Diabetes Closed-Loop Project 6 (DCLP6): Fully Automated Closed-Loop Control in Type 1 Diabetes Using Meal Anticipation
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: University of Virginia

UVA CENTER FOR DIABETES TECHNOLOGY 
Diabetes Closed-Loop Project 6 (DCLP6): Fully 
Automated Closed-Loop Control in Type 1 
Diabetes Using Meal Anticipation  
Protocol Chair 
Sue A. Brown, MD 
University of Virginia 
Center for Diabetes Technology 
Version Number: v2.2 
18-Nov-2021
NCT04877730

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KEY ROLES 
 
Protocol Principal Investigator 
 
Name, degree 
Sue Brown, MD 
Institution Name 
University of Virginia Center for Diabetes Technology  
 
 

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PROTOCOL VERSION HISTORY 
Version 
Number 
Author(s) 
Approver 
Effective 
Date 
Revision Description 
1.0 
Mark DeBoer 
Sue Brown 
11-Feb-2021 Original Protocol 
1.1 
Mary Oliveri  
 
08-Mar-
2021 
FDA Review:  
• Removed Fiasp  
• Added monitoring 
description (section 7.4 ) 
• Added fingerstick blood 
glucose mitigation (6.4 and 
7.6) 
• Updated Overall Study 
Stopping Criteria (section 
11.10.2) 
• Clarified transition to 
personal equipment at study 
end (section 6.7 and 7.9 
• Replaced Figure 1 and 
Figure 2 
1.2 
Mary Oliveri 
 
21-Mar-
2021 
DSMB Review: 
• Mealtime clarifications 
(section 5.3.1. 6.5. 7.7) 
o Minimum/maximum 
carbohydrate  
o Bolus entry  
o Carb counting  
• Discharge ketone values 
clarified (section Chapter 8) 
• Glycemic Treatment 
Guideline added as new 
chapter (Chapter 8) and 
removed as appendix item 
1.3 
Mary Oliveri 
 
 
IRB FB Review: 

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• Removed all references to 
Medical Monitor; replaced 
with study PI oversight.  
• ABACUS questionnaire 
removed from protocol.  
• Deleted DHHS 46.405 
reference removed from 
protocol.  
• Added Statistical and 
Analytic Plans (section 14.1) 
and Statistical Hypotheses 
(section 14.2).  
1.4 
IRB Reviewer 
 
14-May-
2021 
IRB FB Reviewer:  
• Removal of edit that was 
not required by the full 
board and could not be 
included in the conditional 
approval.  
1.5 
Mary Oliveri  
 
24-May-
2021 
Study Team Modifications:  
• Protocol Table Endpoint 
correction:  The primary 
outcome will be time in 
range 70-180 mg/dL for the 
period between breakfast 
and lunch (approximately 
5h). 
• Inclusion criteria edit to 
clarification purposes 
(section 3.4) 
• Removed Accu-Chek study 
glucometer to remain 
consistent with informed 
consent form that states 
personal glucometer will be 
used in trial (section 2.3).  
• Removed questionnaire 
reference (Chapter 5).  

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• Modified COVID policy to 
include CDC and local 
guidelines (section 10.3.1). 
• Modified several references 
to COVID-19 PCR test to FDA 
authorized COVID-19 test.   
• Moved Chapter 9 Medical 
Monitor details to Chapter 
11 (section 6.9 & 7.10).  
• Deleted Medical Monitor 
chapter (formerly Chapter 
9).  
1.6 
Mary Oliveri 
Sue Brown 
14-Jul-2021 
Study Team Modifications:  
• Removed COVID-19 
references in study design 
definition (section 1.3). 
• Added willingness to 
provide a copy of COVID-19 
vaccination record if 
available (section 3.4). 
• Modified COVID-19 policy 
(section 10.3). 
1.7 
Mary Oliveri 
Sue Brown 
20-Jul-2021 
Study Team Modifications:  
• Corrected definition of CDC 
2.0 
Mary Oliveri 
Sue 
Brown, 
Mark DeBoer 
10-Sep-2021 Study Team Modifications:  
• Increased enrollment goal 
from 18 participants to 36 
participants; up to 60 
participants may sign 
consent (Protocol summary, 
section 1.2, 1.3, 1.6.1, 3.1) 
• Increased from a 3-night 
overnight stay to a 4-night 
overnight stay; increased 
hotel admission from about 
76 hours to about 92 hours 
(Protocol Summary, section 
7.1) 

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• Additional admission hours 
reflect increase in 
stabilization period (section 
1.3.4) 
• Edited figure 2 (Figure 2) 
• Medical monitor and DSMB 
references removed (section 
11.9 
2.1 
Mary Oliveri 
Sue Brown 
11-Nov-
2021 
IRB FB Reviewer (prior to 
meeting) / edited 10-Sep-2021 
version: 
• Re-inserted DSMB 
monitoring (section 11.11) 
• Sample size description 
edited (section 13.4) 
2.2 
Mary Oliveri 
Sue Brown 
18-Nov-
2021 
IRB 
FB 
Review 
(prior 
to 
meeting/ edited 11-Nov-2021 
version:  
• Deleted that phase 1 
participants may participate 
in phase 2 (section 1.6.1) 
 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
 
Protocol Title: Diabetes Closed Loop Project 6 (DCLP6): Fully Automated Closed Loop Control in 
Type 1 Diabetes Using Meal Anticipation  
Protocol Version v2.2 
Protocol Date:  18-Nov-2021 
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.  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: 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). 
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: _____ / _____ / _____ 
Investigator’s Name: ________________________________ 
Site Name:  University of Virginia 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADRR 
Average Daily Risk Range 
AP 
Artificial Pancreas 
BG 
Blood Glucose 
BT/BTLE 
Bluetooth, Bluetooth low energy 
CGM 
Continuous Glucose Monitoring 
CLC 
Closed-Loop Control 
CiQ 
Tandem t:slim X2 Insulin Pump with Control-IQ Technology 
CSII 
Continuous Subcutaneous Insulin Injection 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data Safety Monitoring Board 
FCL 
Fully Closed Loop 
FCL+ 
Fully Closed Loop with meal anticipation module 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBGI 
High Blood Glucose Index  
HCL 
Hybrid Closed Loop 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
LBGI 
Low Blood Glucose Index  
POC 
Point-of-Care 
QC 
Quality Control 
rMPC 
Regular Model Predictive Control 
UI 
User Interface 
 
 

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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
Fully Automated Closed-Loop Control (FCL) in Type 1 Diabetes Using Meal Anticipation 
Investigational Device 
UVA Model Predictive Control Artificial Pancreas (RocketAP) with and without prandial 
excursion anticipation 
Objectives 
The purpose of this study is to show the safety and feasibility of a fully new fully automated 
AP controller based on meal anticipation and carbohydrate kinetics estimation, within the 
UVA AP modular architecture. 
Study Design 
A randomized cross-over trial assessing glycemic responses to three different approaches to 
insulin dosing for carbohydrate ingestion all run on an automated insulin delivery AP system:  
1) FCL: without a meal anticipation module and without announced carbohydrate 
2) FCL+: using a meal anticipation module without announced carbohydrate, and 
3) HCL: without a meal anticipation module with announced carbohydrate 
Number of Sites 
One 
Endpoint 
The primary outcome will be time in range 70-180 mg/dL for the period between breakfast 
and lunch (approximately 5h) 
Population 
Key Inclusion Criteria 
• Age 18 and <70 years of age 
• Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one 
year  
• Currently using insulin for at least six months 
• Currently using insulin pump for at least three months  
Sample Size  
• Pilot Study: complete up to 3 participants  
• Main Study: complete up to 36 participants 
Treatment Groups 
• Randomized cross over: RocketAP without meal anticipation module without meal bolus 
(FCL), RocketAP with meal anticipation module without meal bolus (FCL+), and RocketAP 
without meal anticipation module with meal bolus (HCL). 
Participant Duration 
Data Collection Phase of approximately 4 weeks followed by a hotel/rental house admission 
as follows: 
• Pilot Study:  Participants will be admitted to a local hotel or rental house for up to 
approximately 92 hours and will have a dinner with the RocketAP with meal anticipation 
and no-carbohydrate announcement.   
• Main Study: Participants will be admitted to a local hotel for approximately 92 hours.  
Protocol Overview/Synopsis 
Participants will be followed for 4 weeks prior to the hotel study.  During this data collection 
phase, they will wear the study CGM and be instructed to eat breakfast and dinner at 
approximately the same time 4-5 times per week.  They will then be admitted to the hotel 
for a 4-night study, receiving the three controller sessions in random order: 1) FCL: without a 
meal anticipation module and without announced carbohydrate, 2) FCL+: with the meal 
anticipation module and without announced carbohydrate, and 3) HCL: without the meal 
anticipation module and with announced carbohydrate. During the admission, participants 

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will receive structured meals and have blood glucose control followed to compare time in 
range 70-180 mg/dL between Controller sessions.   

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STUDY VISITS AND PROCEDURES SCHEDULE  
 
 
Screening 
Study 
Equipment 
Training 
CGM Run-In 
Phase 
Data Collection 
Pre-Admission 
Check-In 
Study 
Admission 
Post-
Admission 
Check-In 
Location 
Clinic/   
Remote 
Clinic/   
Remote 
Home 
Home 
Phone/ 
Email/Text 
Hotel/Rental 
House 
Phone/ 
Email/Text 
Visit 
1 
2 
x 
x 
3 
4 
5 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
HbA1c  
X 
 
 
 
 
 
 
Pregnancy test (if 
applicable) 
X 
X 
 
 
 
X 
 
Physical Exam 
X 
 
 
 
 
 
 
Vital Signs (height/weight) 
X 
 
 
 
 
X 
 
Randomization 
 
 
 
 
 
X 
 
COVID-19 Testing, non-
vaccinated participants 
 
 
 
 
X 
X (main study 
only) 
 
CGM Use 
 
 
~14 days if 
needed 
X 
 
X 
 
Survey  
 
X 
X 
 
 
X 
 
Review diabetes 
management and AEs 
 
 
X 
 
 
X 
X 

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Table of Contents 
1 
Chapter 1 Background ........................................................................................................... 16 
2 
1.1 Introduction ........................................................................................................................ 16 
3 
1.2 Study Objective ................................................................................................................... 17 
4 
1.3 Study Design........................................................................................................................ 17 
5 
1.4 Study Device Download ...................................................................................................... 21 
6 
1.5 Study System Issues ............................................................................................................ 21 
7 
1.6 Purpose/Objectives of Clinical Study .................................................................................. 21 
8 
Chapter 2 Study Devices ....................................................................................................... 22 
9 
2.1 Insulin Pump ....................................................................................................................... 22 
10 
2.2 Continuous Glucose Monitor .............................................................................................. 22 
11 
2.3 Blood Glucose Meter and Strips ......................................................................................... 22 
12 
2.4 Ketone Meter and Strips ..................................................................................................... 22 
13 
2.5 Study Devices Accountability Procedures ........................................................................... 22 
14 
Chapter 3 Study Screening .................................................................................................... 23 
15 
3.1 Participant Recruitment and Enrollment ............................................................................ 23 
16 
3.2 Informed Consent and Authorization Procedures .............................................................. 23 
17 
3.3 Screening Procedures ......................................................................................................... 23 
18 
3.4 Participant Inclusion Criteria............................................................................................... 23 
19 
3.5 Participant Exclusion Criteria .............................................................................................. 24 
20 
3.6 Eligibility Screening Procedures .......................................................................................... 25 
21 
3.7 Demographic Data Survey .................................................................................................. 26 
22 
Chapter 4 Randomization ..................................................................................................... 27 
23 
4.1 Pilot Study Participants ....................................................................................................... 27 
24 
4.2 Main Study Participants ...................................................................................................... 27 
25 

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Chapter 5 Study Equipment Training ..................................................................................... 28 
26 
5.1 CGM Training ...................................................................................................................... 28 
27 
5.2 Activity Tracker ................................................................................................................... 28 
28 
5.3 Study Insulin Pump ............................................................................................................. 29 
29 
Chapter 6 Pilot Study ............................................................................................................ 30 
30 
6.1 Data Collection Phase ......................................................................................................... 30 
31 
6.2 Qualifications and Role of the Staff .................................................................................... 30 
32 
6.3 Pre-Admission Check-In Visit .............................................................................................. 30 
33 
6.4 Admission Check-In ............................................................................................................. 31 
34 
6.5 Study Meals ......................................................................................................................... 31 
35 
6.6 Admission Activities ............................................................................................................ 32 
36 
6.7 Admission Discharge ........................................................................................................... 32 
37 
6.8 Post Admission Check-In Visit ............................................................................................. 32 
38 
Chapter 7 Main Study ........................................................................................................... 33 
39 
7.1 Hotel Admission .................................................................................................................. 33 
40 
7.2 Data Collection Phase (CGM/Meal Entrainment period) ................................................... 33 
41 
7.3 Qualifications and Role of the Staff .................................................................................... 33 
42 
7.4 Pre-Admission Check-In Visit .............................................................................................. 34 
43 
7.5 Admission Check-In ............................................................................................................. 34 
44 
7.6 Study Meals ......................................................................................................................... 35 
45 
7.7 Admission Activities ............................................................................................................ 36 
46 
7.8 Admission Discharge ........................................................................................................... 36 
47 
7.9 Post Admission Check-In Visit ............................................................................................. 36 
48 
Chapter 8 Glycemic Treatment Guidelines ............................................................................ 37 
49 
Chapter 9 Testing Procedures ............................................................................................... 38 
50 
9.1 Laboratory / Point of Care Testing ...................................................................................... 38 
51 

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Chapter 10 Risks Associated with Clinical Trial ...................................................................... 39 
52 
10.1 Potential Risks and Benefits of the Investigational Device ............................................... 39 
53 
10.2 General Considerations..................................................................................................... 43 
54 
10.3 COVID-19 Risk Mitigation Plan and Justification .............................................................. 43 
55 
Chapter 11 Adverse Events, Device Issues, and Stopping Rules ............................................. 44 
56 
11.1 Definitions ......................................................................................................................... 44 
57 
11.2 Reportable Events ............................................................................................................. 45 
58 
11.3 Relationship of Adverse Event to Study Device ................................................................ 46 
59 
11.4 COVID-19 Transmission..................................................................................................... 47 
60 
11.5 Intensity of Adverse Event ................................................................................................ 47 
61 
11.6 Coding of Adverse Events ................................................................................................. 48 
62 
11.7 Outcome of Adverse Events.............................................................................................. 48 
63 
11.8 Reportable Device Issues .................................................................................................. 49 
64 
11.9 Timing of Event Reporting ................................................................................................ 49 
65 
11.10 Stopping Criteria ............................................................................................................. 50 
66 
11.11 Independent Safety Oversight ........................................................................................ 51 
67 
11.12 Definition of a Data Breach ............................................................................................. 51 
68 
Chapter 12 Miscellaneous Considerations ............................................................................. 52 
69 
12.1 Prohibited Medications, Treatments, and Procedures..................................................... 52 
70 
12.2 Participant Withdrawal ..................................................................................................... 52 
71 
12.3 Confidentiality ................................................................................................................... 52 
72 
Chapter 13 Statistical Consideration ..................................................................................... 53 
73 
13.1 Statistical and Analytical Plans .......................................................................................... 53 
74 
13.2 Statistical Hypotheses ....................................................................................................... 53 
75 
13.3 Design and Randomization ............................................................................................... 53 
76 
13.4 Sample Size ....................................................................................................................... 53 
77 

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13.5 Outcome Measures ........................................................................................................... 54 
78 
13.6 Safety Analyses ................................................................................................................. 55 
79 
13.7 Baseline Descriptive Statistics........................................................................................... 55 
80 
13.8 Device Issues ..................................................................................................................... 56 
81 
Chapter 14 Data Collection and Monitoring .......................................................................... 57 
82 
14.1 Case Report Forms and Device Data ................................................................................. 57 
83 
14.2 Study Records Retention .................................................................................................. 57 
84 
14.3 Protocol Deviations ........................................................................................................... 57 
85 
Chapter 15 Ethics/Protection of Human Participants ............................................................ 58 
86 
15.1 Ethics Standard ................................................................................................................. 58 
87 
15.2 Institutional Review Boards .............................................................................................. 58 
88 
15.3 Informed Consent Process ................................................................................................ 58 
89 
Chapter 16 References .......................................................................................................... 60 
90 
 
91 
 
 
92 

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Chapter 1 Background 
93 
 
94 
A major impediment to maintaining blood glucose (BG) control in Type 1 diabetes (T1D) is missed 
95 
meal boluses, which has been associated with significantly higher HbA1c levels.1  While the 
96 
advent of the artificial pancreas (AP) offers promise of safe reductions in HbA1c, our research 
97 
group previously found that the AP only partly compensates for missed prandial insulin2—
98 
demonstrating that some form of meal announcement is necessary for good BG control, even 
99 
with current AP systems.  One way to automate this process is by having an AP system that is 
100 
able to determine the usual timing of meals for a given individual and provides a small priming 
101 
dose of insulin at this time—a process referred to as meal anticipation.  We previously tested an 
102 
AP system that was programmed to anticipate physical activity and successfully reduced insulin 
103 
delivery during the time of usual exercise.3  We have also recently tested a new artificial pancreas 
104 
system composed of a robust Model Predictive Controller called the RocketAP. We now propose 
105 
to test functionality of a module in RocketAP with anticipation of meal ingestion.      
106 
In the current study, we are testing this RocketAP system for BG response to three conditions:  
107 
1. FCL: without a meal anticipation module and without announced carbohydrate 
108 
2. FCL+: using a meal anticipation module without announced carbohydrate, and 
109 
3. HCL: without a meal anticipation module with announced carbohydrate. 
110 
We will test this system in up to 18 adults with T1D.  Participants will first be asked during a 4-
111 
week period prior to the main study to eat breakfast and dinner at approximately the same time 
112 
for 4-5 times a week to entrain the system regarding when these meals are anticipated.  
113 
Participants will then be admitted to the in-person study and will be started on the RocketAP 
114 
with approximately three 24-hour periods use of the three conditions described above, in 
115 
random order, all implemented on the DiAs platform (MAF 2109).  As an assessment of the 
116 
efficacy of the system in maintaining BG control, participants will be followed for approximately 
117 
24 hours of use of each of three conditions noted above (FCL, FCL+ and HCL).   As an assessment 
118 
of safety (and efficacy), they will also be followed when a meal is consumed at a later time than 
119 
expected (dinner will be consumed approximately 2 hours later than anticipated dinner time) as 
120 
well as when a meal is not anticipated to occur at all (participants will receive a lunch which the 
121 
system has not been anticipated to expect).  Our primary outcome will be one of efficacy in 
122 
assessing BG control (TIR 70-180 mg/dL) in the absence of carbohydrate announcement when 
123 
the new meal anticipation module is on (FCL+) vs. off (FCL). Additional assessments of BG control 
124 
will be made 1) comparing when there is no meal anticipation model and carbohydrate content 
125 
is announced (HCL) vs. when carbohydrate content is not announced (FCL+), and 2) assessing the 
126 

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safety of the system by having dinner later than the usual time—to ensure that this does not 
127 
result excess insulin delivery and hypoglycemia, and 3) how the system responds to a lunch that 
128 
has not been entrained or anticipated during each of the 3 conditions (FCL+, FCL without 
129 
announced carbohydrate and during HCL with announced carbohydrate).   
130 
We hypothesize that performances of RocketAP with meal anticipation (FCL+) will result in 
131 
significant improvement over not using the meal anticipation module (FCL) and without risk of 
132 
significant hypoglycemia when meals are consumed later than expected.  We expect that this will 
133 
constitute an important step toward having a fully automated AP system.  
134 
 
135 
The purpose of this study is to test the meal anticipation module on the RocketAP closed loop 
136 
algorithm, assessing efficacy and safety. We will target completion of up to 36 adults in a 
137 
randomized cross-over trial, comparing blood glucose time in range 70-180 mg/dL following 
138 
meals with and without the meal anticipation module in use (FCL+ vs FCL), and comparing to a 
139 
system with carb announcement instead of a meal anticipation module (HCL).   We will further 
140 
assess safety when dinner is consumed later than usual and when a lunch is consumed without 
141 
having been entrained in the meal anticipation module.  
142 
 
143 
We will consent up to 60 participants, ages 18-70 years, with a goal to have up to 36 participants 
144 
complete the trial. The study will be performed overnight at a local hotel/rental house 
145 
(heretofore referred to as “hotel”). Enrollment in the Pilot Study will proceed with the goal of 
146 
completing 1-3 participants. This admission will be up to 2 days will be in a hotel/rented house.   
147 
 Recruitment and Screening 
148 
Participants will be recruited from the UVa Center for Diabetes Technology registry, social media 
149 
advertisements, physician/health care provider contacts at diabetes clinics in Virginia. Potential 
150 
participants will be informed of the study and will be encouraged to ask the study team questions 
151 
about their study participation. Participants will provide written informed consent.   The 
152 
screening visit may be performed by telephone, video conferencing or in person.   
153 
 CGM Data Collection 
154 
Following study enrollment, participants will be trained in use of the Dexcom G6 system, 
155 
provided with adequate study supplies and have a Dexcom sensor placed.  This training may be 
156 
completed via video conferencing, with supplies sent to the participant in advance of the call.  
157 
This study visit will be followed by 4 weeks of CGM and pump data collection at the participant’s 
158 

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home/usual routine.  Participants will be asked to have breakfast and dinner at approximately 
159 
the same time at least 4-5 times per week during this period. 
160 
Participants will then be randomized to the order that they experience the three controller 
161 
approaches (for 24 hours each): 1) without the meal anticipation module and without 
162 
carbohydrate announcement (FCL), 2) with the meal anticipation module on and without 
163 
carbohydrate announcement (FCL+), or 3) without the meal anticipation module on and with 
164 
carbohydrate announcement (HCL).  This will be performed using three permuted blocks of 6. 
165 
 Study Hardware/Software 
166 
The study itself will involve use of the DiAs prototyping platform (MAF 2109), connected to a 
167 
Tandem t:AP research pump and a Dexcom G6 sensor, and implementing RocketAP with or 
168 
without the meal anticipation module.  Upon arrival at the hotel, participants will be instructed 
169 
in how to use the Tandem research pump as well as the UVa AP system, including stopping the 
170 
system and bolusing for food.  
171 
 Timing of UVa Artificial Pancreas Use 
172 
Upon arrival to hotel, participants will have a 12+ hour stabilization period.  The participant will 
173 
be connected to a Tandem research pump connected to the UVa DiAs platform and their Dexcom 
174 
G6 Transmitter will be linked with DiAs on the morning of Day 1. Participants will then be taught 
175 
how to use DiAs in this configuration. The research pump will be programmed with the 
176 
individual’s usual insulin parameters. Participants will have their blood sugar managed through 
177 
this system during the entirety of the time at hotel. 
178 
 Study Controller Sessions 
179 
Order and timing of controller sessions: During the hotel stay, participants will have three 
180 
separate 24-hour periods during which they will receive three approaches to BG management (in 
181 
random order):  1) without the meal anticipation module and without carbohydrate 
182 
announcement (FCL), 2) with the meal anticipation module on and without carbohydrate 
183 
announcement (FCL+), or 3) without the meal anticipation module on and with carbohydrate 
184 
announcement (HCL).   The timing and potential order of these sessions is shown in Figure 1. 
185 

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186 
Figure 1:  Timeline and randomized order of the Study Controller Sessions 
187 
During these 24-hour periods participants will be followed for the experimental meals as part of 
188 
the Study Controller Sessions to compare blood glucose control using these three different 
189 
approaches to insulin management for carbohydrate control (Figure 1). These study meals 
190 
include a late dinner timed later than the participant’s usual dinner time (to assess how the meal 
191 
anticipation module handles a late meal), a lunch at a time when the system has not been 
192 
entrained to expect it and a breakfast at the participant’s usual breakfast time (see Figure 2).  
193 

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194 
Figure 2:  Timeline of Study Controller Sessions and Study Meals 
195 
The primary outcome will compare the percent time CGM is between 70 and 180 mg/dL after 
196 
breakfast, starting at the time of breakfast and lasting approximately 5 hours afterwards (until 
197 
noon).  For study meals, participants will consume structured breakfast, lunch and dinner (with 
198 
identical protein, fat, and carbohydrate content on each of the days).  During the FCL and FCL+ 
199 
sessions, participants will not announce the carbohydrate content in meals (and all additional 
200 
insulin will be delivered by the AP system, without and with meal anticipation, respectively), 
201 
while during the HCL session, participants will use insulin dosing via normal carbohydrate 
202 
announcement and the DiAs CGM-based bolus calculator.  Study staff who will be present will 
203 
include nursing staff and technical staff; a study physician will be available either on-site or 
204 
nearby off-site at all times. Hyperglycemia and hypoglycemia treatment protocols will be 
205 
followed per CDT protocol. We anticipate more significant cases of hyperglycemia during dinners 
206 
managed without carbohydrate announcement; participants will be encouraged to drink large 
207 
amounts of non-caloric beverages, particularly after these meals. 
208 
The UVa AP systems will be initiated upon arrival to the hotel the morning before the first of the 
209 
Controller Sessions. UVa CDT study staff will monitor CGM output continuously and manage 
210 
glucose control issues.  At the end of the hotel stay, the participant will return to their home 
211 
insulin management.  
212 
Closed Loop
Bkfst
9am
1pm
9am
TBD
Late dinner
TIR
TIR
%<70
Expected dinner
Expected breakfast
TBD
Noon
Noon
4pm
TIR
Expected dinner
Expected breakfast
TBD
lunch
bolus
Controller A
Midnight
Midnight
Controller C
Controller B
StabilizaƟon
Lunch
Lunch
Lunch
TIR
9am
Noon
Friday
Saturday
Sunday
Monday
TBD
TBD
Fixed lunch
Fixed lunch
Fixed lunch
Expected breakfast
Expected dinner
Main Study N=36
Late dinner
%<70
Bkfst
TIR
Late dinner
%<70
Bkfst
TIR
TBD
TBD+2h
4PM
4PM
4PM
TBD+2h
TBD+2h
Thursday

CLINICAL PROTOCOL 
 
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213 
Before discharge from the hotel, all study devices will be turned in to study staff for device 
214 
download and the participants will be placed on usual diabetes management. 
215 
 
216 
If the CGM signal becomes unavailable for more than 20 minutes consecutively, closed loop will 
217 
not operate to automatically adjust insulin.  If the CGM is not connected, the system will revert 
218 
to usual function of the pump and deliver insulin with the insulin dosing parameters programmed 
219 
in the system for that individual. Resumption of closed-loop control will occur automatically once 
220 
CGM signal is available again. 
221 
If the study system is unable to maintain pump connectivity, the pump will automatically revert 
222 
to pre-programmed basal insulin delivery after 30 minutes without any need for instruction from 
223 
the user. 
224 
 
225 
 Study Participants 
226 
Enrollment in the Pilot Study will proceed with the goal of completing 1-3 participants. Up to 6 
227 
participants may sign the consent form. 
228 
Enrollment in the Main Study will proceed with the goal of completing up to 36 participants.  Up 
229 
to 60 participants may sign the Main Study consent form.   
230 
 Clinical Sites 
231 
The study will be performed at the University of Virginia, with screening procedures taking place 
232 
either virtually, at the Clinical Research Unit, or at local hotel.  
 
233 

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Chapter 2 Study Devices 
234 
 
235 
The study systems will utilize the Tandem t:AP research pump connected to the UVa DiAs system 
236 
run on a dedicated external smart phone, running the RocketAP control algorithm with the meal 
237 
anticipation module (which will be turned on or off, depending on the Controller session, with 
238 
the order of these sessions determined randomly). 
239 
 
240 
The study CGM will include Dexcom G6 transmitter and sensors. The CGM sensor is viable for 10 
241 
days. 
242 
 
243 
Study participants will use their personal glucometer during the study.  A study glucometer will 
244 
be provided in the event that the participant’s glucometer cannot be downloaded.  
245 
 
246 
Blood ketone levels will be measured during the hotel admission with the use of the Abbott 
247 
Precision Xtra meters and strips in accordance with the manufacturer’s labelling. The blood 
248 
glucose meter component of the Precision Xtra Device will not be used.   
249 
 
250 
Device serial numbers will be recorded and use of equipment will be tracked. 
 
251 

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Chapter 3 Study Screening  
252 
 
253 
Pilot Study:  Enrollment goal in the Pilot Study will be to complete 1-3 participants. Up to 6 
254 
participants may sign consent forms.  
255 
Main Study:  Enrollment in the study will proceed with the goal of completing up to 36 
256 
participants.  Participants will initially be randomized for the order of their 3 experimental meals 
257 
use during the study.  Up to 60 participants may sign the consent form. 
258 
 
259 
Before consent has been obtained, participants will be asked inclusion/exclusion criteria 
260 
questions during pre-screening to determine study eligibility. Before completing any procedures 
261 
or collecting any data that are not part of usual care, written informed consent, when applicable) 
262 
will be obtained. Potential eligibility may be assessed as part of a routine-care examination.   
263 
A participant is considered enrolled when the informed consent form has been signed by the 
264 
participant and the study team. 
265 
Consenting procedures and documentation is defined in section 15.3.  
266 
 
267 
After informed consent has been signed, a potential participant will be evaluated for study 
268 
eligibility through the elicitation of a medical history, performance of a physical examination 
269 
by licensed personnel, and pregnancy testing (if applicable) to screen for exclusionary medical 
270 
conditions.  If done remotely, a physical exam documented in the prior 18 months can suffice for 
271 
the physical exam but will not serve as an exclusionary criterion if not available. If done remotely, 
272 
participants may self-report height and weight. Individuals who do not initially meet study 
273 
eligibility requirements may be rescreened at a later date per investigator discretion. 
274 
 
275 
The participants must meet all of the following inclusion criteria in order to be eligible to 
276 
participate in the study. 
277 
1. Age ≥18.0 and ≤70 years old at time of consent 
278 
2. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year  
279 
3. Currently using insulin for at least six months 
280 
4. Currently using insulin pump for at least three months  
281 

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5. Using insulin parameters such as carbohydrate ratio and correction factors consistently on 
282 
their pump in order to dose insulin for meals or corrections  
283 
6. Access to internet and willingness to upload data during the study as needed  
284 
7. For females, not currently known to be pregnant or breastfeeding 
285 
8. If female and sexually active, must agree to use a form of contraception to prevent pregnancy 
286 
while a participant in the study.  A negative serum or urine pregnancy test will be required 
287 
for all females of childbearing potential. Participants who become pregnant will be 
288 
discontinued from the study. Also, participants who during the study develop and express 
289 
the intention to become pregnant within the timespan of the study will be discontinued. 
290 
9. Willingness to suspend use of any personal CGM for the duration of the clinical trial once the 
291 
study CGM is in use 
292 
10. Willingness to use the UVa closed-loop system throughout study admission 
293 
11. Willingness to use lispro (Humalog) or aspart (Novolog) during the study admission. 
294 
12. Willingness not to start any new non-insulin glucose-lowering agent during the course of the 
295 
trial (including metformin, GLP-1 agonists, pramlintide, DPP-4 inhibitors, biguanides, 
296 
sulfonylureas and naturaceuticals) 
297 
13. Willingness to eat at least 1 g/kg of carbohydrate per day during the hotel admission 
298 
14. Willingness to reschedule if placed on oral steroids 
299 
15. An understanding and willingness to follow the protocol and signed informed consent  
300 
16. Willingness to comply with COVID-19 precautions as defined by the study team. (Study team 
301 
will reference section 10.3.)  
302 
17. Willingness to provide a copy of COVID-19 vaccination record, if available.  
303 
 
304 
The participant must not have any exclusion criteria in order to be eligible to participate in the 
305 
study.  
306 
1. History of diabetic ketoacidosis (DKA) in the 12 months prior to enrollment 
307 
2. Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior 
308 
to enrollment 
309 
3. Pregnancy or intent to become pregnant during the trial 
310 
4. Currently being treated for a seizure disorder 
311 
5. Planned surgery during study duration  
312 

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6. Treatment with any non-insulin glucose-lowering agent (including metformin, GLP-1 
313 
agonists, pramlintide, DPP-4 inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas and 
314 
naturaceuticals)  
315 
7. A known medical condition that in the judgment of the investigator might interfere with 
316 
the completion of the protocol. 
317 
8. Use of an automated insulin delivery mechanism that is not downloadable by the subject 
318 
or study team 
319 
9. Known contact with a COVID-19 positive individual within 14 days of the hotel/rental 
320 
house studies. 
321 
 
322 
The participant will be evaluated for study inclusion and exclusion eligibility after the informed 
323 
consent form has been signed by the participant and the study team.  
324 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
325 
date per investigator discretion. 
326 
1. Demographics 
327 
o Date of birth 
328 
o Gender  
329 
o Race 
330 
o Ethnicity 
331 
2. Medical History  
332 
o Duration of disease (number of years) 
333 
o Current insulin pump model 
334 
o History of CGM use 
335 
o Current treatment 
336 
i. 
Basal rates 
337 
ii. 
Carbohydrate ratios 
338 
iii. 
Insulin sensitivity factors 
339 
iv. 
Target glucose 
340 
v. 
Average daily insulin 
341 
o History of diabetic ketoacidosis 
342 
o History of severe hypoglycemia  
343 
o History of seizures  
344 
o Loss of consciousness 
345 

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• Surgical history 
346 
• Allergies 
347 
• Concomitant medications 
348 
3. Physical Examination – If performed remotely, a historical history and physical report 
349 
within 18 months of screening appointments may be used but is not required for 
350 
eligibility. If vitals are not available, may include self-reported weight and height.  
351 
o Weight 
352 
o Height 
353 
o Blood pressure 
354 
o Temperature 
355 
o Heart Rate 
356 
4. Screening Labs 
357 
o Hemoglobin A1c point of care  
358 
o Urine or serum pregnancy test for all women of childbearing potential 
359 
Screening procedures will last approximately 1-2 hours. Screening can be performed via 
360 
telephone or video conference.  Once all results of the screening evaluations are available, a 
361 
decision will be made to determine the participant’s eligibility for the study or if one or more part 
362 
of the screening will have to be repeated. If at the first screening or repeat screening an 
363 
exclusionary condition is identified, the participant will be excluded from participation with 
364 
follow up and referred to their primary care physician as needed. The study physician may elect 
365 
to rescreen participants if their clinical situation changes. Notably, screening is for determining 
366 
study eligibility.  Once participants are found to be eligible, they can begin their data collection 
367 
phase as noted in Pilot Participants or Main Study.  
368 
 
369 
The Demographic Data Survey will be electronically administered once eligibility has been met. 
370 

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Chapter 4 Randomization  
371 
Participants will receive the three different experimental condition (FCL, FCL+, HCL) in random 
372 
order as described below. 
373 
 
374 
Pilot participants will not be randomized but will only use the meal anticipation module with an 
375 
experimental meal without carbohydrate announcement and a study meal that is later than the 
376 
usual entrained timing. 
377 
 
378 
Once eligibility is met and the Data Collection Phase (CGM/Meal Entrainment) period is 
379 
complete, the participant may continue to randomization. Screening failures and study dropout 
380 
participants may be replaced. Randomization will determine the order of the Study Controller 
381 
Sessions, with potential order as shown in Figure 1.  Randomization will occur via permuted 
382 
blocks of 6.   
 
383 

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Chapter 5 Study Equipment Training 
384 
Equipment training may begin at arrival to hotel after UVa AP system has been put in place.  The 
385 
purpose of this training is to introduce the study insulin pump and study CGM to the participant.  
386 
The participant’s insulin parameters will be programmed into their study insulin pump by two 
387 
research staff. Subjects will then switch to the study insulin pump. The participant’s personal 
388 
pump and infusion site will be removed. 
389 
The participant will have the insulin pump and sensor on them at all times. Study supplied phones 
390 
will be used if DiAs is the system utilized and otherwise upon participant request.  
391 
 
392 
A study CGM will be provided to all participants at the training session. The participants will be 
393 
provided with CGM equipment and instructed to use the study CGM on a daily basis. If the 
394 
participant has prior use of the CGM, re-training will be specific to the individual. The study team 
395 
may elect to have less frequent CGM users watch the Dexcom online training videos 
396 
(https://www.dexcom.com/training-videos) to assist in the training session.  Study staff training 
397 
may include review of study CGM in real-time to make management decisions and how to review 
398 
the data after an upload for retrospective review. Study staff will specifically identify how alarms 
399 
are set using the app and the frequency that these alarms will repeat. 
400 
The participants personal CGM will be discontinued. The participants will be observed placing the 
401 
sensor and will learn/review how to access the CGM trace via the DiAs phone or the Tandem 
402 
research pump, as needed. The participants will be asked to perform fingerstick blood glucose 
403 
measurements (if needed) in accordance with the labelling of the study CGM device.  
404 
An electronic copy of the CGM user’s guide will be provided for the participants to read. The 
405 
study team will be sure that the participants will leave the training session knowing how to use 
406 
proper use the CGM. The study team will be available for any questions. 
407 
Participants will have the option of using their personal smartphone or receive a study 
408 
smartphone to use in order to collect the data from the devices. If the participant elects to use a 
409 
personal device, the Dexcom app will be downloaded to their phone in order to monitor the 
410 
participant’s CGM values and alerts in real-time may be used. 
411 
 
412 
All participants may be asked to wear an activity tracker (e.g. Fitbit) during the entire study (home 
413 
and hotel admissions) to record information about movement and heart rate though not an 
414 
endpoint in this study. 
415 

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416 
The study team will be responsible monitoring and managing the study insulin pump during the 
417 
hotel admissions. The participants may be provided a quick overview on its functionality if they 
418 
understand the equipment. 
419 
 Study Insulin Pump Topics  
420 
The study team will assist the participant in study pump infusion site initiation and will start the 
421 
participant on the study pump. The study pump will be programmed with the participant’s usual 
422 
basal rates and pump parameters. The participant’s personal pump will be removed. 
423 
The participant will be instructed infusion site initiation, cartridge/priming procedures, setting 
424 
up the pump, charging the pump, navigation through menus, bolus procedures including entering 
425 
meals, stopping a bolus, etc. 
426 
 Other Issues  
427 
The participant will be instructed to notify study staff if they experience any issues with the study 
428 
devices during the hotel admission. Staff will be present in the event that if insulin is delivered 
429 
by any means other than the study pump (e.g. injection of subcutaneous insulin via syringe in the 
430 
event of infusion site failure). If insulin is delivered by any means other than the study pump, the 
431 
study team will be instructed to turn off closed-loop mode for approximately four hours. 
432 
The participant will also be asked to alert the study clinical staff for technical issues with the 
433 
Tandem research pump and/or the DiAs system, including use of the study pump and study CGM 
434 
(open loop mode) during periods of component disconnections or technical difficulties.  
435 
A glucagon emergency kit will be available. Participants who currently do not have one will be 
436 
asked to obtain a prescription for the glucagon emergency kit.  
437 
Glycemic Treatment Guidelines (Chapter 8) will be available for staff use during the study 
438 
admissions. 
439 
 Optimization of Insulin Pump Settings 
440 
Data-driven optimization of pump settings can occur any time prior to the hotel admission, 
441 
particularly if the participant contacts the study physician due to concerns about their pump 
442 
settings due to recurring hypo- or hyperglycemia. No pump settings changes can occur during 
443 
closed loop testing. 
 
444 

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Chapter 6  Pilot Study  
445 
In order to optimize the flow of the study visits during the Main Study, we will perform a Pilot 
446 
Study with up to three pilot participants at a local hotel or rental house. Participants and staff 
447 
will adhere to the COVID -19 Mitigation Plan as outlined in Section 10.3.  The duration of the pilot 
448 
admission will be approximately 24 hours with the intent of collecting appropriate safety data.  
449 
Pilot study participants are eligible to enroll in the Main Study.  
450 
 
451 
Participants will wear the study CGM at home for approximately 28 days.  If currently using a 
452 
Dexcom G6, up to 30 days of data may be obtained from the participant’s personal CGM and 
453 
pump.  The investigators may still ask G6 users to complete this run-in phase at their discretion.  
454 
 
455 
For the pilot study, there will be at least two study staff present at all times at the study site, at 
456 
least one of whom will be clinical staff (e.g. nurse, physician, nurse practitioner). There will be a 
457 
physician available either on-site or off-site within an approximate 20-minute drive at all times.    
458 
In addition, one of the study medical physicians and one senior engineer will be on call during 
459 
the entire admission. Glucagon for the emergency treatment of hypoglycemia will be available 
460 
on-site. 
461 
 
462 
Pilot participants will be contacted by the study team approximately 24-48 hours prior to the 
463 
hotel admission to verify the following information: 
464 
• Inquire about any changes to the participant’s medical history 
465 
• Study equipment (e.g. CGM and activity tracker) initiation has occurred 
466 
• Determine pump profile(s) the participant uses on certain days 
467 
• New CGM sensor has been placed approximately 24-72 hours prior to admission for 
468 
proper warm-up 
469 
• Verify with the participant that the goal CGM reading at time of arrival is less than 200 
470 
mg/dL; this may require contact with the study physician prior to arrival on the day of the 
471 
study visit  
472 
• Should any concerns regarding medical history, pump information, or unforeseen issues 
473 
arise, the admission will be cancelled for that participant at the discretion of the 
474 
investigator 
475 

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476 
For the pilot study, one to two participants will be assessed at a time.  The participant will arrive 
477 
at the hotel or rental house on the first day of the admission.  The study team will perform vital 
478 
signs, and any changes to the participant’s medical history.  Any changes to medical history will 
479 
be communicated to the medical physician to ensure continued eligibility and participation.   
480 
A urine pregnancy test will be collected if relevant. The test must be negative for the participant 
481 
to continue with the study.  
482 
The subject’s CGM reading, and ketone concentration will be recorded. In the event that the 
483 
participant’s CGM reading is not between 80-250 mg/dL or ketone concentration is ≥0.6 mmol/L 
484 
prior to initiation of the UVa AP system, the study physician may recommend additional insulin 
485 
dosing according to the participants’ usual doses. Study physician may elect to cancel 
486 
participant’s participation in the hotel admission if concerned about their medical safety.  This 
487 
participant will not be replaced.  
488 
The participant’s home insulin pump will be discontinued, and the study Tandem research insulin 
489 
pump will be initiated.  The study team will ensure the proper function of the CGM, insulin pump, 
490 
and activity tracker. The goal will be to initiate Closed-Loop Control by approximately lunch time, 
491 
running the RocketAP system on the DiAs platform.  
492 
The CGM used in the study is FDA-approved for the non-adjunctive measurement of blood 
493 
glucose (i.e. the CGM reading can be used for insulin dosing decisions). The CGM readings will be 
494 
the primary source of blood glucose values.  There are no protocol fingerstick blood glucose 
495 
measurements other than at times of CGM calibration (if necessary) and if directed by the study 
496 
team. Fingerstick blood glucose measurements may be taken whenever participants experience 
497 
symptoms, if the CGM glucose is suspected to be erroneous, or any time the participant would 
498 
like to be reassured. 
499 
 
500 
Participants will eat a structured dinner at approximately 6-7 pm during the admission. The 
501 
participant will not announce carbohydrate ingestion, allowing testing of the RocketAP 
502 
controller. Throughout the Pilot study, the participant will remain in closed loop mode.  
503 
Participants will consume approximately 30-90 grams of carbohydrates at each meal. The study 
504 
participant will determine the quantity of carbohydrates in each meal. Staff will separately record 
505 
the calculated carbohydrate count. FCL and FCL+ will be tested during the pilot.   Staff will 
506 
continue to follow the Glycemic Treatment Guidelines detailed in Chapter 8. 
507 

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508 
Participants will be free to engage in low-intensity activity (i.e. walking) during the admission. 
509 
Participants will enjoy quiet activities in the evening. 
510 
 
511 
Discharge will be at approximately 8 a.m. If the CGM values are above 300 mg/dL and ketone 
512 
values are >0.6 mmol/L, the study team will check the insulin pump infusion site and correction 
513 
insulin will be administered per study physician judgement via the subject’s insulin pump.   A 
514 
qualified clinical study team member (e.g. MD, NP, CDE) will assess and discuss the transition 
515 
back to usual care with the study participant.    
516 
Participants will be asked to continue monitoring ketone levels for 24-48 hours after the hotel 
517 
admission if ketones were present at time of discharge. Urine ketone supplies may be provided 
518 
for this testing.  
519 
 
520 
Approximately 24-48 hours after the hotel admission, the study team will contact the participant 
521 
via phone/email/text/text to assess adverse events, adverse device effects, and device issues. 
522 
 
523 

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Chapter 7  Main Study  
524 
 
525 
Main Study participants will participate in hotel admission. Each admission will be up to 
526 
approximately 92 hours in duration. Participants and staff will adhere to the Center for Disease 
527 
Control and Prevention (CDC) and local guidance COVID -19 Mitigation Plan effective at the time 
528 
of the study.   
529 
 
530 
Participants who are not familiar with the Dexcom G6 CGM will have a run-in phase in which they 
531 
wear the equipment at home for approximately 14 days to ensure proper use of the equipment.  
532 
All participants will wear the CGM at home for approximately 28 days, with instructions to eat 
533 
breakfast and dinner at approximately the same time 4-5 days each week. The timing of the 
534 
breakfast will be requested to be at or before 8 am and the timing of the dinner will be requested 
535 
to be between 6-9 pm.  If currently using a Dexcom G6, up to 30 days of data may be obtained 
536 
from the participant’s personal CGM and pump.  If participant reports consistent timing of meals 
537 
in the 30 days before enrollment, these data may be used instead of the CGM/Meal Entrainment 
538 
period at the discretion of the investigators. The investigators may ask current Dexcom G6 CGM 
539 
users to complete this run-in phase at their discretion. Data-driven optimization of insulin dosing 
540 
parameters can occur at any time during and immediately after the CGM/Meal Entrainment 
541 
period.  
542 
 
543 
There will be at least two study staff present at all times at the study site when the investigational 
544 
device is active, with at least one of whom will be clinical staff (e.g. nurse, physician, nurse 
545 
practitioner). There will be a physician at the hotel or nearby on call during the study at all times.  
546 
In addition, at least one senior engineer will be on call during the entire admission. Participants 
547 
will be remotely monitored by at least one study team member using a web-based remote 
548 
monitoring system that has been previously established for DiAs.  The web-based remote 
549 
monitoring system will display real-time insulin delivery, CGM and other system information to 
550 
allow for patient safety monitoring.    In addition, study team members will be trained in all 
551 
protocol and Glycemic Treatment Guideline procedures (Chapter 8). The closed-loop system will 
552 
be managed by the participant with study-staff supervision, particularly at the time of insulin 
553 
boluses.  Glucagon for the emergency treatment of hypoglycemia will be available on-site. 
554 

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555 
Participants will be contacted by the study team approximately 24-72 hours prior to each hotel 
556 
admission if most recent contact with the study participant exceeds 10 days. The study team will 
557 
verify the following information: 
558 
• Inquire about any changes to the participant’s medical history 
559 
• Adhere to relevant sections of 10.3 COVID-19 Risk Mitigation Plan  
560 
• Study equipment (e.g. CGM and activity tracker) initiation has occurred 
561 
• Determine pump profile(s) the participant uses on certain days 
562 
• New CGM sensor has been placed approximately 24-72 hours prior to admission for 
563 
proper warm-up 
564 
• Verify with the subject that the goal CGM reading at time of arrival is less than 200 
565 
mg/dL; this may require contact with the study physician prior to arrival on the day of the 
566 
study visit  
567 
• Should any concerns regarding medical history, pump information, or unforeseen issues 
568 
arise, the admission will be cancelled for that participant at the discretion of the 
569 
investigator 
570 
 
571 
Day 0 Arrival 
572 
Participants will arrive at the hotel on the first day of the admission.  The study team will inquire 
573 
about any changes to the participant’s medical history.  Any changes to medical history will be 
574 
communicated to the medical physician to ensure continued eligibility and participation.   
575 
A new CGM sensor will be placed if the sensor has not been changed within the last 24-48 hours.  
576 
Participants will be provided unstructured dinner (no meal-time restrictions). Participants are on 
577 
their home devices overnight and, therefore, no study staff are required to be present. 
578 
Day 1 Morning 
579 
The study team will perform vital signs. The subject’s CGM reading, and ketone concentration 
580 
will be recorded. In the event that the participant’s CGM reading is not between 80-250 mg/dL 
581 
or ketone concentration is ≥0.6 mmol/L prior to initiation of the UVa artificial pancreas system, 
582 
the study physician may recommend additional insulin dosing according to the participants’ usual 
583 
doses. Study physician may elect to cancel participant’s participation in the hotel admission if 
584 
concerned about their medical safety.  This participant will not be replaced. A urine pregnancy 
585 
test will be collected for female participants of childbearing age within 24 hours prior to 
586 

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transitioning to the AP Controller. The test must be negative for the participant to continue with 
587 
the study. 
588 
 
589 
The participant’s home insulin pump will be discontinued, and the study insulin pump will be 
590 
initiated. The insulin site will be changed   and the participants may use the Tandem t:AP2 pump 
591 
without the DiAs platform for basal delivery until transition to AP. The study team will ensure the 
592 
proper function of the CGM, insulin pump, and activity tracker.  
593 
The CGM used in the study is FDA-approved for the non-adjunctive measurement of blood 
594 
glucose (i.e. the CGM reading can be used for insulin dosing decisions). The CGM readings will be 
595 
the primary source of blood glucose values.  There are no protocol fingerstick blood glucose 
596 
measurements other than at times of CGM calibration (if necessary) and if directed by the study 
597 
team.  Fingerstick blood glucose measurements may be taken whenever participants experience 
598 
symptoms, if the CGM glucose is suspected to be erroneous, or any time the participant would 
599 
like to be reassured. Glycemic Treatment Guidelines to be used during the hotel admission are 
600 
defined in a separate document.  
601 
 
602 
Participants will eat structured study meals during the admission, with the same amount of 
603 
carbohydrate, protein, and fat for the same meals (breakfast, lunch, dinner) on different days 
604 
(days 1, 2, and 3). Meal content may differ on the same day.  The dinners will occur approximately 
605 
2 hours after the time that is usual for the participant from the Data Collection Phase (CGM/Meal 
606 
Entrainment period, defined as the median time of recorded meals between 6 and 8pm).  The 
607 
breakfasts will occur at approximately the time that is usual for the participant from the Data 
608 
Collection Phase (CGM/Meal Entrainment period, defined as the median time of recorded meals 
609 
between 5am and 8am), and the lunches will occur at approximately noon (see Figure 2).   
610 
Participants will consume approximately 30-90 grams of carbohydrates at each meal. The study 
611 
participant will determine the quantity of carbohydrates in each meal and will enter this 
612 
information into the insulin pump with staff supervision during HCL. Staff will separately record 
613 
the calculated carbohydrate count at each meal. The carbohydrate content of the system will 
614 
only be announced during the HCL Controller period.  During HCL, correction doses of insulin will 
615 
also be calculated at the time of meals. During FCL and FCL+, study staff will be monitoring the 
616 
closed-loop system as usual to identify insulin administration in the setting of postprandial 
617 
hyperglycemia. Staff will continue to follow the Glycemic Treatment Guidelines detailed in 
618 
Chapter 8.  Snacks with carbohydrates will not be allowed unless for the treatment of low blood 
619 
sugars. Non-carbohydrates snacks are allowed throughout the protocol.  Blood glucose levels will 
620 

CLINICAL PROTOCOL 
 
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be followed via continuous glucose monitor and glucose values will be managed by the AP system 
621 
as usual.  
622 
 
623 
Participants will be free to engage in low-intensity activity (i.e. walking) during the hotel 
624 
admission. Participants may leave the hotel to be outside, provided they are accompanied by a 
625 
study staff member and masking and distancing are observed, as described in Section 10.3. 
626 
Participants will enjoy quiet activities in the evening. 
627 
 
628 
Discharge will be at approximately 4 pm. If the CGM values are above 300 mg/dL and ketone 
629 
values are >0.6 mmol/L, the study team will check the insulin pump infusion site and correction 
630 
insulin will be administered per study physician judgement via the subject’s insulin pump. A 
631 
qualified clinical study team member (e.g. MD, NP, CDE) will assess and discuss the transition 
632 
back to usual care with the study participant.   Study team will reference the Glycemic Treatment 
633 
Guidelines.  
634 
Participants will be asked to continue monitoring ketone levels for 24-48 hours after the hotel 
635 
admission if ketones were present at time of discharge. Urine ketone supplies may be provided 
636 
for this testing.  
637 
 
638 
Approximately 24-48 hours after the hotel admission, the study team will contact the participant 
639 
via phone/email/text to assess adverse events, adverse device effects, and device issues.  
640 
 
 
641 

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Chapter 8 Glycemic Treatment Guidelines 
642 
The following guidelines will be used for both the Pilot Study and the Main Study Admissions to 
643 
the hotel/rental house.  
644 
The study physician will suggest appropriate treatment If CGM is <70 mg/dL or >250 mg/dL, or 
645 
ketone test is >0.6 mmol/L at the start of the hotel admission. The study subject may continue 
646 
participation in the trial once CGM is between 70-250 mg/dL and ketone concentration is ≤0.6 
647 
mmol/L.   
648 
If CGM <60 mg/dL at any time, subjects will be given approximately 8-16 grams of fast-acting 
649 
rescue carbohydrates. Study team will monitor CGM rise and will consider treating again if CGM 
650 
<80 mg/dL after approximately 15-20 minutes. Hypoglycemic treatments can occur at any time 
651 
per study physician request. Glucagon will be available at the study site and will be administered 
652 
in the event of loss of consciousness or seizure related to hypoglycemia.  
653 
The study team may request fingersticks as needed. Any fingerstick readings obtained will be 
654 
addressed the same way as the CGM values.   
655 
If CGM is >250 for more than 3 hours or >400 mg/dL at any time, study physician will 
656 
be notified, and ketones will be checked. In addition, insulin administration by the closed-loop 
657 
system will be evaluated and infusion sites assessed. If ketone concentration is >0.6 mmol/L, the 
658 
study team will check the insulin pump infusion site and consider changing and correction insulin 
659 
will be administered via the subject’s insulin pump or subcutaneous as needed. If subcutaneous 
660 
injection is administered, physician will determine if closed-loop control needs to be temporarily 
661 
stopped for up to 4 hours. The study team will monitor CGM changes and ketones will be checked 
662 
every 60 minutes until ketone concentration is ≤0.6 mmol/L. If ketone concentration is ≥3.0 
663 
mmol/L, the study physician will recommend the appropriate medical treatment.  
664 
The study physician will suggest appropriate treatment If CGM is <70 mg/dL or >300 mg/dL and 
665 
ketone test is >0.6 mmol/L at the conclusion of the hotel admission. The study subject may be 
666 
discharged home once CGM is between 70-300 mg/dL and ketone concentration is ≤0.6 mmol/L.  
667 

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Chapter 9  Testing Procedures 
668 
 
669 
 HbA1c  
670 
A blood sample will be obtained at screening to obtain a baseline hemoglobin A1c level. A Blood 
671 
test obtained within 2 weeks prior to enrollment may be used. 
672 
HbA1c level may be measured by study team using the DCA2000, a comparable point of care 
673 
device, at time of screening  
674 
Labs may be obtained at a local laboratory (e.g. LabCorp) convenient to the participant. 
675 
 Pregnancy Test 
676 
A serum or urine pregnancy test will be required for women of childbearing potential at in person 
677 
visit and admission.  Test must be negative to participate in the study.  
678 
  COVID-19 Testing (Non-vaccinated participants/staff)  
679 
Non-vaccinated participants and study staff (research coordinators, technicians, nurses, and 
680 
physicians) will be tested with an FDA authorized COVID-19 test approximately 72 hours before 
681 
starting the study hotel, and upon admission to the study hotel (main study only).  Individuals 
682 
with COVID-19 positive tests will be excluded from the study.   
683 
 Demographic Data Survey 
684 
The Demographic Data Survey will be asked at only the screening appointment and will reflect 
685 
the status of the participant.   
 
686 

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Chapter 10 Risks Associated with Clinical Trial 
687 
 
688 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are 
689 
handled to minimize this risk. Hypoglycemia, hyperglycemia and ketone formation are always a 
690 
risk in participants with type 1 diabetes and participants will be monitored for these symptoms.  
691 
 Venipuncture Risks 
692 
A hollow needle/plastic tube may be placed in the arm for taking blood samples (e.g. external 
693 
HbA1c measurements for inclusion criteria). Blood draws can cause some common reactions like 
694 
pain, bruising, or redness at the sampling site.  Less common reactions include bleeding from the 
695 
sampling site, formation of a small blood clot or swelling of the vein and surrounding tissues, and 
696 
fainting. 
697 
 Fingerstick Risks 
698 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
699 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital 
700 
laboratory tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount 
701 
of bleeding under the skin will produce a bruise. A small scar may persist for several weeks. The 
702 
risk of local infection is less than 1 in 1000. This should not be a significant contributor to risks in 
703 
this study as finger sticks are part of the usual care for people with diabetes. 
704 
 Subcutaneous Catheter Risks (CGM) 
705 
Participants using the CGM will be at low risk for developing a local skin infection at the site of 
706 
the sensor needle placement. If a catheter is left under the skin for more than 24 hours it is 
707 
possible to get an infection where it goes into the skin, with swelling, redness and pain.  There 
708 
may be bleeding where the catheter is put in and bleeding under the skin causes a bruise (1 in 10 
709 
risk). 
710 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
711 
leave a small portion of the sensor under the skin that may cause redness, swelling, or pain at 
712 
the insertion site. The participant should be further instructed to notify the study coordinator 
713 
immediately if this occurs. 
714 
 Risks of Hypoglycemia  
715 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a low 
716 
blood sugar (hypoglycemia). The frequency of hypoglycemia should be no more and possibly less 
717 

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than it would be as part of daily living. Symptoms of hypoglycemia can include sweating, 
718 
jitteriness, and not feeling well.  Just as at home, there is the possibility of fainting or seizures 
719 
(convulsions) and that for a few days the participant may not be as aware of symptoms of 
720 
hypoglycemia.  A CGM functioning poorly and significantly over-reading glucose values could lead 
721 
to inappropriate insulin delivery. 
722 
 Risks of Hyperglycemia  
723 
Hyperglycemia is likely because of the study design including unannounced carbohydrate 
724 
ingestion.  Also, hyperglycemia and ketonemia could occur if insulin delivery is attenuated or 
725 
suspended for an extended period or if the pump or infusion set is not working properly.  A CGM 
726 
functioning poorly and significantly under-reading glucose values could lead to inappropriate 
727 
suspension of insulin delivery. 
728 
 Risks of Device Reuse  
729 
Participant will be informed that FDA or relevant national authorities have approved the insulin 
730 
pump, CGM, glucometer and ketone meter for single use and that by using them among multiple 
731 
patients, bloodborne pathogens (i.e. Hepatitis B) may be spread through the use of multiple 
732 
users. 
733 
The study CGM system is labelled for single use only. The sensor (the component of the system 
734 
that enters the skin) will be single use only. The transmitter and receiver may be reused during 
735 
the study after cleaning the device using a hospital-approved cleaning procedure. The transmitter 
736 
is attached to the sensor but does not enter the skin and the receiver, if used, is a handheld 
737 
device.  
738 
The study insulin pumps are labelled for single-patient use. During the study, this device may be 
739 
reused after cleaning adhering to a hospital-approved cleaning procedure. All infusion set 
740 
equipment will be single patient use only (infusion set insertion kits, tubing, cartridges etc.).   
741 
The study blood glucose meter and blood ketone meter are labelled for single-patient use. 
742 
During the study, these devices may be reused after cleaning adhering to a hospital-approved 
743 
cleaning procedure.   
744 
 Device Cleaning Instructions 
745 
CGM cleaning instructions are provided in the Dexcom G4 Platinum (Professional) Cleaning and 
746 
Disinfection manual (current edition) and a similar approach will be applied for the G6 version 
747 
used in this study. The transmitter should be cleaned with Clorox Healthcare® Bleach Germicidal 
748 
Cleaner or any disinfectant product in a spray bottle containing a bleach solution of 6500 parts 
749 
per million with the EPA registration number 56392-7.  The transmitter will be submerged in this 
750 

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solution and then placed on an absorbent wipe or clean surface.  Two sprays will be dispensed 
751 
from the Clorox cleaner onto each side of the transmitter. A nylon brush will be used to scrub the 
752 
transmitter on all sides for 30 seconds.  The transmitter will be placed in the Clorox Cleaner 
753 
solution for one minute. Transmitter is then rinsed under flowing tap water for ten seconds. The 
754 
transmitter will then be disinfected using a disinfectant product with EPA registration number 
755 
56392-7 using similar procedures as the cleaning process.   
756 
Per the pump manufacturer, the insulin pump will be cleaned with a damp lint-free cloth. Use of 
757 
household or industrial cleaners, solvents, bleach, scouring pads, chemicals, or sharp instruments 
758 
are prohibited. The pump should never be submerged in water. If needed, use only a very mild 
759 
detergent, such as a bit of liquid soap with warm water. A soft towel will be used to dry the pump.  
760 
The glucometer is cleaned and disinfected with two separate Super Sani-Cloths (EPA number 
761 
9480-4). The entire surface will be cleaned, making sure the surface stays wet for 2 minutes. This 
762 
step is repeated with a clean cloth for disinfecting the device.  
763 
The Precision Xtra User’s Guide suggests that healthcare professionals use 10% bleach, 70% 
764 
alcohol or 10% ammonia to clean the device.  
765 
Equipment that touches intact skin will be cleaned with ethyl or isopropyl alcohol (70-90%), 
766 
quaternary ammonium germicidal detergent (i.e. Cavicide, EPA number 46781) or household 
767 
bleach. The contact time on the surface depends on the method used to clean the equipment. 
768 
Cavicide requires three minutes on the surface of the equipment. Clorox Germicidal Bleach Wipes 
769 
require two minutes on the equipment. The surface should remain wet (i.e. slightly damp) with 
770 
the disinfectant to be considered effective though not wet enough to leave drops of liquid.  
771 
In the event a manufacturer updates cleaning procedures for their device, the study team will 
772 
adhere to the most current recommendations.  
773 
There is the risk of blood sampling collection and contamination from sampling techniques. Hand 
774 
washing with either soap & water or waterless hand sanitizer will be used prior to caring for the 
775 
study subject. Gloves will be worn during blood sample collection and processing. Medical 
776 
personnel will continue to practice hygiene for the subject’s protection (i.e. hand washing, 
777 
changing gloves frequently, disposing needles properly). Gloves will be removed, and hands 
778 
washed or sanitized prior to leaving and upon return to the subject’s room. Soiled linen will be 
779 
changed to minimize the transfer of pathogenic organisms. 
780 
 Hb1Ac Risk 
781 
An NGSP Point of Care analyzer (i.e. DCA Vantage Analyzer) will be utilized at the research site to 
782 
obtain the subject’s HbA1c level. 
783 

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 Other Risks  
784 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
785 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
786 
If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, 
787 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
788 
medication may be required. 
789 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump infusion 
790 
sites are inserted under the skin.  It is possible that any part that is inserted under the skin may 
791 
cause an infection.  These occur very infrequently, but, if an infection was to occur, oral and/or 
792 
topical antibiotics can be used.  The risk of skin problems could be greater if you use a sensor for 
793 
longer than it is supposed to be used.  Therefore, participants will be carefully instructed about 
794 
proper use of the sensor. 
795 
Data downloaded from the CGM, pump, glucometer, and ketone meter will be collected for the 
796 
study as measures of diabetes self-management behaviors. Some people may be uncomfortable 
797 
with the researchers' having such detailed information about their daily diabetes habits. 
798 
 Known Potential Benefits  
799 
It is expected that this protocol will yield increased knowledge about using an automated closed-
800 
loop system with anticipatory action to control glucose levels. The individual participant may not 
801 
benefit from study participation. 
802 
 Risk Assessment 
803 
Based on the facts that (1) adults with diabetes experience mild hypoglycemia and hyperglycemia 
804 
frequently as a consequence of the disease and its management, (2) the study intervention 
805 
involves periodic automated insulin dosing that may increase the likelihood of hypoglycemia, and 
806 
periodic automated attenuation of insulin delivery that may increase the likelihood of 
807 
hyperglycemia, (3) mitigations are in place, and have been tested in prior studies using the 
808 
investigational device system in the home setting, that limit the likelihood of excessive insulin 
809 
dosing or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and 
810 
hyperglycemia can be achieved.. In addition, it is the belief of the investigators that this study 
811 
also presents prospect of direct benefit to the participants and general benefit to others with 
812 
diabetes. 
813 

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814 
The study is being conducted in compliance with the policies described in the study policies 
815 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
816 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
817 
Whenever possible, data will be directly collected in electronic case report forms, which will be 
818 
considered the source data. 
819 
The protocol is considered a significant risk device study, due to the fact that the closed-loop 
820 
system is experimental.  Therefore, an investigational device exemption (IDE) from the U.S. Food 
821 
and Drug Administration (FDA) is required to conduct the study. 
822 
 
823 
The study team will follow CDC guidelines that are in effect at the time of the study admission. 
824 
Participants who do not provide a copy of their COVID-19 vaccination record will be considered 
825 
not vaccinated.  
826 
        Participants and Study Personnel 
827 
We will follow a combination of approaches to increase our likelihood of having all COVID-free 
828 
environment:    
829 
• We will follow CDC and local guidelines in effect at the time of the study. 
830 
• All participants will be ineligible if they have had known COVID-19 exposure or symptoms 
831 
within 14 days of hotel admission.  
832 
• Non-vaccinated participants and study staff (research coordinators, technicians, nurses, 
833 
and physicians) will be tested with an FDA authorized COVID-19 test approximately 72 
834 
hours before their participation in the study hotel.  Those with positive tests will be 
835 
excluded from the study.   
836 
• Any participants with positive test will be discharged from the study.  Hotel rooms of 
837 
these participants will be restricted from future use. We will limit any personal 
838 
interaction between study personnel and these individuals.  We will follow local 
839 
guidelines in effect at the time of study to guide interactions.  
840 
•   All study staff onsite will abide by UVa clinical protocols currently in place at the time of 
841 
the study for healthcare workers which stands as the standard-of care for those involved 
842 
in patient care.  This protocol may include use of the HOOS Health Check app.     
843 
  
Environment 
844 
The study team will adhere to current hotel guidelines.  
 
845 

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Chapter 11   Adverse Events, Device Issues, and Stopping Rules 
846 
 
847 
 Adverse Events (AE) 
848 
Any untoward medical occurrence in a study participant, irrespective of the relationship between 
849 
the adverse event and the device(s) under investigation (section 11.2) for reportable adverse 
850 
events for this protocol). 
851 
Positive pregnancy test will be not considered adverse event.  
852 
 Serious Adverse Event (SAE) 
853 
 Any untoward medical occurrence that: 
854 
• Results in death. 
855 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
856 
have become life-threatening, is not necessarily considered a serious adverse event). 
857 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
858 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
859 
ability to conduct normal life functions (life threatening). 
860 
• Is a congenital anomaly or birth defect. 
861 
• Is considered a significant medical event by the investigator based on medical judgment 
862 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
863 
prevent one of the outcomes listed above). 
864 
 Unanticipated Adverse Device Effect (UADE) 
865 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
866 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
867 
nature, severity, or degree of incidence in the investigational plan or application (including a 
868 
supplementary plan or application), or any other unanticipated serious problem associated with 
869 
a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
870 
 Adverse Device Effect (ADE) 
871 
Any untoward medical occurrence in a study participant which the device may have caused or to 
872 
which the device may have contributed. 
873 

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 Device Complaints and Malfunctions 
874 
A device complication or complaint is something that happens to a device or related to device 
875 
performance, whereas an adverse event happens to a participant. A device complaint may occur 
876 
independently from an AE, or along with an AE. An AE may occur without a device complaint or 
877 
there may be an AE related to a device complaint.  A device malfunction is any failure of a device 
878 
to meet its performance specifications or otherwise perform as intended.  Performance 
879 
specifications include all claims made in the labelling for the device.  The intended performance 
880 
of a device refers to the intended use for which the device is labelled or marketed. (21 CFR 803.3).   
881 
 
882 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
883 
meets one of the following criteria: 
884 
• A serious adverse event as defined in section 11.2 
885 
• An Adverse Device Effect as defined in section 11.1.4, unless excluded from reporting in 
886 
section 11.7 
887 
• An Adverse Event as defined in section 11.1.1 occurring in association with a study 
888 
procedure 
889 
• An AE as defined in section 11.1.1 which leads to discontinuation of a study device for 2 
890 
or more hours 
891 
• Hypoglycemia meeting the definition of severe hypoglycemia as defined in section 11.2.1  
892 
• Diabetic ketoacidosis (DKA) as defined in section 11.2.2 or in the absence of DKA, a 
893 
hyperglycemic or ketosis event meeting the criteria defined below 
894 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
895 
events unless associated with an Adverse Device Effect. Skin reactions from sensor placement 
896 
are only reportable if severe and/or required treatment. 
897 
 Hypoglycemia Event 
898 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
899 
when the following definition for severe hypoglycemia is met:   
900 
• the event required assistance of another person due to altered consciousness, and 
901 
required another person to actively administer carbohydrate, glucagon, or other 
902 
resuscitative actions 
903 
• impaired cognitively to the point that he/she was unable to treat himself/herself, was 
904 
unable to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or 
905 

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experienced seizure or coma. These episodes may be associated with sufficient 
906 
neuroglycopenia to induce seizure or coma 
907 
• if plasma glucose measurements are not available during such an event, neurological 
908 
recovery attributable to the restoration of plasma glucose to normal is considered 
909 
sufficient evidence that the event was induced by a low plasma glucose concentration 
910 
 Hyperglycemia Events/Diabetes Ketoacidosis 
911 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
912 
event when one of the following four criteria is met:  
913 
• the event involved DKA, as defined by the Diabetes Control and Complications Trial 
914 
(DCCT) and described below evaluation or treatment was obtained at a health care 
915 
provider facility for an acute event involving hyperglycemia or ketosis 
916 
• blood ketone level ≥1.5 mmol/L and communication occurred with a health care provider 
917 
at the time of the event 
918 
• blood ketone level ≥3.0 mmol/L, even if there was no communication with a health care 
919 
provider 
920 
Hyperglycemic events are classified as DKA if the following are present: 
921 
• Symptoms such as polyuria, polydipsia, nausea, or vomiting 
922 
• Serum ketones ≥1.5 mmol/L or large/moderate urine ketones 
923 
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15 
924 
• Treatment provided in a health care facility 
925 
All reportable Adverse Events—whether volunteered by the participant, discovered by study 
926 
personnel during questioning, or detected through physical examination, laboratory test, or 
927 
other means—will be reported on an adverse event form online.  Each adverse event form is 
928 
reviewed by the study PI to verify the coding and the reporting that is required. 
929 
 
930 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
931 
by determining if there is a reasonable possibility that the adverse event may have been caused 
932 
by the study device. 
933 
To ensure consistency of adverse event causality assessments, investigators should apply the 
934 
following general guideline when determining whether an adverse event is related: 
935 
• There is a plausible temporal relationship between the onset of the adverse event and 
936 
the study intervention, and the adverse event cannot be readily explained by the 
937 

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participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
938 
adverse event follows a known pattern of response to the study intervention; and/or the 
939 
adverse event abates or resolves upon discontinuation of the study intervention or dose 
940 
reduction and, if applicable, reappears upon re-challenge. 
941 
• Evidence exists that the adverse event has an etiology other than the study intervention 
942 
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, or 
943 
concomitant medication); and/or the adverse event has no plausible temporal 
944 
relationship to study intervention. 
945 
 
946 
While we are taking significant steps to prevent transmission of COVID-19 during this study, there 
947 
is a possibility that participants, based either on exposure before the hotel admission or during 
948 
the stay, are infected with COVID-19.  Infection with COVID-19 could be determined by testing 
949 
48-hours prior to study admission and the day of admission for participants (in which case would 
950 
be deemed not related to the study) or onset of new symptoms during the stay. Any appearance 
951 
of COVID-19 symptoms in participants will be cause for repeat COVID-19 testing and quarantine 
952 
until test results are returned.  If this COVID -19 test is positive, the participant will be discharged 
953 
from the study. Study team follow applicable local guidelines in effect at the time of study.   
954 
In the event of a COVID-19 positive test in a participant, the study team will follow up with the 
955 
participant via phone until conclusion of treatment for the COVID-19 related symptoms. All 
956 
participants will be asked to follow up via phone with the study team in the event of a positive 
957 
test within 14 days after discharge from the hotel.  
958 
 
959 
The intensity of an adverse event will be rated on a three-point scale: (1) mild, (2) moderate, or 
960 
(3) severe. It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 
961 
event is not necessarily serious. For example, itching for several days may be rated as severe, but 
962 
may not be clinically serious. 
963 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
964 
participant’s daily activities. 
965 
• MODERATE: Usually causes a low level of inconvenience or concern to the participant 
966 
and may interfere with daily activities but is usually ameliorated by simple therapeutic 
967 
measures. 
968 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic 
969 
drug therapy or other treatment. 
970 

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971 
Adverse events will be coded by the Study PI per the UVA IRB website instructions (i.e. mild, 
972 
moderate, severe).  The study PI will review the investigator assessment of causality and may 
973 
agree or disagree.  The study PI assessments will be recorded.  The study PI will have the final say 
974 
in determining the causality. 
975 
Adverse events that continue after the participant’s discontinuation or completion of the study 
976 
will be followed until their medical outcome is determined or until no further change in the 
977 
condition is expected. 
978 
 
979 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
980 
• RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae.  
981 
Record the AE/SAE stop date. 
982 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
983 
without change in the event anticipated.  Record the AE/SAE stop date. 
984 
• FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that 
985 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the 
986 
time of death; however, were not the cause of death, will be recorded as “resolved” at 
987 
the time of death. 
988 
• NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as the 
989 
event was ongoing with an undetermined outcome. 
990 
• An ongoing outcome will require follow-up by the site in order to determine the final 
991 
outcome of the AE/SAE. 
992 
• The outcome of an ongoing event at the time of death that was not the cause of death, 
993 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
994 
date. 
995 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant or 
996 
the participant’s records to determine the outcome (for example, a participant that was 
997 
lost to follow-up). 
998 
All clinically significant abnormalities of clinical laboratory measurements or adverse events 
999 
occurring during the study and continuing at study termination should be followed by the 
1000 
participant’s physician and evaluated with additional tests (if necessary) until diagnosis of the 
1001 
underlying cause, or resolution. Follow-up information should be recorded on source documents. 
1002 
If any reported adverse events are present when a participant completes the study, or if a 
1003 
participant is withdrawn from the study due to an adverse event, the participant will be 
1004 

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contacted for re-evaluation within 2 weeks.  If the adverse event has not resolved, additional 
1005 
follow-up will be performed as appropriate.  Every effort should be made by the Investigator or 
1006 
delegate to contact the participant until the adverse event has resolved or stabilized. 
1007 
 
1008 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
1009 
whether an adverse event occurred, except in the following circumstances. 
1010 
The following device issues are anticipated and will not be reported but will reported as an 
1011 
Adverse Event if the criteria for AE reporting described above are met: 
1012 
• Component disconnections 
1013 
• CGM sensors lasting fewer than the number of days expected per CGM labelling 
1014 
• CGM tape adherence issues 
1015 
• Pump infusion set occlusion not leading to ketosis 
1016 
• Battery lifespan deficiency due to inadequate charging or extensive wireless 
1017 
communication 
1018 
• Intermittent device component disconnections/communication failures not leading to 
1019 
system replacement 
1020 
• Device issues clearly addressed in the user guide manual that do not require additional 
1021 
troubleshooting 
1022 
• Skin reactions from CGM sensor placement or pump infusion set placement that do not 
1023 
meet criteria for AE reporting 
1024 
 
1025 
• UADEs must be reported within 10 working days to the FDA after the sponsor first 
1026 
receives notice of the adverse effect. 
1027 
• Other reportable adverse events, device malfunctions (with or without an adverse event) 
1028 
and device complaints should be reported promptly, but there is no formal required 
1029 
reporting period. 
1030 
• The IDE Sponsor will investigate the UADE and if indicated, report the results of the 
1031 
investigation to the IRBs FDA and DSMB within 10 working days of the study team 
1032 
becoming aware of the UADE per 21CFR 812.46(b) (2).  
1033 
• The FDA and DSMB will determine if the UADE presents an unreasonable risk to 
1034 
participants. If so, the Study PI must ensure that all investigations, or parts of 
1035 
investigations presenting that risk, are terminated as soon as possible but no later than 5 
1036 

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working days makes this determination and no later than 15 working days after first 
1037 
receipt notice of the UADE. 
1038 
• In the case of a device system component malfunction (e.g. pump, CGM, control 
1039 
algorithm), information will be forwarded to the responsible manufacturer by the study 
1040 
personnel. 
1041 
 
1042 
 Participant Discontinuation  
1043 
Rules for discontinuing study device use are described below. 
1044 
• The investigator believes it is unsafe for the participant to continue on the intervention.  
1045 
This could be due to the development of a new medical condition or worsening of an 
1046 
existing condition; or participant behavior contrary to the indications for use of the 
1047 
device that imposes on the participant’s safety 
1048 
• The participant requests that the treatment be stopped 
1049 
• The participant tests positive for COVID-19 (during study testing or otherwise within 14 
1050 
days of study start) or subsequently develops symptoms for COVID-19 and tests positive. 
1051 
• Two distinct episodes of DKA, or one distinct episode of DKA attributable to study device 
1052 
use. 
1053 
• Two distinct severe hypoglycemia events meeting the definition in section 11.2.1 of the 
1054 
protocol, or one distinct severe hypoglycemia event attributable to study device use and 
1055 
meeting the definition in section 11.2.1 of the protocol. 
1056 
 Suspending/Stopping Overall Study 
1057 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
1058 
hyperglycemia event (as defined in section 11.2.2), use of the study device system will be 
1059 
suspended while the problem is diagnosed. 
1060 
In the event that two distinct episodes of DKA or two distinct severe hypoglycemia events as 
1061 
defined in section 11.2 occur, the overall study would be suspended while the underlying 
1062 
conditions are determined.   
1063 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
1064 
study device requires stoppage of device use for safety reasons (e.g. product recall).  The affected 
1065 
study activities may resume if the underlying problem can be corrected by a protocol or system 
1066 
modification that will not invalidate the results obtained prior to suspension. The Study PI will 
1067 
review all adverse events and adverse device events that are reported during the study. The 
1068 

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Study PI may request suspension of study activities or stoppage of the study is deemed necessary 
1069 
based on the totality of safety data available.  
1070 
 
1071 
A Data and Safety Monitoring Board (DSMB) will review compiled safety data at periodic intervals. In 
1072 
addition, the DSMB will review all DKA and severe hypoglycemia irrespective of relatedness to study 
1073 
device use, and all serious events (including UADEs) related to study device use at the time of 
1074 
occurrence. The DSMB can request modifications to the study protocol or suspension or outright 
1075 
stoppage of the study if deemed necessary based on the totality of safety data available. Details 
1076 
regarding DSMB review will be documented in a separate DSMB document. 
1077 
 
1078 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, access, 
1079 
or use of protected health information (PHI) that compromises the security or privacy of such 
1080 
information.  
 
1081 

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Chapter 12 Miscellaneous Considerations  
1082 
 
1083 
Participants using glulisine at the time of enrollment will be asked to contact their personal 
1084 
physician to change their prescribed personal insulin to lispro or aspart for the duration of the 
1085 
trial. 
1086 
The study devices (study insulin pump, study CGM) must be removed before Magnetic Resonance 
1087 
Imaging (MRI), Computed Tomography (CT) or diathermy treatment. Participants may continue 
1088 
in the trial after temporarily discontinuing use if requiring one of the treatments above. 
1089 
 
1090 
Participation in the study is voluntary. Participant may withdraw at any time.  For participants 
1091 
who do withdraw from the study, the study team will determine if their data will be used in 
1092 
analysis.  
1093 
 
1094 
For security and confidentiality purposes, subjects will be assigned an identifier that will be used 
1095 
instead of their name.  Protected health information gathered for this study may be shared with 
1096 
the third-party collaborators.  De-identified subject information may also be provided to 
1097 
collaborators involved in the study after the appropriate research agreement has been executed. 
1098 

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Chapter 13 Statistical Consideration 
1099 
 
1100 
We will conduct a paired comparison of outcomes between each admission (FCL vs. FCL+, HCL vs 
1101 
FCL, and FCL+ vs HCL), using Student paired t-test for percent in ranges and average CGM, and 
1102 
Wilcoxon test for overtly non normally distributed residuals (which often occur with outcomes 
1103 
such as % time below 70mg/dL, as well as 50, or 60mg/dL, and % time above 250mg/dL). 
1104 
Furthermore, we will use repeated measure ANOVA 3x2 with within factors and contrasts (to 
1105 
differentiate the repeated measures) if covariates are deemed necessary in the analysis. 
1106 
We do not plan to correct for multiple comparisons. 
1107 
We do not expect substantial missing values in this highly supervised study, but if more than 3 
1108 
subjects have one or more missing admissions, we will consider switching from RANOVA to mixed 
1109 
model repeated measures. 
1110 
 
1111 
The hypotheses for the primary outcome are: 
1112 
a. Null Hypothesis: There is no difference in the time spent in the 70-180mg/dL range within the 
1113 
breakfast postprandial period (mealtime to mealtime+5h) between FCL and FCL+ (without and 
1114 
with anticipation respectively) 
1115 
b. Alternative Hypothesis: There is a difference in the time spent in the 70-180mg/dL range within 
1116 
the breakfast postprandial period (mealtime to mealtime+5h) a between FCL and FCL+ (without 
1117 
and with anticipation respectively). 
1118 
 
1119 
The main study is itself a pilot study to assess glycemic responses to three different approaches 
1120 
to insulin dosing for carbohydrate ingestion, with different approaches to the RocketAP system 
1121 
(1) without the meal anticipation module and without carbohydrate announcement (FCL), 2) with 
1122 
the meal anticipation module on and without carbohydrate announcement (FCL+), or 3) with the 
1123 
meal anticipation module on and with carbohydrate announcement (HCL), in random order).  
1124 
This information is detailed in Table 1.  
1125 
Randomization will occur via selection from the above list using permuted blocks in groups of 6.   
1126 
 
1127 
As a Preliminary Study, the goal will be to complete up to 36 participants in the main study to 
1128 
provide data from a variety of individuals. This number was chosen out of feasibility and not from 
1129 

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a formal power calculation, and revised when new data (see reference 5) indicated that the 
1130 
outcome variance was likely to be greater than originally assumed. The pilot study for this 
1131 
proposal will assess ease of system use in up to 3 individuals prior to the beginning of the main 
1132 
study. Based on this empirical sample size, we would detect an effect size of approximately 0.5 
1133 
at 80% power, and 0.6 at 95% power. Based on the recommended MCID of 5% TIR over a day, 
1134 
and assuming no influence of meal on overnight (midnight-6AM) control at TIR=90%, this would 
1135 
lead to an improvement in TIR of approximately 11% during the breakfast regimen. Considering 
1136 
the broad variability observed during un-bolused prandial control (SDTIR≈22% from Garcia-Tirado 
1137 
et al 2021, reference 5), this leads to a MCID-derived Cohen-d effect size of approximately 0.5  
1138 
 
1139 
 Primary Efficacy Endpoint  
1140 
The study design allows for multiple comparisons of blood glucose control during the study meals 
1141 
and treatment sessions, with for the primary comparison of interest being between the RocketAP 
1142 
with and without the meal anticipation module, without announcement of carbohydrate. Our 
1143 
primary endpoint is CGM time-in-range 70-180 mg/dL for the period between breakfast and 
1144 
lunch (approximately 5h). Additional comparisons are made between the RocketAP system 
1145 
without vs. with normal carbohydrate announcement (which determines efficacy vs. premeal 
1146 
bolus). 
1147 
 Secondary Outcomes 
1148 
Each admission is separated in 5 windows of analysis: 
1149 
1. The entirety of the admission (24h: 4pm to 4pm) 
1150 
2. The 2 hours between expected dinner time and actual dinner time (day 1). 
1151 
3. The overnight period (midnight to 6am day 2) 
1152 
4. The window between the expected breakfast time and noon on day 2, ~5h (primary 
1153 
outcome) 
1154 
5. The 4h following lunch (noon-4pm day 2) 
1155 
For each of these periods we will compute the following outcomes: 
1156 
5. Number of hypoglycemia events defined as at least two consecutive CGM values 
1157 
<70mg/dL or a hypoglycemia treatment (two events separated by less than 30 minutes 
1158 
are counted as one). 
1159 

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6. Percent CGM time <70 mg/dL 
1160 
7. Percent CGM time between 80-140mg/dL 
1161 
8. Percent CGM time between 70-180mg/dL 
1162 
9. Percent CGM time >180 mg/dL 
1163 
10. Percent CGM time >250 mg/dL 
1164 
11. Units of insulin injected  
1165 
12. Area under the curve when accounting for starting BG  
1166 
13. Low Blood Glucose Index 
1167 
14. High Blood Glucose Index 
1168 
15. CGM coefficient of variation 
1169 
 
1170 
We will assess for the system’s functionality, including the ability of the system to run its code 
1171 
without error (delivering insulin safely, as planned), as well as its ability to avoid low BG <70 
1172 
mg/dL. 
1173 
 
1174 
Baseline demographic and clinical characteristics of the cohort of all randomized participants will 
1175 
be summarized in a table using summary statistics appropriate to the distribution of each 
1176 
variable. Descriptive statistics will be displayed overall and by treatment group. 
1177 
Will include: 
1178 
1. Age 
1179 
2. HbA1c 
1180 
3. Gender 
1181 
4. Race/ethnicity 
1182 
5. CGM use before enrollment 
1183 
6. AID use before enrollment 
1184 

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7. Diabetes duration 
1185 
8. BMI 
1186 
9. Total Daily Insulin 
1187 
 
1188 
The following tabulations and analyses will be performed during time on the UVa AP systems to 
1189 
assess device issues: 
1190 
1. Device malfunctions requiring study team contact and other reported device issues 
1191 
2. % time CGM data available 
1192 
3. % time with closed loop control 
 
1193 

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Chapter 14  Data Collection and Monitoring 
1194 
 
1195 
The study data are collected through a combination of case report forms (electronic and paper) 
1196 
and electronic device data files obtained from the software and individual hardware 
1197 
components. These electronic device files and electronic CRFs are considered the primary source 
1198 
documentation. 
1199 
When data are directly collected in electronic case report forms, this will be considered the 
1200 
source data.  Records will be maintained in accordance with ICH E6 and institutional regulatory 
1201 
requirements for the protection of confidentiality of participants. 
1202 
 
1203 
Study documents should be retained for a minimum of 2 years after the last approval of a 
1204 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1205 
applications in an ICH region or until at least 2 years have elapsed since the formal 
1206 
discontinuation of clinical development of the investigational product.  These documents should 
1207 
be retained for a longer period, however, if required by local regulations. No records will be 
1208 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
1209 
sponsor to inform the investigator when these documents no longer need to be retained. 
1210 
 
1211 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practices 
1212 
(GCP), or procedure requirements.  The noncompliance may be either on the part of the 
1213 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions 
1214 
may be developed by the site and implemented as appropriate.  Major deviations will be reported 
1215 
to the IRB-HSR within 7 calendar days of when the study team becomes aware of the event.  
1216 

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Chapter 15  Ethics/Protection of Human Participants 
1217 
 
1218 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1219 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
1220 
CFR Part 56, and/or the ICH E6. 
1221 
 
1222 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1223 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1224 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1225 
require review and approval by the IRB before the changes are implemented to the study.  All 
1226 
changes to the consent form will be IRB approved; a determination will be made regarding 
1227 
whether previously consented participants need to be re-consented. 
1228 
 
1229 
 Consent Procedures and Documentation 
1230 
Informed consent is a process that is initiated prior to an individual’s agreement to participate in 
1231 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
1232 
risks and possible benefits of participation will be provided.  Consent forms will be IRB approved 
1233 
and the participant will be asked to read and review the document.  The investigator or their 
1234 
delegate will explain the research study to the participant and answer any questions that may 
1235 
arise.  All participants will receive a verbal explanation in terms suited to their comprehension of 
1236 
the purposes, procedures, and potential risks of the study and of their rights as research 
1237 
participants.  Participant will have the opportunity to carefully review the written consent form 
1238 
and ask questions prior to signing. 
1239 
The participant and the parent(s)/legal guardians will sign the informed consent document prior 
1240 
to any procedures being done specifically for the study. The consent forms may be signed 
1241 
electronically with the use of the HIPAA compliant version of DocuSign. A copy of the informed 
1242 
consent document will be given to the participant for their records.  The rights and welfare of the 
1243 
participants will be protected by emphasizing to them that the quality of their medical care will 
1244 
not be adversely affected if they decline to participate in this study. 
1245 

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 Participant and Data Confidentiality 
1246 
The study monitor, representatives of the IRB or device company supplying study product may 
1247 
inspect all documents and records required to be maintained by the investigator, including but 
1248 
not limited to, medical records (office, clinic, or hospital) for the participants in this study.   
1249 
The study participant’s contact information will be securely stored at the clinical site for internal 
1250 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
1251 
location for as long a period as dictated by local IRB and Institutional regulations. 
1252 
Study participant research data, which is for purposes of statistical analysis and scientific 
1253 
reporting, will be transmitted to and stored at the University of Virginia Center for Diabetes 
1254 
Technology.  The study data entry and study management systems used by research staff will be 
1255 
secured and password protected.  At the end of the study, all study databases may be de-
1256 
identified and archived at the University of Virginia Center for Diabetes Technology. 
1257 

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Chapter 16 References  
1258 
1. 
Burdick J, Chase HP, Slover RH, et al. Missed insulin meal boluses and elevated 
1259 
hemoglobin A(1c) levels in children receiving insulin pump therapy. Pediatrics. Mar 
1260 
2004;113(3):E221-E224. doi:10.1542/peds.113.3.e221 
1261 
2. 
Cherñavvsky DR, DeBoer MD, Keith-Hynes P, et al. Use of an artificial pancreas among 
1262 
adolescents for a missed snack bolus and an underestimated meal bolus. Pediatr 
1263 
Diabetes. Feb 2016;17(1):28-35. doi:10.1111/pedi.12230 
1264 
3. 
Garcia-Tirado J, Brown SA, Laichuthai N, et al. Anticipation of Historical Exercise Patterns 
1265 
by a Novel Artificial Pancreas System Reduces Hypoglycemia During and After Moderate-
1266 
Intensity Physical Activity in People with Type 1 Diabetes. Diabetes Technol Ther. Dec 
1267 
2020;doi:10.1089/dia.2020.0516 
1268 
4. Voysey, Merryn and Costa Clemens, Sue Ann and Madhi, Shabir A. et al and Group, Oxford 
1269 
COVID Vaccine Trial, Single Dose Administration, And The Influence Of The Timing Of The 
1270 
Booster Dose On Immunogenicity and Efficacy Of ChAdOx1 nCoV-19 (AZD1222) Vaccine. 
1271 
Available at SSRN: https://ssrn.com/abstract=3777268 
1272 
5.Garcia-Tirado J, Diaz JL, Esquivel-Zuniga R, Koravi CL, Corbett JP, Dawson M, Wakeman C, 
1273 
Barnett CL, Oliveri MC, Myers H, Krauthause K. Advanced Closed-Loop Control System 
1274 
Improves Postprandial Glycemic Control Compared With a Hybrid Closed-Loop System 
1275 
Following Unannounced Meal. Diabetes Care. 2021 Oct 1;44(10):2379-87. 
1276