 
257 
adjustments to insulin infusion doses including basal rate, insulin-to-carbohydrate ratio (ICR), 
258 
and insulin sensitivity factor (ISF) in response to: 1) clinically-important hypoglycemia (<54 
259 
mg/dL) and 2) prolonged hyperglycemia (>250 mg/dL for >1 hour). 
260 
Hypothesis 2: The Omnipod 5/Horizon AID system is safe and provides adequate (>55% TIR) 
261 
glycemic control in non-ICU hospitalized patients. 
262 
This proposal addresses multiple unique opportunities for the transformation of inpatient 
263 
diabetes care, including: the (1) translation of HCL/automated insulin delivery to the inpatient 
264 
setting, (2) the efficacy of these technologies in improving inpatient glycemic control and rates 
265 
of iatrogenic hypoglycemia in patients admitted with DM and diverse admission diagnoses, and 
266 
(3) the potential for future studies testing the use of remote HCL and CGM technology for 
267 
administration of insulin, as it pertains to patients who have isolation precautions, including for 
268 
COVID-19. 
269 
1.3 Preliminary Data 
270 
Our preliminary data from a pooled analysis of inpatient CGM studies including 4,067 matched 
271 
CGM and POC glucose values from non-ICU patients with T1 and T2DM showed an overall 
272 
mean absolute relative difference (MARD) of 12.8%. The MARD decreased with time as 
273 
expected (12 hours: 16.4%, 24 hours: 14.4%, All values: 12.8%). The proportion of CGM values 
274 
with in ±15, 20 and 30% of POC reference values for glucose levels >100 mg/dL and ±15, 20 or 
275 
30 mg/dL for POC glucose levels ≤100 mg/dL (%15/15, %20/20, %30/30) increased between the 
276 
first 12-hours (57.0, 69.2, 85.9%)  and 24-hours (63, 75.6, 89.2%) of sensor life. The overall 
277 
proportion of CGM 
278 
values meeting %15/15, 
279 
%20/20, %30/30 
280 
criteria were 68.7, 81.7, 
281 
93.8%, respectively 
282 
(Table 2). MARD and 
283 
median ARD varied 
284 
according to categories 
285 

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of hemoglobin level and POC glucose level strata with minor variations according to renal 
286 
function categories. The highest MARD was observed for patients with glucose levels in the 
287 
hypoglycemic range (50-70mg/dL; MARD 14.5%) and for those with severe anemia 
288 
(hemoglobin <7g/dL; MARD 17.8%), Figure 4. 
289 
A Clarke error grid (CEG) analysis of all matched pair data showed 98.7% of values falling in 
290 
CEG Zones A+B (Zone A, 80.9%; Zone B, 17.8%; Zone C, 0.1%; Zone D, 1.1%, Zone E, 0.0%), 
291 
Figure 5. 
292 
At Emory, for patients in the ICU with 
293 
COVID-19, we have already begun using 
294 
the Dexcom G6 CGM in conjunction 
295 
with Glucommander-directed IV insulin 
296 
therapy. Conceptually, this system 
297 
parallels closely what we here propose to 
298 
undertake with HCL therapy. Like HCL, 
299 
Glucommander uses an algorithm to 
300 
adjust insulin delivery based upon 
301 
frequent glucose data input (every 1-2 
302 
hours); however, in this case, insulin is 
303 
provided intravenously, as is appropriate 
304 
for critically ill patients. As such, beyond 
305 
the CGM, the components of this system 
306 
differ considerably from the Omnipod 
307 
5/Horizon, which automates 
308 
subcutaneous insulin delivery. In our 
309 
Figure 5. Clark Error Grid analysis of inpatient CGM values  
compared to POC glucose testing (preliminary data, unpublished). 
Figure 4. MARD and median ARD comparing CGM with POC in non-ICU hospitalized patients with diabetes, 
according to eGFR, glucose, and hemoglobin categories (preliminary data, unpublished). 

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early experience with the 
310 
Dexcom G6/Glucommander 
311 
system, we have observed 
312 
reliable adjustments to IV 
313 
insulin infusion based on the 
314 
CGM values using an 
315 
intermittent validation protocol 
316 
comparing CGM to POC 
317 
glucose values to ensure 
318 
ongoing CGM accuracy. We 
319 
have used a similar protocol for 
320 
routine validation of CGM 
321 
readings in the ICU as we have 
322 
proposed in this study. This 
323 
involved creation of an 
324 
embedded glucose 
325 
documentation and validation 
326 
tool in the electronic health 
327 
record (EHR) system (EPIC) 
328 
itself, which after receiving the 
329 
necessary POC glucose values, 
330 
advises nursing staff on the 
331 
necessary accuracy range in 
332 
which the CGM glucose value 
333 
must lie in comparison to the POC glucose entered (±20% for glucose values over 100 mg/dL), 
334 
Figure 6. Criteria were also developed to ensure ongoing sensor reliability, with 
335 
recommendations to revert back to POC glucose testing in cases of: 1) CGM sensor signal loss, 
336 
2) loss of CGM trend arrow, and 3) rapid changes in sensor glucose values (>3 mg/dL/min). To 
337 
investigate feasibility and reliability of the Omnipod5/Horizon AID system in the inpatient 
338 
setting, we assessed the ability of the pump (pod) and CGM devices to communicate with one 
339 
another and with the Personal Diabetes Manager (PDM). The PDM is a dedicated android 
340 
smartphone for the Omnipod5/Horizon and Dexcom applications, which allows for remote 
341 
control of the insulin pump and reception of CGM glucose values. Reliability of remote bolus 
342 
insulin delivery and glucose monitoring in COVID-19-specific rooms was tested at Stanford and 
343 
Emory.  The CGM was connected to a “walk-about” sensor simulator and paired with the HCL 
344 
pod. The CGM and pump (HCL pod) were separated from each other by 3-4 feet to simulate 
345 
placement on a patient. Because of current PPE shortages, and to avoid unnecessary personnel 
346 
exposure risk on an active COVID-19 unit, only unoccupied rooms were tested. Communication 
347 
was tested from the patient inside the room to the PDM stationed outside the room after closing 
348 
room doors: (1) in different locations within the patient room (including bathroom); (2) with staff 
349 
personnel acting as an intervening body; (3) in proximity to multiple activated patient care 
350 
devices with interference potential (telemetry monitor, lights, TV, EKG, ultrasound, iPad, IV 
351 
pumps); and (4) with variable external PDM locations (wall, hall table). Throughout the testing, 
352 
A 
B
Figure 6. EHR documentation and validation. A) flowsheet shows upper and 
lower 20% range of POC to document validation (yes/no), B) remote EHR 
access to documented CGM values trend (green) and POC values.   

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and in every room for each configuration, CGM data remained continuous, with stable readings 
353 
every five minutes. Each remote bolus was transmitted successfully. An 18-hour overnight test 
354 
was also completed without any lapse in CGM data or HCL functionality at Stanford. 
355 
1.4 Potential Risks and Benefits of the [Investigational Device] 
356 
1.4.1 Known Potential Risks 
357 
The protocol constitutes greater than minimal risk.  
358 
1.4.1.1 Hyperglycemia and Hypoglycemia Risks 
359 
The Hybrid Closed Loop System (Omnipod5/Horizon) will have a glucose target lower than 
360 
what is in the typical range for target glucose in most hospitals. As such, there may be greater 
361 
risk for hypoglycemia. However, with use of CGM and close monitoring by the study team and 
362 
hospital staff, this risk should be small. In outpatient studies of patients with T1DM using the 
363 
Omnipod5/Horizon AID system, the median percent of glucose values <70 mg/dL was 
364 
<2%.  Hypoglycemia, if it occurs, could potentiate a cardiac arrhythmia. If hypoglycemia is 
365 
severe enough a seizure, loss of consciousness, and even death is possible. These are risks 
366 
common to all people on insulin therapy.  
367 
Hyperglycemia is a known risk with having diabetes, and can occur with rapid changes in diet, or 
368 
the use of medications such as glucocorticoids, or significant worsening of an underlying 
369 
medical condition which can result in resistance to the effect of insulin on lowering glucose 
370 
levels.  The pod only uses rapid-acting insulins, so if an insulin infusion catheter was dislodged 
371 
or became kinked or the insulin flow was blocked, then there is an increased risk of developing 
372 
hyperglycemia and with hours of interrupted insulin delivery this can lead to ketosis or diabetic 
373 
ketoacidosis (DKA) which can lead to shock, coma, or death. The glucose values will be 
374 
monitored continuously and remotely by study staff, so prolonged hyperglycemia is unlikely to 
375 
occur. 
376 
Hypoglycemia and hyperglycemia could also result if there is over or under delivery of insulin 
377 
due to a device defect, failure or malfunction of any of the components of the system including 
378 
communication issues, or sensor issues.   
379 
Although there is potential for harm from glucose management that is more intensive with a 
380 
lower glucose goal than standard glucose management, the potential benefit exceeds the potential 
381 
risk since outcomes of hospitalized diabetic individuals with uncontrolled dysglycemia 
382 
frequently are poor.  
383 
Once the study is completed, participants will need to be transitioned from AID to a 
384 
subcutaneous insulin regimen. The study team will have knowledge of insulin doses delivered by 
385 
the Omnipod 5/Horizon AID system, which will be converted into a standard basal-bolus insulin 
386 
regimen with corrective insulin. This transition to usual care could result in episodes of 
387 
hypoglycemia or hyperglycemia. 
388 
We do not foresee any long-term risks from participating in this study.  
389 

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The study principal investigators at each site will be closely monitoring for hypoglycemia, 
390 
hyperglycemia, and device function (errors or failures).  The site investigator will be notified 
391 
when the amount of hypoglycemia exceeding a pre-specified threshold has occurred.  Any severe 
392 
hypoglycemia, DKA, or unanticipated device issues will be reviewed by the Medical Monitor.    
393 
1.4.1.2 Other risks 
394 
Insertion of the pod infusion set catheter and/or the sensor wire can result in bruising, 
395 
bleeding, redness, induration, infection, pain and discomfort.  The adhesives used to secure the 
396 
pod and CGM sensor can cause local skin reactions, itching, redness, and allergic reactions to the 
397 
adhesives. 
398 
On rare occasions the CGM sensor wire may break off or be retained under the skin.  Rarely this 
399 
could cause local redness, swelling, or pain at the insertion, and even require surgical removal.  
400 
Blood draws as well as fingersticks for blood glucose monitoring are part of routine care, but are 
401 
also required by this study.  Blood draws and fingersticks may cause local pain, bruising and 
402 
rarely can result in an infection or fainting. 
403 
Loss of confidentiality is a potential risk; however, data are handled to minimize this risk. Data 
404 
downloaded from the CGM and AID device will be collected for the study as measures of 
405 
diabetes self-management behaviors. Some people may be uncomfortable with the researchers' 
406 
having such detailed information about their daily diabetes habits or with the questionnaires. 
407 
1.4.2 Known Potential Benefits 
408 
There are recognized benefits to simply being in a clinical study, including close clinical 
409 
monitoring. The use of AID offers the prospect of direct benefit. As described above in this 
410 
protocol, AID therapy is a Food and Drug Administration (FDA) approved therapy for T1DM in 
411 
people 7-75 years of age with other AID systems. However, its efficacy in treating hospitalized 
412 
patients with DM or inpatient hyperglycemia is unknown.  At this time, it is not the standard of 
413 
care for hospitalized patients.   
414 
AID may benefit patients if improved glucose control is achieved that reduces the incidence of 
415 
adverse outcomes due to infection or other conditions that lead to the need for 
416 
hospitalization.  The information generated by the study will have generalizable value to adults 
417 
with insulin needs who are hospitalized for serious illnesses. If this therapy is well accepted by 
418 
hospital personnel and hospital physicians, it could become the standard of care for patients with 
419 
DM who are hospitalized and require insulin therapy. The risk to patients is relatively small and 
420 
the potential benefit is great if improved glucose control reduces the incidence of adverse 
421 
hospital outcomes.  
422 
1.4.3 Risk Assessment 
423 
The risks for events such as DKA and severe hypoglycemia are no greater, and possibly less 
424 
likely, with use of AID therapy compared with usual care not using a HCL system. The study 
425 
offers the prospect of direct benefit, including the potential for improved glycemic control. Study 
426 
team and nursing staff will also be using CGM remote monitoring of their glucose values, which 
427 

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should reduce the risks of severe low blood glucose levels or prolonged high glucose levels. In 
428 
addition to monitoring, the CGM validation procedures described in section 3.1 mitigate the risk 
429 
of bolus or corrective insulin dosing based on an inaccurate CGM reading. Therefore, this 
430 
protocol is consistent with the United States Department of Health and Human Services, 
431 
Protection of Human Subjects, Subpart D, section 46.405 (research involving greater than 
432 
minimal risk but presenting the prospect of direct benefit to the individual subjects involved in 
433 
the research). 
434 
1.5 General Considerations 
435 
The study is being conducted in compliance with the policies described in the study policies 
436 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
437 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
438 
When feasible, data will be directly collected in electronic case report forms (CRF), which will 
439 
be considered the source data. 
440 
The protocol is considered a significant risk device study, due to the fact that the use of the 
441 
Omnipod5/Horizon AID system is experimental and not approved for use in a hospital setting.  
442 
The Dexcom G6 sensor is also not approved for use in a hospital setting.  Therefore, an 
443 
investigational device exemption (IDE) from the U.S. Food and Drug Administration (FDA) is 
444 
required to conduct the study. 
445 

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Chapter 2: Study Enrollment and Screening 
446 
2.1 Participant Recruitment and Enrollment 
447 
Enrollment will proceed with the goal of at least 18 patients completing the study. Up to 30 
448 
patients may be enrolled to achieve this enrollment goal.  Study participants will be recruited 
449 
from 3 clinical centers in the United States and no clinical centers outside the United States.  All 
450 
eligible participants will be included without regard to gender, race, or ethnicity.   
451 
Potential study participants will be identified clinically from the hospital service for people 
452 
admitted with insulin-treated DM (T1 or T2) requiring inpatient insulin therapy, and from 
453 
consults sent to the endocrine service for hyperglycemia management. After a potential 
454 
candidate for enrollment in the study is identified, their primary physician/inpatient team will be 
455 
contacted to see if they would like to have the patient approached about the study.  If so, one of 
456 
the research staff, coordinator or research physician will explain the study to the patient to see if 
457 
they are interested in participating.   
458 
Participants: Eligible patients meeting inclusion and exclusion criteria as described below will 
459 
be invited to participate during hospital admission. IRB-approved informed consent will be 
460 
obtained by study personnel designated at each site (Figure 1). 
461 
 
Three sites will participate in this study (Emory, Stanford, UVA). 
462 
 
Eighteen patients will be included; up to 30 patients may be enrolled to achieve 
463 
this enrollment target (accounting for possible early hospital discharge, mortality and 
464 
study withdrawal). 
465 
 
Enrollment will proceed stepwise as below:  
466 
 
Phase 1: Nine patients will receive AID (Omnipod 5/Horizon HCL with Dexcom 
467 
G6 CGM) combined with intensified POC glucose monitoring (standard of care before 
468 
meals and at bedtime, adding overnight glucose assessments at approximately 12AM and 
469 
3AM, or approximately every 4 hours as clinically indicated). 
470 
 
Phase 2: Nine patients will receive AID combined with standard-of-care POC 
471 
glucose monitoring (before meals and bedtime, or approximately every 6 hours as 
472 
clinically indicated). 
473 
2.2 Informed Consent and Authorization Procedures 
474 
Potential eligibility may be assessed as part of a routine-care examination.  Before completing 
475 
any procedures or collecting any data that are not part of usual care, written informed consent 
476 
will be obtained.  
477 
For potential study participants the study protocol will be discussed with study staff.  The 
478 
potential study participant will be given the Informed Consent Form to read.  Potential study 
479 
participants will be encouraged to discuss the study with family members and their personal 
480 
physicians(s) before deciding whether to participate in the study. 
481 
As part of the informed consent process, each participant will be asked to sign an authorization 
482 
for release of personal information.  The investigator, or his or her designee, will review the 
483 

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study-specific information that will be collected and to whom that information will be disclosed.  
484 
After speaking with the participant, questions will be answered about the details regarding 
485 
authorization. 
486 
A participant is considered enrolled when the informed consent form has been signed. 
487 
2.3 Participant Eligibility 
488 
2.3.1 Inclusion Criteria 
489 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
490 
in the study. 
491 
 
Any patient ≥18 years of age with insulin-requiring T1 or T2DM admitted to 
492 
general (non-ICU) medical-surgical hospital service requiring inpatient insulin therapy. 
493 
2.3.2 Participant Exclusion Criteria 
494 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from 
495 
study participation. 
496 
 
Patients admitted to ICU  
497 
 
Patients anticipated to require less than 48 hours admission 
498 
 
Evidence of hyperglycemic crises (diabetic ketoacidosis or hyperosmolar 
499 
hyperglycemic state) 
500 
 
Severely impaired renal function (eGFR < 30 ml/min/1.73m2) or clinically 
501 
significant liver failure 
502 
 
Severe anemia with hemoglobin <7 g/dL 
503 
 
Evidence of hemodynamic instability 
504 
 
Hypoxia (SpO2 <95% on supplemental oxygen) 
505 
 
Pre-admission or inpatient total-daily insulin dose >100 units daily 
506 
 
Mental condition rendering the participant unable to consent or answer 
507 
questionnaires 
508 
 
Pregnant or breast-feeding at time of enrollment 
509 
 
Unable or unwilling to use rapid-acting insulin analogs (Humalog, Admelog, 
510 
Novolog or Apidra) during the study 
511 
 
Use of hydroxyurea or high dose ascorbic acid (known interference with CGM 
512 
system)  
513 
 
COVID -19 infection or Person under investigation (PUI) on isolation precautions   
514 
2.4 Screening Procedures 
515 
After informed consent has been signed, a potential participant will be evaluated for study 
516 
eligibility through the elicitation of a medical history, performance of a physical examination by 
517 
study personnel and local laboratory testing (if needed) to screen for exclusionary medical 
518 
conditions. 
519 

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2.5 Data Collection and Testing 
520 
Admitting vital signs and height and weight measurements will be recorded.  A limited physical 
521 
exam to assess the participant’s skin and suitability for wearing the study devices will be 
522 
performed by the study investigator or designee (a physician, resident/fellow, nurse practitioner 
523 
or a physician assistant). 
524 
The following procedures will be performed/data collected/eligibility criteria checked and 
525 
documented: 
526 
• 
Inclusion and exclusion criteria assessed 
527 
• 
Demographics (date of birth, sex, race and ethnicity) 
528 
• 
Contact information (retained at the site and not entered into study database) 
529 
• 
Medical history 
530 
• 
Substance use history (drinking, smoking, and drug habits) 
531 
• 
Concomitant medications 
532 
• 
Physical examination to include: 
533 
 
Weight, height 
534 
 
Vital signs including measurement of blood pressure and pulse 
535 
• 
Blood glucose obtained at time of admission to the hospital if on insulin prior to 
536 
admission, or blood glucose at the time insulin therapy was started in the hospital 
537 
• 
Record latest O2 saturation if one has been obtained 
538 
• 
Order HbA1c if one has not been ordered 
539 
• 
Order Creatinine if one has not been ordered 
540 
• 
Urine or serum pregnancy test for all women who have reached menarche and are 
541 
premenopausal and are not surgically sterile 
542 
2.5.1 Daily data recording 
543 
Each day the medications given will be recorded in our database, with the time and dose of 
544 
the medication. The lowest O2 saturation, Hct, and highest creatinine will be recorded if they 
545 
were obtained. 
546 
The date and time of any laboratory measurements of serum glucose will be recorded into 
547 
our database 
548 
Chapter 3: Study Procedures 
549 
3.1 Omnipod 5/Horizon automated insulin delivery system 
550 
All participants will receive treatment with the Omnipod Horizon AID system with integrated 
551 
Dexcom G6 CGM. These devices will communicate with a patient-specific Samsung smartphone 
552 
(the PDM) secured outside of the patient room and remotely monitored by nursing station and 
553 
study team (see Figure 3). HCL therapy will continue until discharge or for 10 days from 
554 
enrollment, whichever is shorter (see discontinuation below). Study procedures will be 
555 

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conducted in medical-surgical floors where study team has provided dedicated in-service 
556 
training. 
557 
Nursing staff in medical-surgical units (AM and PM shifts) will receive dedicated in-service 
558 
training about the technology and the study protocol. Once a patient is identified by the study 
559 
team, the nursing staff on the floor will be notified the patient will be on automated insulin 
560 
delivery.  The nurse who will be working with the patient will receive an additional review of 
561 
study procedures and the devices being used.  Specific training will be focused on responding to 
562 
sensor alerts, and how to give a meal bolus and/or a correction insulin dose (using CGM vs POC 
563 
glucose value).  The nursing staff will notify the research staff for any device alarms.  Study 
564 
investigators will document enrollment of the patient in the EHR and provide nursing staff with 
565 
24-hour contact information. The nurse will be instructed on how to respond to a hypoglycemic 
566 
alarm, by obtaining a point of care meter glucose reading, and treating as per hospital standard of 
567 
care if the meter BG is <80 mg/dL.   
568 
 
Specific topics that will be reviewed with the nurse taking care of the patient: 
569 
1) How to give a bolus using the bolus calculator on the Horizon app using the 
570 
CGM glucose or a meter BG reading if the CGM reading does not meet 
571 
accuracy criteria. 
572 
2) How the home screen appears when the subject is in open or closed-loop 
573 
3) How to assess if the CGM is working properly, i.e. showing a glucose reading 
574 
and trend. 
575 
Research staff will initiate the system and replace any components of the system requiring 
576 
replacement during the study (pods or sensors).  Research staff will be notifying the nurse when 
577 
there is hyperglycemia and the need for a correction dose.  
578 
Patients will not interact with the AID system and will not be provided access to real-time CGM 
579 
glucose data for self-monitoring.  Patients would not receive training or learn how to use the AID 
580 
system for insulin delivery. The AID and CGM devices for control and monitoring will be 
581 
secured in a locked container outside of the patient room to prevent unauthorized access to the 
582 
system. Only trained personnel will be provided access. The secured PDM will be placed within 
583 
approximately 15 feet of the patient to minimize potential for signal loss. Should the PDM not be 
584 
communicating with the Pod/CGM, the research and nursing teams will receive an alert for 
585 
signal loss >30 minutes to ensure communication is re-established.  
586 
NOTE: communication with the PDM is not necessary to maintain closed-loop functionality, but 
587 
is necessary for delivering bolus insulin and for remote system monitoring. 
588 
Horizon app setup and AID initiation (to be performed by research staff): 
589 
• For safety, a unique identifier will be assigned to the patient and entered into the Horizon 
590 
App.  
591 
• Basic set up will be verified including correct date and time. Two-person verification of 
592 
pump settings for ICR, ISF, and basal rates will be individually customized and thereafter 
593 

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adjusted for each patient by the study investigators using their clinical judgment. The target 
594 
glucose will be set to 120 mg/dL initially. The appropriateness of these settings will be 
595 
reviewed every 24 hours by the research physicians at each site.  
596 
• 
Initial basal rates will be determined using either 60% of current total daily insulin 
597 
dose (TDD) or 50% of weight-based TDD estimate if not on insulin prior to admission.  
598 
• 
Pod application instructions: Fill a pod, clean skin, place pod, then activate pod.  Do 
599 
not enter sensor transmitter ID until the sensor has been activated on the Dexcom app.  
600 
• 
The pump can remain in manual mode.  A temporary basal rate may be required if the 
601 
patient has long acting insulin on-board.  
602 
• 
To determine where the Dexcom sensor will be inserted and where the pod will be 
603 
inserted.  They should be “in line of sight” of each other, and in areas where the patient is 
604 
unlikely to be laying on them. 
605 
• 
Dexcom G6 sensor will be inserted as per the user manual.  The transmitter ID will be 
606 
recorded and entered into the Dexcom app on the PDM.  The sensor will be inserted and 
607 
activated using the sensor code.  The sensor code will be recorded in the sensor log.  Share 
608 
function will be activated and the nursing station remote monitoring tablet will be invited to 
609 
follow, as well as the approved research team members.  Sensor alerts will be set for a 
610 
threshold of <80 mg/dL, and >250 mg/dL. 
611 
• 
Once the sensor has been activated on the Dexcom app, the transmitter ID can be 
612 
activated on the Horizon app. Automated insulin delivery will not commence until the 
613 
Dexcom CGM accuracy is validated (see below). 
614 
• 
The PDM will be kept in a locked container outside of the patient’s room, within 
615 
approximately 15 feet of the patient.  
616 
3.1.1 Dexcom CGM validation 
617 
• 
All blood glucose values used to validate the CGM sensor glucose values will 
618 
result from hospital point-of-care glucometers. The type of glucometer used by the 
619 
hospital will be documented in the study source documentation. 
620 
• 
CGM validation should not be attempted during times of rapid glucose 
621 
fluctuations (indicated by one or more vertical CGM trend arrows). In this event, 
622 
assessment will be attempted after stabilization of glucose, indicated by a single 
623 
horizontal or angled CGM trend arrow. 
624 
• 
Validation will be performed at the initiation of a new sensor/transmitter 
625 
session and confirmed if the CGM sensor glucose value satisfies the below criteria:  
626 
o 
CGM glucose is within the range of 20% of BG for BG values ≥70 mg/dL 
627 
[Validation range: (BG x 0.8) to (BG x 1.2)] 
628 
o 
CGM glucose is within the range of 20 mg/dL of BG for BG values <70 
629 
mg/dL [Validation range: (BG – 20) to (BG + 20)] 
630 
• 
Once validation is confirmed, the patient will be transitioned to HCL/AID mode.  
631 
• 
If validation criteria are not met within the first 12 hours of sensor wear, the CGM 
632 
will be calibrated with the POC glucose value, and the system will remain in the 
633 
manual/open-loop setting. Reassessment for CGM validation will occur every 2 to 8 
634 
hours until criteria are met, or until an additional 12 to 24 hours has elapsed. If 12 to 24 
635 
hours pass following calibration without a successful validation, a new sensor will be 
636 
placed, and the process will be reattempted.  
637 

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• 
If a successful CGM validation is not achieved after 48 hours despite the above 
638 
measures, the patient will instead be placed on standard insulin therapy under the care of 
639 
the primary admitting service.  
640 
3.1.2 Ongoing glucose monitoring 
641 
POC glucose monitoring will be determined based on stepwise enrollment phase as below:  
642 
Phase 1: POC glucose monitoring will occur at a minimum of 6x per day (below) as clinically 
643 
appropriate 
644 
- 
Before meals, at bedtime, approximately 12AM and 3AM or  
645 
- 
Approximately every 4 hours 
646 
Phase 2:  Standard of care POC glucose monitoring with additional POC tests as clinically 
647 
appropriate  
648 
- 
Before meals and at bedtime or 
649 
- 
Approximately every 6 hours 
650 
CGM values will be validated as above and prior to any meal or correction insulin bolus. 
651 
The CGM glucose value will be compared to a concurrent POC glucose value to verify device 
652 
accuracy (validation criteria as above). If validation criteria are not met by the CGM glucose 
653 
value, the POC glucose value will be used for bolus or correction insulin dose calculation by the 
654 
HCL/AID system in lieu of the CGM glucose value.  
655 
At investigator discretion, or if >3 consecutive CGM values do not meet validation criteria 
656 
during ongoing POC glucose monitoring after initial validation, calibration or sensor 
657 
change will be performed. 
658 
Insulin boluses will be given remotely by nursing staff or study team, but doses will be 
659 
calculated by the HCL/AID system based on current CGM or POC glucose information and 
660 
carbohydrate content of meal or snack. Correction boluses will also be delivered as advised by 
661 
the HCL/AID system. 
662 
POC glucose assessments will be used instead of CGM sensor values in the setting of: 1) CGM 
663 
signal loss for >1 hour, 2) loss of CGM trend arrow for >1 hour, and 3) any concerning clinical 
664 
status changes. The pump will be transitioned to manual/open-loop mode until the issue is 
665 
corrected or the patient’s clinical status is deemed appropriate by study investigators for 
666 
transition back to HCL/AID mode. 
667 
3.1.3 Insulin Delivery 
668 
Nursing Training:  Nursing staff and hospital staff working with these patients will receive 
669 
training on how the AID system works, and how to administer insulin boluses, and how to 
670 
change an OmniPod5 pod (see competency checklist for health care professionals for using 
671 
the AID system in appendix A). 
672 

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• 
Basal: Basal insulin delivery settings will be initiated and adjusted at the discretion of 
673 
the study investigators.  Basal infusion rates will be dictated by the HCL algorithm when in 
674 
automated (closed-loop) mode. 
675 
• 
Prandial: Nursing staff will bolus prandial insulin calculated by the HCL/AID system 
676 
from current validated CGM (or POC) glucose value and meal size/carbohydrate content 
677 
using the pre-set ICR. 
678 
• 
Corrective: Non-mealtime correctional boluses will be calculated by the HCL system 
679 
(or determined by the pre-set ISF in open-loop settings), and will be given under the 
680 
guidance of the research team. 
681 
o NOTE: No CGM-based insulin dosing calculations will be made or administered if 
682 
CGM validation is not completed and active. 
683 
• 
Target Glucose:  The target glucose will initially be set at 120 mg/dL.  It is adjustable 
684 
to targets between 110 to 150 mg/dL, and it can be programmed to have higher or lower 
685 
targets at different times of the day.  The research staff will use their clinical judgement to 
686 
modify the glucose targets for patient safety or to improve glycemic control.  
687 
• 
HCL/Automated Mode: in this mode, validated CGM values are used by the device 
688 
algorithm to automatically adjust insulin infusion rates to target glucose value of 120 mg/dL. 
689 
• 
Open-loop/Manual Mode: in this mode, insulin delivery depends only on preset basal 
690 
rates, ICR, ISF and DIA; no CGM glucose data is required, but may be utilized for insulin 
691 
dose decisions. 
 
692 
3.2 Unit-based monitoring 
693 
CGM data will be available to nursing staff at the nursing station on a dedicated tablet screen (or 
694 
smartphone) and can also be viewed on the PDM stationed outside the patient room in a locked 
695 
container.  
696 
• 
Nursing staff working with these patients will receiving training on using CGM 
697 
data and will complete a competency checklist (Appendix A). 
698 
• 
CGM alerts will be programmed at the nursing station (tablet) and on the PDM to 
699 
alarm for glucose values <80 mg/dL. PDMs will be mobile, as they will need to move 
700 
with the patient for any transfers. 
701 
• 
For hypoglycemia alarms (CGM glucose <80 mg/dL), nursing staff will assess the 
702 
patient and perform POC BG. If concurrent POC BG is <80 mg/dL, patient will be 
703 
treated by institutional hypoglycemia protocol. If concurrent POC BG is >100 mg/dL, 
704 
POC BG will be reassessed in 1 hour. If CGM glucose remains in hypoglycemic range, 
705 
but repeat POC BG remains discordant (>80 mg/dL), the study team will be contacted for 
706 
further recommendations. 
707 
• 
Battery on PDM will be assessed and charged at least daily. 
708 
3.3 Remote monitoring by research staff 
709 
• 
The Dexcom Share app for research staff will be set to alarm for hypoglycemia as 
710 
above, as well as for CGM glucose values >250 mg/dL for >1 hour.  The research staff 
711 
will review patient glucose values, insulin delivery and patient status and determine if a 
712 
corrective dose of insulin is indicated.   
713 

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• 
For unexplained hyperglycemic range CGM values (>300 mg/dL) exceeding 60 
714 
minutes, POC glucose values will be obtained hourly for those with T1DM and every 2 
715 
hours for those with T2DM to minimize the risk of hyperglycemic crises. If the CGM 
716 
glucose remains above 300 mg/dL [>1 hour in T1DM or > 2 hours in T2D]  following a 
717 
corrective insulin dose by the AID system, the study team will be alerted and additional 
718 
correction action will be taken, with the nursing staff assessing the infusion site, changing 
719 
the pod or initiating alternative insulin delivery methods (i.e. subcutaneous injections or 
720 
IV insulin infusion).   
721 
• 
Ketones will be assessed at the discretion of the study physician or primary 
722 
hospital service for any concern about possible ketosis or DKA by drawing a serum 
723 
sample (beta-hydroxybutyrate) to be processed at the hospital laboratory.  
724 
• 
Study team will be alerted if there are no CGM readings for 30 minutes and will 
725 
contact the floor teams to assess the situation and reestablish communication.  
726 
3.4 Interruption of HCL Therapy 
727 
Imaging/Procedures: if pump and CGM must be removed for any incompatible 
728 
imaging/procedure (e.g. CT, MRI, surgery, electrocautery), management will depend on length 
729 
of required discontinuation:39-41 
730 
 Short: <1 hour 
731 
BG 180-300: administer corrective bolus insulin 
732 
If BG is >300: consider transition to IV insulin infusion or continued subcutaneous 
733 
correction protocol 
734 
 Intermediate: 1-3 hours 
735 
BG 110-180: administer bolus insulin equal to 70% of the sum of basal rate over the 
736 
prior 2-3 hours (do not administer if BG is <110). 
737 
BG 180-300: administer corrective bolus insulin 
738 
If BG is >300: consider transition to IV insulin infusion or continued subcutaneous 
739 
correction protocol 
740 
 Long: >3 hours 
741 
Consider transition to IV insulin infusion or continued subcutaneous insulin regimen 
742 
within 1 hour of pump discontinuation and determine ability to transition back to 
743 
HCL post-procedure. 
744 
Surgical intervention: patients will discontinue HCL insulin therapy and will be 
745 
treated with subcutaneous or IV insulin as per hospital perioperative glycemic 
746 
management protocol. 
747 
ICU transfers: patients requiring ICU transfer for any reason will be managed by ICU team 
748 
for diabetes management (i.e. subcutaneous insulin or continuous intravenous insulin 
749 
infusion). HCL/AID will be discontinued, but use of the Dexcom CGM for glucose 
750 
monitoring may be continued at ICU team discretion. Upon transfer out of the ICU, patients 
751 
may resume HCL therapy for diabetes management when appropriate. Patients with 
752 
worsening clinical condition (hypoxia or hemodynamically unstable) who do not meet ICU 
753 
transfer criteria may resume the AID system once those conditions are under control.  
754 

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Emergency use of insulin for non-glucose-related indications: in the event that a patient requires 
755 
insulin for a non-glucose-related indication, such as an IV insulin dose for the treatment of 
756 
hyperkalemia, HCL therapy should may be suspended temporarily at the discretion of the 
757 
investigator until confirmed resolution of the underlying condition (e.g. hyperkalemia resolves). 
758 
If HCL therapy is suspended for >6 hours, the patient should be transitioned to and maintained 
759 
on subcutaneous insulin until the underlying condition resolves and HCL therapy can be 
760 
resumed. 
761 
3.5 Discontinuation of HCL/AID 
762 
Criteria for discontinuation of HCL therapy for an individual participant, as well as study hold 
763 
parameters are detailed below in sections 6.6.1 and 6.6.2.  
764 

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Chapter 4: Study Devices 
765 
4.1 Description of the Investigational Device 
766 
The Omnipod5/Horizon™ System is composed of three primary components (Figure 7): 
767 
 Omnipod5/Horizon™ Controller – Horizon App (PDM) and Algorithm 
768 
 Omnipod5/Horizon™ Alternate Controller Enabled (ACE) Pump – Pod 
769 
 Dexcom G6 – CGM  
770 
The Omnipod5/Horizon™ System will provide automated insulin delivery when connected to a 
771 
Dexcom G6 CGM. The system is expected to reduce hypoglycemia without incurring an 
772 
unacceptable increase in hyperglycemia and mean glucose. The system is also expected to reduce 
773 
the extent and magnitude of hyperglycemia associated with meals. Optimal post-prandial control 
774 
requires the user to deliver meal boluses as in current “open-loop” therapy, but the normal 
775 
operation of the control algorithm will be expected to compensate for mismatched meal boluses 
776 
and prevent prolonged hyperglycemia. The system uses a control-to-target strategy that attempts 
777 
to achieve and maintain a set target glucose level, with target setpoints at 110 mg/dL, 120 
778 
mg/dL, 130 mg/dL, 140 mg/dL and 150 mg/dL. Target setpoints can be adjusted by the 
779 
user/healthcare provider, and patterns of higher or lower setpoints at different times of the day 
780 
can be programmed into the Horizon application.    
781 
 
782 
The Omnipod5/Horizon™ Controller is composed of two parts: the Horizon application (“app”) 
783 
and the model predictive control (MPC) algorithm on the Pod. The MPC algorithm provides 
784 
insulin micro-boluses once every 5 minutes based upon the predicted glucose over a 60-minute 
785 
prediction horizon. Optimal post-prandial control will require meal boluses in the same manner 
786 
as current pump therapy, but normal operation of the MPC algorithm will compensate for late or 
787 
missed or underestimated meal boluses and mitigate prolonged hyperglycemia. The MPC 
788 
algorithm uses the control-to-target strategy to achieve and maintain a set target glucose value, 
789 
thereby reducing the duration of prolonged hyperglycemia and hypoglycemia. The MPC 
790 
Figure 7. Components of the Omnipod5/Horizon AID and Dexcom G6 CGM system. 

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algorithm resides on the Pod (Pump) component of the Omnipod5/Horizon™ System (similar to 
791 
the DASH alternate controller enabled (ACE) pump cleared in K191679, as described further 
792 
below).  
793 
The Horizon™ app will be the primary interface and will be used to start and stop a Pod, 
794 
program basal and bolus calculator settings for manual mode as well as program settings specific 
795 
for Automated Mode (hybrid closed-loop).   
796 
Manual (“Open-loop”) Mode:  
797 
In Manual Mode, the Omnipod5/Horizon™ System will function equivalently to the Omnipod® 
798 
DASH System, which was first cleared under K180045, most recently under K191679. This 
799 
includes delivering insulin at programmed basal rates and bolus amounts with the option to set 
800 
temporary basal profiles. The Omnipod5/Horizon™ Controller will also have the ability to 
801 
function as a sensor augmented pump in Manual Mode, using sensor glucose data provided by 
802 
the CGM to populate the bolus calculator.  
803 
Automated (“Hybrid closed-loop”) Mode:  
804 
In Automated Mode, the system will support the use of multiple target glucose values, currently 
805 
intended to be 110-150 mg/dL in 10 mg/dL increments. The research team will program basal 
806 
rates, glucose targets and bolus calculator settings (see section 3.2). These in turn will inform the 
807 
MPC algorithm for insulin dosing parameters. The insulin dosing parameters will be adapted 
808 
over time based on the total daily insulin (TDI) delivered during each Pod use. A temporary 
809 
hypoglycemia protection mode (Hypo Protect) may be implemented by the user for various time 
810 
durations during Automated Mode. With Hypo Protect, the algorithm reduces insulin delivery 
811 
and is intended for use over temporary durations when insulin sensitivity is expected to be 
812 
higher, such as with discontinuation of steroids, or a significant improvement in illness-related 
813 
stress, and exercise for ambulatory patients. This function would be enabled at the discretion of 
814 
the research physicians.   
815 
The Omnipod5/Horizon™ System will include two apps on a locked-down smartphone (the 
816 
Samsung J3), referred to as Personal Diabetes Manager (PDM): the Horizon App and the 
817 
Dexcom App. This phone has shown good communication between the Pod and Dexcom G6 
818 
sensor in the hospital setting, communicating from the hallway to far corners of the patient’s 
819 
room (including bathrooms), with multiple hospital monitoring devices and pumps functioning in 
820 
the room. The Horizon App, which will have a similar interface to the cleared Omnipod® DASH 
821 
System (K191679), will allow the use of large text, graphics, and on-screen instructions to 
822 
prompt the user through set-up processes. It will also be used to program the user’s custom basal 
823 
insulin delivery profile, check the Pod status, initiate bolus doses of insulin, make changes to a 
824 
patient’s insulin delivery profile, handle system alerts and alarms, and enter Automated Mode.   
825 
The Dexcom App interface is identical to the current app of the interoperable Dexcom G6 
826 
Continuous Glucose Monitoring System (K191450) and will provide CGM data, alerts, and 
827 
alarms to the user.   
828 

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The Horizon App and Dexcom App will not directly communicate with one another. Instead, the 
829 
CGM transmitter will communicate estimated glucose values (EGV) directly to the Pod. The 
830 
Dexcom transmitter number must be entered into the Horizon App, and this information is sent 
831 
to the Pod to allow transmission of EGV. The Pod will pair directly to the transmitter to receive 
832 
EGV for the algorithm and also sends the EGV back to the Horizon App as shown in Figure 7. 
833 
The Omnipod5/Horizon™ Controller provides the ability to calculate a suggested bolus dose 
834 
through the use of the bolus calculator. The bolus calculator will have the option to use the EGV, 
835 
which is communicated to the app via the Pod. If the sensor has passed validation criteria for the 
836 
day, it is preferred that the EGV be used for correction and meal boluses, since the algorithm will 
837 
also use the sensor rate of change information in calculating the insulin dose.  This allows for 
838 
less insulin delivery when the estimated glucose is decreasing and more insulin delivery when 
839 
the estimated glucose is increasing.  Insulin-on-board (IOB) is calculated by the algorithm taking 
840 
into account any manual bolus and insulin delivered by the algorithm.  
841 
As with the cleared Omnipod® DASH System, Insulet will utilize a proprietary encrypted 
842 
security stack embedded within the Bluetooth Low Energy (BLE) communication. 
843 
4.1.1 Omnipod5/Horizon™ automated insulin delivery system 
844 
The Pod component of the Omnipod5/Horizon™ System is similar to the Omnipod® DASH 
845 
ACE Pump cleared under K191679. Compared to the DASH ACE Pump (K191679), the 
846 
Horizon™ ACE Pump (Pod) has additional software to optimize communication to accept inputs 
847 
from the CGM (Dexcom G6) and the Horizon™ Controller. The insulin delivery mechanism and 
848 
the patient and fluid contacting components are identical to the DASH Pod.   
849 
The Pod is a lightweight, self-adhesive device that the user fills with U-100 rapid-acting insulin 
850 
and wears directly on their body. The Pod delivers insulin into the user’s body through a small 
851 
flexible tube, called a cannula, based on the commands from the compatible controller. In the 
852 
Omnipod5/Horizon™ System, the Pod will house the MPC algorithm and communicate directly 
853 
with the CGM and the Horizon App. The algorithm commands the Pod’s insulin delivery in the 
854 
form of micro-boluses based on predicted glucose values. As with the cleared Omnipod® DASH 
855 
System, the Pod of the Omnipod5/Horizon™ System will come pre-packaged in a sterile 
856 
container with a fill needle and a fill syringe. Figure 8 below is a representation of the Pod. The 
857 
Omnipod5 has not been approved for commercial sale and has not been tested for use on 
858 
hospitalized patients and is therefore considered experimental.  
859 

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860 
4.1.2 Continuous Glucose Monitoring 
861 
The second component of the Omnipod5/Horizon™ System is the CGM. The 
862 
Omnipod5/Horizon™ System will be interoperable with a compatible CGM, currently the 
863 
Dexcom G6 CGM System (K191450). The Pod will communicate with the Dexcom G6 via 
864 
Bluetooth Low Energy (BLE). Glucose values from the Dexcom transmitter will be sent to the 
865 
MPC algorithm residing on the Pod and will be used in insulin dosing adjustments. The glucose 
866 
values from the Dexcom transmitter will be sent independently to the Dexcom App on the 
867 
controller. The Dexcom G6 sensor is not approved for use in a hospital setting and is therefore 
868 
considered experimental. Alarms will be set as described in sections 3.1.3 and 3.1.4. 
869 
4.1.3 Horizon Data Portal 
870 
Data are securely uploaded from the PDM to the Insulet Cloud by cellular connection. Data are 
871 
then transferred from Insulet Cloud to the Horizon Data Portal (HDP), which is a platform for 
872 
data review and management. The HDP runs on an Amazon-based web server. The HDP will 
873 
provide insights including but not limited to: insulin delivery, time in range, time at each target 
874 
BG, automated/manual mode comparisons, and time spent in each mode.  
875 
The research investigators will have access to all uploaded data and be able to view historical 
876 
trends.  
877 
The Insulet Artificial Pancreas Remote Monitoring System (APRMS) allows remote monitoring 
878 
of glucose levels and insulin delivery in real-time, allowing remote evaluation of hospitalized 
879 
patients by research staff.   
880 
4.1.4 Blood Glucose Meter and Strips 
881 
The point of care glucose meter approved by the hospital will be used for POC blood glucose 
882 
readings. The meter undergoes quality control testing and the nurses are trained on its use. The 
883 
specific meter used will vary by hospital. 
884 
Figure 8:  The Pod of the Omnipod5/Horizon™ ACE pump 

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4.1.5 Study Device Accountability Procedures 
885 
Device accountability procedures will be detailed in the site procedures manual. 
886 
4.2 Safety Measures 
887 
4.2.1 CGM verification of validation 
888 
Each new study CGM will be validated prior to use of AID. See section 3.1.1. 
889 
4.2.2 Pump Failure 
890 
In the event of an early pod failure, the research staff or nursing staff trained on pod filling and 
891 
activation will initialize a new pod and remove the old pod. Pods will be disposed of in a 
892 
biohazard waste container. 
893 
4.2.3 Hypoglycemia Threshold Alarm and Safety Protocol 
894 
The low glucose threshold alarm setting will initially be set to 80 mg/dL, this may be adjusted by 
895 
the research investigators as the study progresses, or for an individual patient, but will never be 
896 
less than 70 mg/dL.  See sections 3.1.3 and 3.1.4. 
897 
4.2.4 Hyperglycemia Threshold Alarm and Safety Protocol 
898 
During the course of the study and for individual patients, researchers will be permitted to 
899 
change this setting within a range of 200 to 300 mg/dL.  Initially this alarm will be set to 250 
900 
mg/dL. See sections 3.1.3 and 3.1.4. 
901 
During the time period when the closed-loop system is operational and active, if a participant’s 
902 
CGM reading is >300 mg/dL for over 1 hour or ≥400 mg/dL at any point, the following steps 
903 
will be taken: Ketones will be assessed at the discretion of the study physician or primary 
904 
hospital service for any concern about possible ketosis or DKA by drawing a serum sample 
905 
(beta-hydroxybutyrate) to be processed at the hospital laboratory.  
906 

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Chapter 5: Testing Procedures and Questionnaires 
907 
5.1 Laboratory Testing 
908 
HbA1c: to be ordered after enrollment if not obtained within one month prior to admission.    
909 
Urine or serum pregnancy test: to be ordered after enrollment for all female enrollees of 
910 
childbearing potential. 
911 
Additional biologic samples will not be collected or ordered expressly for the purpose of this 
912 
study. However, certain lab results (i.e. CBC, CRP, D-dimer, or IL-6 levels) obtained during the 
913 
hospital admission as part of the participant’s medical care will be recorded in our data 
914 
collection. 
915 
5.2 Surveys and Questionnaires 
916 
We will obtain feedback and suggestions from both the health care providers and the patients 
917 
who are interacting with the Omnipod5/Horizon HCL system.  
918 
At completion of the study, health care workers who used the system (e.g. hospitalists, nurses) 
919 
will be asked to complete:  
920 
• 
The 10-item System Usability questionnaire (Appendix X)  
921 
• 
A brief, 9-item questionnaire (Appendix Y) on their perceptions of using the system and 
922 
their suggestions for future use of the system  
923 
We acknowledge that the inpatient providers will be the primary interactive users with these 
924 
devices and also that hospitalized patients may have varying degrees of illness, and therefore 
925 
limited ability to participate in questionnaires. However, we believe patient input and 
926 
feedback is also of great potential benefit. As such, we have included patient surveys, but have 
927 
limited them to 8-items, to be answered if able.  
928 
After patients are taken off the system they will be asked to:  
929 
• 
Fill out a brief, 8-item questionnaire (Appendix Z) 
930 

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Chapter 6: Unanticipated Problem, Adverse Event, and Device Issue 
931 
Reporting 
932 
6.1 Unanticipated Problems 
933 
Site investigators will promptly report to the study Principal Investigator and to the Medical 
934 
Monitor all unanticipated problems meeting the criteria below within seven days. For this 
935 
protocol, an unanticipated problem is an incident, experience, or outcome that meets all of the 
936 
following criteria: 
937 
 Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
938 
that are described in the protocol related documents, such as the IRB-approved research 
939 
protocol and informed consent document; and (b) the characteristics of the subject 
940 
population being studied. 
941 
 Related or possibly related to participation in the research (possibly related means there is 
942 
a reasonable possibility that the incident, experience, or outcome may have been caused 
943 
by the procedures involved in the research) 
944 
 Suggests that the research places participants or others at a greater risk of harm than was 
945 
previously known or recognized (including physical, psychological, economic, or social 
946 
harm) 
947 
These instances must be reported to the JCHR IRB within seven calendar days of recognition. 
948 
The Director of the Human Research Protection Program will report to the appropriate regulatory 
949 
authorities if the IRB determines that the event indeed meets the criteria of an Unanticipated 
950 
Problem requiring additional reporting. 
951 
6.2 Adverse Events 
952 
6.2.1 Definitions 
953 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
954 
relationship between the adverse event and the device(s) under investigation. 
955 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
956 
 Results in death. 
957 
 Is life-threatening; (a non-life-threatening event which, had it been more severe, 
958 
might have become life-threatening, is not necessarily considered a serious adverse 
959 
event). 
960 
 Requires prolongation of current hospitalization. 
961 
 Results in persistent or significant disability/incapacity or substantial disruption of the 
962 
ability to conduct normal life functions. 
963 
 Is considered a significant medical event by the investigator based on medical 
964 
judgment (e.g., may jeopardize the participant or may require medical/surgical 
965 
intervention to prevent one of the outcomes listed above). 
966 

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Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
967 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
968 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
969 
investigational plan or application (including a supplementary plan or application), or any other 
970 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
971 
welfare of participants (21 CFR 812.3(s)). 
972 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
973 
the device may have caused or to which the device may have contributed (Note that an Adverse 
974 
Event Form is to be completed in addition to a Device Deficiency or Issue Form, unless excluded 
975 
from reporting as defined in section 6.2). An event that occurs solely due to user error in which 
976 
the device functions properly generally will not be considered an ADE unless it is determined 
977 
that the instructions on the screen of the device or user manual (or similar training materials) 
978 
may have contributed to the event (note: the event may still meet criteria for reporting as an 
979 
adverse event). 
980 
Device Complaints and Malfunctions: A device complication or complaint is something that 
981 
happens to a device or related to device performance, whereas an adverse event happens to a 
982 
participant. A device complaint may occur independently from an AE, or along with an AE.  An 
983 
AE may occur without a device complaint or there may be an AE related to a device complaint.  
984 
A device malfunction is any failure of a device to meet its performance specifications or 
985 
otherwise perform as intended. Performance specifications include all claims made in the 
986 
labeling for the device. The intended performance of a device refers to the intended use for 
987 
which the device is labeled or marketed (21 CFR 803.3). Note: for reporting purposes, sites will 
988 
not be asked to distinguish between device complaints and malfunctions. 
989 
6.2.2 Reportable Adverse Events 
990 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
991 
meets one of the following criteria: 
992 
1. An ADE as defined in section 6.2.1, unless excluded from reporting in section 8.3 
993 
2. An AE as defined in section 6.2.1 occurring in association with a study procedure 
994 
3. An AE as defined in section 6.2.1 that affects the participant’s ability to complete any 
995 
study procedures 
996 
4. Hypoglycemia meeting the definition of severe hypoglycemia as defined below 
997 
5. Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, hyperglycemia 
998 
or ketosis event meeting the criteria defined below. 
999 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
1000 
events unless associated with an Adverse Device Effect. Skin reactions from sensor placement 
1001 
are only reportable if severe and/or required treatment. 
1002 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
1003 
during questioning, or detected through physical examination, laboratory test, or other means—
1004 
will be reported on an AE form. Each AE form will be reviewed by the Medical Monitor to 
1005 
assess for safety and study continuation. 
1006 

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6.2.3 Hypoglycemic Events 
1007 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an Adverse 
1008 
Event when either of the following parameters are met: 
1009 
 The episode is associated with acute severe cognitive impairment, including incoherence, 
1010 
disorientation, and/or combativeness, seizure, or loss of consciousness. Note: If plasma 
1011 
glucose measurements are not available during such an event, neurological recovery 
1012 
attributable to the restoration of plasma glucose to normal is considered sufficient 
1013 
evidence that the event was induced by a low plasma glucose concentration. 
1014 
 Capillary glucose is <40 mg/dL 
1015 
When a hypoglycemic event meets the above reporting requirements, a Hypoglycemia Form 
1016 
should be completed in addition to the Adverse Event Form. Severe hypoglycemia events should 
1017 
be considered to be serious adverse events with respect to reporting requirements. 
1018 
6.2.4 Hyperglycemic/Ketotic Events 
1019 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an Adverse 
1020 
Event if the event involved DKA. Hyperglycemic events are classified as DKA if the following 
1021 
are present: 
1022 
 Symptoms such as polyuria, polydipsia, nausea, or vomiting;  
1023 
 Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
1024 
 Either arterial blood pH <7.30, venous pH <7.24, or serum bicarbonate (or CO2) <15 
1025 
mEq/L 
1026 
 DKA is suspected as either the primary or a contributing cause for these findings 
1027 
When a hyperglycemia/ketotic event meets the above reporting requirements, an Adverse 
1028 
Event Form should be completed. Events meeting DKA criteria should be considered 
1029 
serious adverse events with respect to reporting requirements. Hyperglycemia events not 
1030 
meeting criteria for DKA generally will not be considered as serious adverse events 
1031 
unless one of the SAE criteria in section 6.2.1 is met. 
1032 
6.2.5 Relationship of Adverse Event to Study Investigational Device 
1033 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1034 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1035 
by the study device. 
1036 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1037 
following general guideline when determining whether an adverse event is related: 
1038 
 Unrelated: The AE is clearly not related to a study drug/device and a likely alternative 
1039 
etiology exists such as an underlying disease, environmental or toxic factors or other therapy. 
1040 

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 Unlikely Related: The AE does not follow a reasonable temporal sequence during or after 
1041 
use of study drug/device and a more likely alternative etiology exists such as an underlying 
1042 
disease, environmental or toxic factors, or other therapy.  
1043 
 Possibly Related: The AE occurred in a reasonable time during or after use of study 
1044 
drug/device; but could be related to another factor such as an underlying disease, 
1045 
environmental or toxic factors, or other therapy; and there is a possible, though weak, 
1046 
scientific basis for establishing a causal association between the AE and the study 
1047 
drug/device. 
1048 
 Probably Related: The AE occurred in a reasonable time during or after use of study 
1049 
drug/device; is unlikely to be related to another factor such as an underlying disease, 
1050 
environmental or toxic factors, or other therapy; and there is a plausible, though not strong, 
1051 
scientific basis for establishing a causal association between the AE and the study 
1052 
drug/device.  
1053 
 Definitely Related: The AE occurred in a reasonable time during or after use of study 
1054 
drug/device; cannot be explained by another factor such as an underlying disease, 
1055 
environmental or toxic factors, or therapy; and there is a strong scientific basis for 
1056 
establishing a causal association between the AE and the study drug/device.  
1057 
 Not Assessable: Causality of an adverse event cannot be judged because information is 
1058 
insufficient or contradictory, and which cannot be supplemented or verified. 
1059 
6.2.6 Severity (Intensity) of Adverse Events 
1060 
The severity (intensity) of an adverse event will be rated on a three-point scale: (1) mild, (2) 
1061 
moderate, or (3) severe. A severity assessment is a clinical determination of the intensity of an 
1062 
event. Thus, a severe adverse event is not necessarily serious. For example, itching for several 
1063 
days may be rated as severe, but may not be clinically serious. 
1064 
 MILD: Usually transient, requires no special treatment, and does not interfere with the 
1065 
participant’s daily activities. 
1066 
 MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
1067 
participant and may interfere with daily activities but is usually ameliorated by simple 
1068 
therapeutic measures and participant is able to continue in study. 
1069 
 SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
1070 
cause discontinuation of study device, and generally requires systemic drug therapy or other 
1071 
treatment. 
1072 
6.2.7 Expectedness 
1073 
For a serious adverse event that is considered possibly related to study device, the Medical 
1074 
Monitor will classify the event as unexpected if the nature, severity, or frequency of the event is 
1075 
not consistent with the risk information previously described in section 1.4 
1076 
6.2.8 Coding of Adverse Events 
1077 
The Medical Monitor will review the investigator’s assessment of causality and may agree or 
1078 
disagree.  Both the investigator’s and Medical Monitor’s assessments will be recorded.  The 
1079 

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Medical Monitor will have the final say in determining the causality as well as whether an event 
1080 
is classified as a serious adverse event and/or an unanticipated adverse device effect. 
1081 
6.2.9 Outcome of Adverse Events 
1082 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1083 
 RECOVERED/RESOLVED – The participant recovered from the AE/SAE 
1084 
without sequelae.  Record the AE/SAE stop date. 
1085 
 RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had 
1086 
stabilized without change in the event anticipated.  Record the AE/SAE stop date. 
1087 
 FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the 
1088 
event that was the cause of death should be reported as fatal.  AEs/SAEs that were 
1089 
ongoing at the time of death; however, were not the cause of death, will be 
1090 
recorded as “resolved” at the time of death. 
1091 
 NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is 
1092 
defined as the event was ongoing with an undetermined outcome. 
1093 
An ongoing outcome will require follow-up by the site in order to determine the 
1094 
final outcome of the AE/SAE. 
1095 
The outcome of an ongoing event at the time of death that was not the cause of 
1096 
death, will be updated and recorded as “resolved” with the date of death recorded 
1097 
as the stop date. 
1098 
 UNKNOWN – An unknown outcome is defined as an inability to access the 
1099 
participant or the participant’s records to determine the outcome (for example, a 
1100 
participant that was lost to follow-up). 
1101 
If any reported adverse events are ongoing when a participant completes the study (or 
1102 
withdraws), adverse events classified UADEs will be followed until they are either resolved, or 
1103 
have no prospect of improvement or change, even after the participant has completed all 
1104 
applicable study visits/contacts. For all other adverse events, data collection will end at the time 
1105 
the participant completes the study. Note: participants should continue to receive appropriate 
1106 
medical care for an adverse event after their participation in the study ends.  
1107 
6.3 Reportable Device Issues 
1108 
All UADEs and ADEs as defined in section 6.2.1 will be reported on both a device issue form 
1109 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
1110 
placement that do not require pharmacologic treatment. As noted in section 6.2.1, events that 
1111 
occur due to user error generally will not require completion of a device issue form. 
1112 
Device complaints and device malfunctions will be reported except in the following 
1113 
circumstances. These occurrences are expected and will not be reported on a Device Issue Form 
1114 
assuming criteria for a UADE or ADE have not been met: 
1115 
 CGM sensor lasting fewer days than expected per manufacturer 
1116 
 CGM tape adherence issues 
1117 

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 Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
1118 
 Intermittent device component disconnections/communication failures not requiring system 
1119 
replacement or workaround/resolution not specified in user guide/manual. 
1120 
 Device issues clearly addressed in the user guide manual that do not require additional 
1121 
troubleshooting 
1122 
6.4 Timing of Event Reporting 
1123 
SAEs possibly related to a study device or study participation and UADEs must be reported to 
1124 
the Coordinating Site (Emory University) within 24 hours of the site becoming aware of the 
1125 
event. This can occur via phone or email, or by completion of the online serious adverse event 
1126 
form and device issue form if applicable. If the form is not initially completed, it should be 
1127 
competed as soon as possible after there is sufficient information to evaluate the event. All other 
1128 
reportable ADEs and other reportable AEs should be submitted by completion on the on-line 
1129 
form within 7 days of the site becoming aware of the event. 
1130 
The Coordinating Site will notify all participating investigators of any adverse event that is 
1131 
serious, related, and unexpected. Notification will be made within 10 working days after the 
1132 
Coordinating Site becomes aware of the event. 
1133 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1134 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1135 
Ethics Committee. Where the JCHR IRB is the overseeing IRB, sites must report all serious, 
1136 
related adverse events within seven calendar days. 
1137 
Upon receipt of a qualifying event, the Sponsor will investigate the event to determine if a 
1138 
UADE is confirmed, and if indicated, report the results of the investigation to all overseeing 
1139 
IRBs, and the FDA within 10 working days of the Sponsor becoming aware of the UADE per 
1140 
21CFR 812.46(b) (2).  The Medical Monitor must determine if the UADE presents an 
1141 
unreasonable risk to participants.  If so, the Medical Monitor must ensure that all investigations, 
1142 
or parts of investigations presenting that risk, are terminated as soon as possible but no later than 
1143 
5 working days after the Medical Monitor makes this determination and no later than 15 working 
1144 
days after first receipt notice of the UADE. 
1145 
Device malfunctions will be handled by the Sponsor or designee as described below. In the case 
1146 
of a device malfunction, information will be forwarded to Insulet by the study staff to be 
1147 
addressed by approved company personnel.  
1148 
6.5 Safety Oversight 
1149 
The study Medical Monitor will review all adverse events and adverse device events that are 
1150 
reported during the study.  Severe adverse events (SAE) typically will be reviewed within 24 
1151 
hours of reporting.  Other AEs typically will be reviewed on a weekly basis. Additionally, the 
1152 
Medical Monitor will review compiled safety data at the end of phase 1 (n=9) and phase 2 (n=9).  
1153 
 
1154 

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Safety parameter review: assessment for any of the below attributed to sensor error or 
1155 
inappropriate insulin delivery by the AID system will be reviewed in aggregate after each phase.  
1156 
 Severe hypoglycemia is defined as severe if the event required assistance of another 
1157 
person to actively administer carbohydrate, glucagon, or other resuscitative actions due to 
1158 
altered consciousness.  
1159 
 UADE: means any serious adverse effect on health or safety or any life-threatening 
1160 
problem or death caused by, or associated with, a device, if that effect, problem, or death 
1161 
was not previously identified in nature, severity, or degree of incidence in the 
1162 
investigational plan or application (including a supplementary plan or application), or any 
1163 
other unanticipated serious problem associated with a device that relates to the rights, 
1164 
safety, or welfare of subjects. 
1165 
 Diabetic Ketoacidosis (requires all four criteria to be met): 
1166 
(1) Symptoms such as polyuria, polydipsia, nausea, or vomiting 
1167 
(2) Serum ketones > 1.5 mmol/L or large/moderate urine ketones 
1168 
(3) Either arterial blood pH < 7.30 or venous pH < 7.24 or serum bicarbonate < 15 
1169 
(4) DKA is suspected as either the primary or a contributing cause for these findings 
1170 
The Clinical Study Director will be informed of all cases of severe hypoglycemia and DKA 
1171 
and the Medical Monitor’s assessment of relationship to the study device; and informed of all 
1172 
reported device issues. 
1173 
6.6 Stopping Criteria 
1174 
6.6.1 Participant Discontinuation of Study Device 
1175 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA 
1176 
event (or a malfunction that could have led to severe hypoglycemia or DKA), use of the HCL 
1177 
system will be suspended while the problem is diagnosed. The UADE will be reported to the 
1178 
IRB and the FDA. After assessment of the problem and any correction, use of the system will not 
1179 
be restarted until approval is received from the IRB and the FDA. 
1180 
HCL therapy will be discontinued and patients will be transitioned to standard subcutaneous 
1181 
insulin therapy with continued management by the primary medical/surgical team or inpatient 
1182 
endocrine consult service (as clinically warranted) if any of the following occur: 
1183 
 The investigator believes it is unsafe for the participant to continue on the intervention.  
1184 
This could be due to the development of a new medical condition or worsening of an 
1185 
existing condition; or participant behavior contrary to the indications for use of the device 
1186 
that imposes on the participant’s safety 
1187 
 Participant’s clinical team feels transition to IV insulin infusion or MDI regimen is 
1188 
necessary for glycemic control 
1189 

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 A successful CGM validation has not been achieved per the protocol detailed in section 
1190 
3.1.1 on two consecutive CGM sensors 
1191 
 The participant requests that the treatment be stopped 
1192 
 Participant pregnancy 
1193 
 Participant requires hemodialysis or continuous renal replacement therapy (CRRT) 
1194 
 Participant requires treatment with hydroxyurea or high dose ascorbic acid 
1195 
 One episode of DKA as defined in section 6.2.4 
1196 
 One episode of severe hypoglycemia as defined in section 6.2.3 
1197 
 One episode of DKA as defined in section 6.2.4 and one severe hypoglycemia event as 
1198 
defined in section 6.2.3 
1199 
 Participant is anticipated to be discharged from the hospital without plan to continue 
1200 
HCL insulin therapy in outpatient setting; transition to subcutaneous insulin regimen will 
1201 
be initiated prior to discharge. 
1202 
Transfers to the ICU will prompt discontinuation of use of the HCL component of the system 
1203 
(CGM may be used at described in section 3.2.1). However, participant may be transitioned back 
1204 
to HCL therapy after transferring out of the ICU to a non-ICU ward based on study team 
1205 
assessment. ICU transfers will not be reported as AE or ADE unless the specific reason for 
1206 
transfer is glycemia-related (i.e. severe hypoglycemia or DKA). 
1207 
6.6.2 Criteria for Suspending or Stopping Overall Study 
1208 
In addition to the suspension of device use due to a UADE as described in section 6.6.1, study 
1209 
activities could be similarly suspended if the manufacturer of any constituent study device 
1210 
requires stoppage of device use for safety reasons (e.g. product recall). The affected study 
1211 
activities may resume if the underlying problem can be corrected by a protocol or system 
1212 
modification that will not invalidate the results obtained prior to suspension. 
1213 
Additionally, the entire study will be placed on hold pending further review and 
1214 
recommendations by the Medical Monitor and IRB for any of the following:  
1215 
 Adverse events attributable to study device (including DKA or seizure) 
1216 
 
Two patients with ≥1 episode of severe hypoglycemia attributable to insulin delivered by 
1217 
study device. 
1218 
 
 
1219 

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Chapter 7: Miscellaneous Considerations 
1220 
7.1 Drugs Used as Part of the Protocol 
1221 
Participants will be limited to the insulin approved for pump use (i.e. insulin lispro or insulin 
1222 
aspart). 
1223 
7.2 Collection of Medical Conditions and Medications 
1224 
Pre-Existing Condition: Any medical condition that is either present at screening, a chronic 
1225 
disease, or a prior condition that could impact the participant’s health during the course of the 
1226 
study (e.g., prior myocardial infarction or stroke). 
1227 
Medical Conditions during the study: In addition to conditions meeting the reporting 
1228 
requirements for an adverse event or device issue as described above, the following medical 
1229 
conditions should also be reported: (1) new diagnosis of a chronic disease (i.e., not present at the 
1230 
time of enrollment), and (2) any medical condition that could affect the participant’s ability to 
1231 
carry out any aspect of the protocol or could affect an outcome assessment. 
1232 
Medications: All medication for the treatment of chronic pre-existing conditions, medical 
1233 
conditions (including medical conditions that do not require recording), and/or adverse events 
1234 
that the participant is currently taking at screening and during the course of the study should be 
1235 
recorded. Nutraceuticals and preventative treatment also should be recorded. Medications only 
1236 
taken as needed will only be recorded if used during the study (e.g. Glucagon for treatment of 
1237 
severe hypoglycemia). 
1238 
7.3 Prohibited Medications, Devices, Treatments, and Procedures 
1239 
Non-insulin antihyperglycemics: non-insulin agents will be discontinued at enrollment  
1240 
Additional insulins: Treatment of hyperglycemia with additional insulin beyond what is 
1241 
delivered by HCL therapy will not be permitted in conjunction with ongoing HCL use. For 
1242 
participants who require alternative or additional insulin therapy at the discretion of the patient’s 
1243 
inpatient providers, the HCL system will be discontinued, as described in section 6.6.1. 
1244 
Emergency use on insulins for non-glucose-related indications, such as hyperkalemia, are 
1245 
permitted; however, HCL therapy may be temporarily suspended at the discretion of the 
1246 
investigator and subsequently resumed as described in section 3.2.1. 
1247 
Hydroxyurea: Participants who require treatment with hydroxyurea will discontinue HCL 
1248 
therapy, as described in section 6.6.1. 
1249 
High-dose ascorbic acid (>1g/day): Participants who require treatment with ascorbic acid will 
1250 
discontinue HCL therapy, as described in section 6.6.1. 
1251 

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All study devices (insulin pump, CGM) must be removed before Magnetic Resonance Imaging 
1252 
(MRI) or diathermy treatment. CGM equipment may be worn during Computed Tomography 
1253 
(CT).  
1254 
7.4 Precautionary Medications, Treatments, and Procedures 
1255 
Acetaminophen doses of >1 gram every 6 hours may cause CGM readings to be artificially 
1256 
elevated. Acetaminophen use should be limited to ≤4 grams per day. 
1257 
7.5 Prophylactic Medications, Treatments, and Procedures 
1258 
This section is not applicable to this study. 
1259 
7.6 Rescue Medications, Treatments, and Procedures 
1260 
All rescue therapies are allowed at the discretion of the participant’s inpatient providers. HCL 
1261 
therapy should be discontinued in the event that certain medications are required, as described in 
1262 
sections 3.2.1, 6.6.1, and 7.3. 
1263 
7.7 Pregnancy Reporting 
1264 
Pregnancy occurring during this study is highly unlikely. However, if pregnancy is discovered 
1265 
after enrollment, the participant will be discontinued from the study. The occurrence of 
1266 
pregnancy will be reported to the Coordinating Site within seven days and to the JCHR IRB as 
1267 
an Unanticipated Problem within seven calendar days.  
1268 
7.8 Participant Compensation 
1269 
Participant compensation will be specified in the informed consent form. 
1270 
7.9 Participant Withdrawal 
1271 
Participation in the study is voluntary, and a participant may withdraw at any time. For 
1272 
participants who withdraw, their data will be used up until the time of withdrawal. 
1273 
7.10 Confidentiality 
1274 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1275 
used instead of their name. Protected health information gathered for this study will be shared 
1276 
with the Statistical Center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
1277 
participant information may also be provided to research sites involved in the study.
1278 

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Chapter 8: Statistical Considerations 
1279 
8.1 Statistical and Analytical Plans 
1280 
The approach to sample size and statistical analyses are summarized below.   
1281 
8.2 Statistical Hypotheses 
1282 
This is a pilot and feasibility trial and is not powered to reach statistical conclusions. 
1283 
8.3 Sample Size 
1284 
The sample size was a convenient sample size by which to obtain preliminary data on 
1285 
implementing the HCL/AID system in a hospital setting. The maximum number of participants 
1286 
to be consented for participation in this study (n=30) is based upon the goal of enrolling 18 
1287 
patients with at least 48 hours of data during HCL therapy and to account for the potential for 
1288 
early device wear termination, ICU transfer, or early discharge. 
1289 
8.4 Outcome Measures 
1290 
Primary Endpoints: 
1291 
Aim 1: Proportion of time spent in HCL after CGM validation 
1292 
Aim 2: Percentage of time sensor glucose is within target glucose range [time-in-range (TIR)], 
1293 
defined as sensor glucose 70-180 mg/dL. 
1294 
Secondary Endpoints: 
1295 
Aim 1.1: System function 
1296 
 
Time from enrollment to start of HCL therapy  
1297 
 
Percent of time with CGM readings 
1298 
 
Percentage of validations that were successful 
1299 
 
Number of CGM readings within %15/15 of POC readings and within %20/20 of 
1300 
POC readings with the cut point at 70 mg/dL.   
1301 
 
1302 
Aim 1.2: Implementation processes and adoptability of inpatient HCL therapy by clinical staff 
1303 
and patients (Qualitative analyses) 
1304 
 
Patient and Providers: Open-ended feedback 
1305 
 
Patient and Providers: Survey questionnaire results 
1306 
Aim 2.1: Glycemic control 
1307 

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   
Number of hypoglycemic (<70 mg/dL) and clinically-important hypoglycemic (<54 
1308 
mg/dL) episodes per patient and per patient-day 
1309 
 
Percent time below range (TBR, <70mg/dL) 
1310 
 
Percent time in clinically-important hypoglycema(<54 mg/dL) 
1311 
 
Percent time above range (TAR, >180 mg/dL) 
1312 
 
Percent time in severe hyperglycemia (>250 mg/dL) 
1313 
 
Glycemic variability (CV and SD) 
1314 
Aim 2.2: HCL Settings 
1315 
 
Frequency of setting adjustments for clinically-important hypoglycemia (<54 
1316 
mg/dL): Overall, to basal rate, to ICR, to ISF  
1317 
 
Frequency of setting adjustments for prolonged severe hyperglycemia (>250 
1318 
mg/dL for >1 hour), Overall, to basal rate, to ICR, to ISF 
1319 
 
Insulin requirements: Total daily insulin (TDI), Total daily basal insulin, Total 
1320 
daily bolus insulin 
1321 
8.5 Analysis Dataset 
1322 
All relevant participant data will be included in the analysis of a single data set for this feasibility 
1323 
study. 
1324 
8.6 Analysis of the Primary Efficacy Endpoint(s) 
1325 
The primary purpose of this pilot study is to assess the feasibility HCL use in the inpatient 
1326 
setting; therefore, no formal power calculations were performed. The main objectives of this 
1327 
study are to improve the quality and efficiency of the main study. In addition, it is conducted in 
1328 
order increase the investigators’ experience with the technology in a different setting. We will 
1329 
list values for each patient as well as provide summary statistics appropriate to the distribution. 
1330 
To determine the operability of AID in the hospital (Aim 1) we will calculate the proportion of 
1331 
time spent in HCL after CGM sensor values meet validation criteria [sensor glucose values are 
1332 
within ±20% of POC values for glucose levels ≥70 mg/dL or ±20 mg/dL for POC glucose values 
1333 
<70 mg/dL]. To evaluate glycemic control (Aim 2) we will determine the percentage of time 
1334 
sensor glucose values are within target glucose range [time-in-range (TIR); 70-180 mg/dL], 
1335 
during closed-loop insulin delivery. 
1336 
8.7 Analysis of the Secondary Endpoints 
1337 
The analysis of secondary endpoints will parallel that described above for the primary analysis 
1338 
with summary statistics given for each of the metrics listed in Section 8.4  
1339 
8.8 Safety Analyses 
1340 
Safety endpoints will be analyzed using summary statistics during treatment. AEs will be coded 
1341 
as described in section 6.2.8. Severity and relationship of AE to study agent will be determined 
1342 
as described in section 6.2. The event start date, stop date, severity, relationship, outcome, and 
1343 

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duration will also be recorded. The Medical Monitor will conduct a review of safety parameters 
1344 
at the end of each study phase, as described in Section 6.5.  
1345 
The following will be tabulated during the feasibility study: 
1346 
• 
Number of adverse events 
1347 
• 
Number of participants with at least one event 
1348 
• 
Number of serious adverse events 
1349 
• 
Number of participants with at least one serious adverse event 
1350 
• 
Number of unexpected device events 
1351 
• 
Number of unexpected serious device events 
1352 
• 
Number of ICU transfers 
1353 
• 
Number of adverse events thought by investigator to be related to study device 
1354 
• 
Number of participants who stopped the intervention in response to an adverse 
1355 
event 
1356 
• 
Number of severe hypoglycemic events as defined in the protocol 
1357 
• 
Number of severe hypoglycemic events associated with seizure or loss of 
1358 
consciousness 
1359 
• 
Number of diabetic ketoacidosis events as defined in the protocol 
1360 
8.9 Intervention Adherence 
1361 
The adherence to the protocol will be determined by daily use of HCL after enrollment and will 
1362 
be calculated from time of enrollment to ICU transfer or hospital discharge. We will obtain 
1363 
preliminary estimates about the frequency and reasons for discontinuation of the intervention 
1364 
during this feasibility study.  
1365 
8.10 Protocol Adherence and Retention 
1366 
Potential study subjects will be identified and pre-screened among non-ICU patients with 
1367 
hyperglycemia requiring insulin therapy. Strategies to address potential problems with 
1368 
recruitment will include bi-weekly communications with Drs. Pasquel, Davis, Buckingham, Lal, 
1369 
and Brown. 
1370 
A study coordinator or investigator will conduct informed consent in eligible subjects prior to 
1371 
any study procedures. Screening and recruitment reports will be generated monthly that include 
1372 
actual and expected recruitment statistics. Based on preliminary studies with inpatient use of 
1373 
CGM we expect to retain most patients in this study.  
1374 
8.11 Baseline Descriptive Statistics 
1375 
Baseline characteristics will be collected and reported for all participants in this feasibility study.  
1376 

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8.12 Device Issues 
1377 
Any technical issues will be reported to Insulet Corporation. Any device issues affecting patient 
1378 
care will be reported as below and reviewed by the Medical Monitor.  
1379 
8.13 Planned Interim Analyses 
1380 
The criteria below will be considered events prompting an interim review and safety analysis 
1381 
prior to continuation of the study. The study investigators and statisticians will perform the 
1382 
statistical analysis that will be reviewed by the Medical Monitor. There are no blinding 
1383 
procedures to be addressed in this feasibility study.  
1384 
 Adverse events attributable to study device (including DKA or seizure) 
1385 
 
Two patients with ≥1 episode of severe hypoglycemia attributable to insulin delivered by 
1386 
study device. 
1387 
8.14 Sub-Group Analyses 
1388 
Not applicable in this feasibility study. 
1389 
8.15 Multiple Comparison/Multiplicity 
1390 
Not applicable in this single-arm feasibility study. 
1391 
8.16 Exploratory Analyses 
1392 
No additional exploratory analyses are planned. 
1393 
8.17 Additional Tabulations and Analyses 
1394 
Not applicable in this single-arm feasibility study. 
1395 

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Chapter 9: Data Collection and Monitoring 
1396 
9.1 Case Report Forms and Other Data Collection 
1397 
The main study data are collected on electronic case report forms (eCRFs). When data are 
1398 
directly collected in electronic case report forms, this will be considered the source data. For any 
1399 
data points for which the eCRF is not considered source (e.g. lab results that are transcribed from 
1400 
a printed report into the eCRF), the original source documentation must be maintained in the 
1401 
participant’s study chart or medical record. This source must be readily verifiable against the 
1402 
values entered into eCRF. Even where all study data are directly entered into the eCRFs at office 
1403 
visits, evidence of interaction with a live subject must be recorded (e.g., office note, visit record, 
1404 
etc.)    
1405 
Electronic device data files are obtained from the study software and individual hardware 
1406 
components.  These electronic device files are considered the primary source documentation. 
1407 
9.2 Study Records Retention 
1408 
Each participating site will maintain appropriate medical and research records for this trial, in 
1409 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1410 
confidentiality of participants.  
1411 
Study documents should be retained for a minimum of 3 years after final reporting. These 
1412 
documents should be retained for a longer period, however, if required by local regulations.  No 
1413 
records will be destroyed without the written consent of the sponsor, if applicable.  It is the 
1414 
responsibility of the sponsor to inform the investigator when these documents no longer need to 
1415 
be retained. 
1416 
9.3 Quality Assurance and Monitoring 
1417 
Designated personnel from Emory University will be responsible for maintaining quality 
1418 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1419 
conducted and data are generated, documented and reported in compliance with the protocol, 
1420 
Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure 
1421 
that the rights and wellbeing of trial participants are protected and that the reported trial data are 
1422 
accurate, complete, and verifiable.  Adverse events will be prioritized for monitoring. 
1423 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1424 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1425 
Investigations — A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and 
1426 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. This plan describes in 
1427 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
1428 
of detail monitoring will be performed, and the distribution of monitoring reports. 
1429 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1430 
events. Therefore, the RBM plan will focus on these areas.  As much as possible, remote 
1431 

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monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1432 
verity and completeness of the key site data.  Elements of the RBM may include: 
1433 
• 
Qualification assessment, training, and certification for sites and site personnel 
1434 
• 
Oversight of Institutional Review Board (IRB) coverage and informed consent 
1435 
procedures 
1436 
• 
Central (remote) data monitoring: validation of data entry, data edits/audit trail, 
1437 
protocol review of entered data and edits, statistical monitoring, study closeout 
1438 
• 
On-site monitoring (site visits): source data verification, site visit report 
1439 
• 
Agent/Device accountability 
1440 
• 
Communications with site staff 
1441 
• 
Patient retention and visit completion 
1442 
• 
Quality control reports 
1443 
• 
Management of noncompliance 
1444 
• 
Documenting monitoring activities 
1445 
• 
Adverse event reporting and monitoring 
1446 
Coordinating Site (Emory University) representatives or their designees may visit the study 
1447 
facilities at any time in order to maintain current and personal knowledge of the study through 
1448 
review of the records, comparison with source documents, observation and discussion of the 
1449 
conduct and progress of the study. The investigational site will provide direct access to all trial 
1450 
related sites, source data/documents, and reports for the purpose of monitoring and auditing by 
1451 
the sponsor, and inspection by local and regulatory authorities. 
1452 
9.4 Protocol Deviations 
1453 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1454 
requirements.  The noncompliance may be either on the part of the participant, the investigator, 
1455 
or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
1456 
and implemented promptly. 
1457 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. 
1458 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1459 

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Chapter 10: Ethics/Protection of Human Participants 
1460 
10.1 Ethical Standard 
1461 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1462 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1463 
21 CFR Part 56, and/or the ICH E6. 
1464 
10.2 Institutional Review Boards 
1465 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1466 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
1467 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
1468 
require review and approval by the IRB before the changes are implemented to the study. All 
1469 
changes to the consent form will be IRB approved; a determination will be made regarding 
1470 
whether previously consented participants need to be re-consented. 
1471 
10.3 Informed Consent Process 
1472 
10.3.1 Consent Procedures and Documentation 
1473 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1474 
the study and continues throughout the individual’s study participation. Extensive discussion of 
1475 
risks and possible benefits of participation will be provided to the participants and their families.  
1476 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
1477 
document. The investigator will explain the research study to the participant and answer any 
1478 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
1479 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1480 
research participants. Participants will have the opportunity to carefully review the written 
1481 
consent form and ask questions prior to signing. 
1482 
The participants should have the opportunity to discuss the study with their surrogates or think 
1483 
about it prior to agreeing to participate. The participant will sign the informed consent document 
1484 
prior to any procedures being done specifically for the study. The participants may withdraw 
1485 
consent at any time throughout the course of the trial. A copy of the informed consent document 
1486 
will be given to the participants for their records. The rights and welfare of the participants will 
1487 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1488 
affected if they decline to participate in this study. 
1489 
10.3.2 Participant and Data Confidentiality 
1490 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1491 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
1492 
samples and genetic tests in addition to the clinical information relating to participants.  
1493 
Therefore, the study protocol, documentation, data, and all other information generated will be 
1494 
held in strict confidence. No information concerning the study or the data will be released to any 
1495 
unauthorized third party without prior written approval of the sponsor. 
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The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1497 
regulatory agencies or company supplying study product may inspect all documents and records 
1498 
required to be maintained by the investigator, including but not limited to, medical records 
1499 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
1500 
study site will permit access to such records. 
1501 
The study participant’s contact information will be securely stored at each clinical site for 
1502 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1503 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1504 
sponsor requirements. 
1505 
Study participant research data, which is for purposes of statistical analysis and scientific 
1506 
reporting, will be transmitted to and stored at the Coordinating Site and Statistical Center. This 
1507 
will not include the participant’s contact or identifying information, unless otherwise specified in 
1508 
the informed consent form. Rather, individual participants and their research data will be 
1509 
identified by a unique study identification number. The study data entry and study management 
1510 
systems used by clinical sites will be secured and password protected. At the end of the study, all 
1511 
study databases will be de-identified and archived. 
1512 
10.3.3 Future Use of Stored Specimens and Data 
1513 
Biologic samples from participants will not be stored for the purposes of this study. Genetic 
1514 
testing will not be performed as part of this study. 
1515 

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Chapter 11: References 
1516 
1. 
Pasquel FJ, Umpierrez GE. Individualizing Inpatient Diabetes Management During the 
1517 
Coronavirus Disease 2019 Pandemic. J Diabetes Sci Technol. 2020;14(4):705-707. 
1518 
2. 
Team CC-R. Preliminary Estimates of the Prevalence of Selected Underlying Health 
1519 
Conditions Among Patients with Coronavirus Disease 2019 - United States, February 12-
1520 
March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382-386. 
1521 
3. 
Killerby ME, Link-Gelles R, Haight SC, et al. Characteristics Associated with 
1522 
Hospitalization Among Patients with COVID-19 - Metropolitan Atlanta, Georgia, March-
1523 
April 2020. MMWR Morb Mortal Wkly Rep. 2020;69(25):790-794. 
1524 
4. 
Gold JAW, Wong KK, Szablewski CM, et al. Characteristics and Clinical Outcomes of 
1525 
Adult Patients Hospitalized with COVID-19 - Georgia, March 2020. MMWR Morb 
1526 
Mortal Wkly Rep. 2020;69(18):545-550. 
1527 
5. 
Auld S, Caridi-Scheible M, Blum JM, et al. ICU and ventilator mortality among critically 
1528 
ill adults with COVID-19. medRxiv. 2020. 
1529 
6. 
Bally L, Thabit H, Hartnell S, et al. Closed-Loop Insulin Delivery for Glycemic Control 
1530 
in Noncritical Care. N Engl J Med. 2018;379(6):547-556. 
1531 
7. 
Boughton CK, Bally L, Martignoni F, et al. Fully closed-loop insulin delivery in 
1532 
inpatients receiving nutritional support: a two-centre, open-label, randomised controlled 
1533 
trial. Lancet Diabetes Endocrinol. 2019;7(5):368-377. 
1534 
8. 
Thabit H, Hartnell S, Allen JM, et al. Closed-loop insulin delivery in inpatients with type 
1535 
2 diabetes: a randomised, parallel-group trial. Lancet Diabetes Endocrinol. 
1536 
2017;5(2):117-124. 
1537 
9. 
Vanhorebeek I, Van den Berghe G. Hormonal and metabolic strategies to attenuate 
1538 
catabolism in critically ill patients. Curr Opin Pharmacol. 2004;4(6):621-628. 
1539 
10. 
Van den Berghe G. How does blood glucose control with insulin save lives in intensive 
1540 
care? J Clin Invest. 2004;114(9):1187-1195. 
1541 
11. 
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically 
1542 
ill patients. N Engl J Med. 2001;345(19):1359-1367. 
1543 
12. 
Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin 
1544 
therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 
1545 
2003;31(2):359-366. 
1546 
13. 
Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in 
1547 
critically ill patients. N Engl J Med. 2009;360(13):1283-1297. 
1548 
14. 
Investigators N-SS, Finfer S, Liu B, et al. Hypoglycemia and risk of death in critically ill 
1549 
patients. N Engl J Med. 2012;367(12):1108-1118. 
1550 
15. 
Wintergerst KA, Buckingham B, Gandrud L, Wong BJ, Kache S, Wilson DM. 
1551 
Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and 
1552 
death in the pediatric intensive care unit. Pediatrics. 2006;118(1):173-179. 
1553 
16. 
Kulkarni H, Bihari S, Prakash S, et al. Independent Association of Glucose Variability 
1554 
With Hospital Mortality in Adult Intensive Care Patients: Results From the Australia and 
1555 
New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation 
1556 
Binational Registry. Crit Care Explor. 2019;1(8):e0025. 
1557 
17. 
Chao WC, Tseng CH, Wu CL, Shih SJ, Yi CY, Chan MC. Higher glycemic variability 
1558 
within the first day of ICU admission is associated with increased 30-day mortality in 
1559 
ICU patients with sepsis. Ann Intensive Care. 2020;10(1):17. 
1560 

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18. 
Zhu L, She ZG, Cheng X, et al. Association of Blood Glucose Control and Outcomes in 
1561 
Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 
1562 
2020;31(6):1068-1077 e1063. 
1563 
19. 
Sardu C, D'Onofrio N, Balestrieri ML, et al. Outcomes in Patients With Hyperglycemia 
1564 
Affected by COVID-19: Can We Do More on Glycemic Control? Diabetes Care. 
1565 
2020;43(7):1408-1415. 
1566 
20. 
Pasquel FJ, Fayfman M, Umpierrez GE. Debate on Insulin vs Non-insulin Use in the 
1567 
Hospital Setting-Is It Time to Revise the Guidelines for the Management of Inpatient 
1568 
Diabetes? Curr Diab Rep. 2019;19(9):65. 
1569 
21. 
Rayman G, Lumb AN, Kennon B, et al. Dexamethasone therapy in COVID-19 patients: 
1570 
implications and guidance for the management of blood glucose in people with and 
1571 
without diabetes. Diabetic Medicine. 2020;n/a(n/a). 
1572 
22. 
Horby P, Lim WS, Emberson JR, et al. Dexamethasone in Hospitalized Patients with 
1573 
Covid-19 - Preliminary Report. N Engl J Med. 2020. 
1574 
23. 
Davis GM, Galindo RJ, Migdal AL, Umpierrez GE. Diabetes Technology in the Inpatient 
1575 
Setting for Management of Hyperglycemia. Endocrinol Metab Clin North Am. 
1576 
2020;49(1):79-93. 
1577 
24. 
Umpierrez GE, Klonoff DC. Diabetes Technology Update: Use of Insulin Pumps and 
1578 
Continuous Glucose Monitoring in the Hospital. Diabetes Care. 2018;41(8):1579-1589. 
1579 
25. 
Galindo RJ, Aleppo G, Klonoff DC, et al. Implementation of Continuous Glucose 
1580 
Monitoring in the Hospital: Emergent Considerations for Remote Glucose Monitoring 
1581 
During the COVID-19 Pandemic. J Diabetes Sci Technol. 2020;14(4):822-832. 
1582 
26. 
Migdal AL, Spanakis EK, Galindo RJ, et al. Accuracy and Precision of Continuous 
1583 
Glucose Monitoring in Hospitalized Patients Undergoing Radiology Procedures. J 
1584 
Diabetes Sci Technol. 2020:1932296820930038. 
1585 
27. 
Pasquel FJ, Lansang MC, Khowaja A, et al. A Randomized Controlled Trial Comparing 
1586 
Glargine U300 and Glargine U100 for the Inpatient Management of Medicine and 
1587 
Surgery Patients With Type 2 Diabetes: Glargine U300 Hospital Trial. Diabetes Care. 
1588 
2020;43(6):1242-1248. 
1589 
28. 
Galindo RJ, Migdal AL, Davis GM, et al. Comparison of the FreeStyle Libre Pro Flash 
1590 
Continuous Glucose Monitoring (CGM) System and Point-of-Care Capillary Glucose 
1591 
Testing (POC) in Hospitalized Patients With Type 2 Diabetes (T2D) Treated With Basal-
1592 
Bolus Insulin Regimen. Diabetes Care. 2020. 
1593 
29. 
Teles M, Sacchetta T, Matsumoto Y. COVID-19 Pandemic Triggers Telemedicine 
1594 
Regulation and Intensifies Diabetes Management Technology Adoption in Brazil. J 
1595 
Diabetes Sci Technol. 2020;14(4):797-798. 
1596 
30. 
Shehav-Zaltzman G, Segal G, Konvalina N, Tirosh A. Remote Glucose Monitoring of 
1597 
Hospitalized, Quarantined Patients With Diabetes and COVID-19. Diabetes Care. 
1598 
2020;43(7):e75-e76. 
1599 
31. 
Reutrakul S, Genco M, Salinas H, et al. Feasibility of Inpatient Continuous Glucose 
1600 
Monitoring During the COVID-19 Pandemic: Early Experience. Diabetes Care. 2020. 
1601 
32. 
Singh LG, Satyarengga M, Marcano I, et al. Reducing Inpatient Hypoglycemia in the 
1602 
General Wards Using Real-Time Continuous Glucose Monitoring: The Glucose 
1603 
Telemetry System, a Randomized Clinical Trial. Diabetes Care. 2020. 
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33. 
Fortmann AL, Spierling Bagsic SR, Talavera L, et al. Glucose as the Fifth Vital Sign: A 
1605 
Randomized Controlled Trial of Continuous Glucose Monitoring in a Non-ICU Hospital 
1606 
Setting. Diabetes Care. 2020. 
1607 
34. 
Lal RA, Basina M, Maahs DM, Hood K, Buckingham B, Wilson DM. One Year Clinical 
1608 
Experience of the First Commercial Hybrid Closed-Loop System. Diabetes Care. 
1609 
2019;42(12):2190-2196. 
1610 
35. 
Sherr JL, Buckingham BA, Forlenza GP, et al. Safety and Performance of the Omnipod 
1611 
Hybrid Closed-Loop System in Adults, Adolescents, and Children with Type 1 Diabetes 
1612 
Over 5 Days Under Free-Living Conditions. Diabetes Technol Ther. 2020;22(3):174-184. 
1613 
36. 
Anderson SM, Buckingham BA, Breton MD, et al. Hybrid Closed-Loop Control Is Safe 
1614 
and Effective for People with Type 1 Diabetes Who Are at Moderate to High Risk for 
1615 
Hypoglycemia. Diabetes Technol Ther. 2019;21(6):356-363. 
1616 
37. 
Lawton J, Blackburn M, Rankin D, et al. Participants' Experiences of, and Views About, 
1617 
Daytime Use of a Day-and-Night Hybrid Closed-Loop System in Real Life Settings: 
1618 
Longitudinal Qualitative Study. Diabetes Technol Ther. 2019;21(3):119-127. 
1619 
38. 
Buckingham B, Brown SA, Bode B, Levy C, GP F, Criego A. Omnipod® 5 Automated 
1620 
Glucose Control System, Powered by Horizon™. American Diabetes Association Annual 
1621 
Scientific Meeting; June 12th, 2020, 2020; Chicago, Virtual. 
1622 
39. 
Partridge H, Perkins B, Mathieu S, Nicholls A, Adeniji K. Clinical recommendations in 
1623 
the management of the patient with type 1 diabetes on insulin pump therapy in the 
1624 
perioperative period: a primer for the anaesthetist. Br J Anaesth. 2016;116(1):18-26. 
1625 
40. 
Sobel SI, Augustine M, Donihi AC, Reider J, Forte P, Korytkowski M. Safety and 
1626 
efficacy of a peri-operative protocol for patients with diabetes treated with continuous 
1627 
subcutaneous insulin infusion who are admitted for same-day surgery. Endocr Pract. 
1628 
2015;21(11):1269-1276. 
1629 
41. 
Vanderhoek SM, Wolf RM. Use of continuous subcutaneous insulin infusion (CSII) 
1630 
therapy in pediatric diabetes patients in the perioperative period. Paediatr Anaesth. 
1631 
2019;29(9):901-906. 
1632 
 
1633