Adaptive Motif-Based Control (AMBC): Pilot 1 - Neural Net Implementation of Automated Insulin Delivery
Phase: NA
Conditions: Type1 Diabetes
Sponsor: University of Virginia

 
UVA CENTER FOR DIABETES TECHNOLOGY
 
 
 
 
 
 
Adaptive Motif-Based Control (AMBC):  
Pilot 1 – Neural Net Implementation of 
Automated Insulin Delivery 
 
Running Title: Neural Net Artificial Pancreas 
(NAP) 
 
 
 
Protocol Principal Investigator 
Sue A. Brown, MD 
 
 
University of Virginia 
Center for Diabetes Technology 
 
 
NCT#05876273 
Version Number: v1.3 
19-Jun-2023 
 

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KEY ROLES 
 
 
 
Name, degree 
Institution Name 
Protocol Principal Investigator 
Sue Brown, MD 
University of Virginia Division of 
Endocrinology and Metabolism 
Study Sponsor 
Boris Kovatchev, PhD 
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 
Boris Kovatchev 
Sue Brown 
20-Feb-2023 
Original Protocol 
1.1 
Mary Oliveri 
Sue Brown 
08-Mar-2023 
FSDA Modifications 
1.2 
Sue Brown 
Sue Brown 
07-Apr-2023 
Study team mods 
1.3 
Mary Oliveri 
Sue Brown 
19-Jun-2023 
Study team mods 
• 
Revised Risk of Device 
Reuse section to identify 
equipment that may be 
reused during the trial after 
cleaning (section 9.1.6) 
• 
Added Device Cleaning 
Instructions (section 9.1.7) 
 
 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
 
Protocol Title: Adaptive Motif-Based Control (AMBC): Pilot 1 – Neural Net Implementation of 
Automated Insulin Delivery 
Running Title: Neural Net Artificial Pancreas (NAP) 
Protocol Version/Date: v1.3  19-Jun-2023 
 
I have read the protocol specified above.  In my formal capacity as a 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 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AID 
Automated Insulin Delivery 
AMBC 
Adaptive Motif-Based Control 
AP 
Artificial Pancreas 
BG 
Blood Glucose 
CDCES 
Certified Diabetes Care and Education Specialist 
CDT  
Center for Diabetes Technology 
CF 
Correction Factor 
CGM 
Continuous Glucose Monitoring 
CIQ 
Control-IQ AP system, Tandem Diabetes Care, San Diego, CA 
CSII 
Continuous Subcutaneous Insulin Injection 
DCCT 
Diabetes Control and Complications Trial 
DiAs 
Diabetes Assistant – the UVA algorithm prototyping system 
DKA 
Diabetic Ketoacidosis 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ICR 
Insulin-to-carbohydrate ratio  
iDCL 
International Diabetes Closed-Loop trial 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
NAP 
Neural Net Artificial Pancreas 
NIDDK 
National Institute for Diabetes and Digestive and Kidney Diseases 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
POC 
Point-of-Care 
SAE 
Serious Adverse Event 
T1D 
Type 1 Diabetes 
TAR 
Time above range, above 180 mg/dL 
TBR 
Time below range, below 70 mg/dL 
TIR 
Time within the range 70-180 mg/dL  
UMPC 
UVA’s Model-Predictive Control Algorithm 
UADE 
Unanticipated Adverse Device Effect 
UVA 
University of Virginia 
 
 

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PROTOCOL SUMMARY 
PROTOCOL 
SECTION 
DESCRIPTION 
Title 
Adaptive Motif-Based Control (AMBC): Pilot 1 – Neural Net Implementation of 
Automated Insulin Delivery 
Investigational Devices 
Neural Net Artificial Pancreas (NAP) implementation of the UVA model predictive 
control algorithm (UMPC); Both NAP and UMPC are investigational devices. 
Objectives 
The purpose of this study is to test the safety and feasibility of a neural net 
implementation of an established AP controller, known as UMPC, previously 
approved by IDE G200206, and tested in the following randomized controlled 
clinical trials: ClinicalTrials.gov NCT04545567, NCT04877730, and 
NCT05528770. 
Study Design 
A randomized cross-over trial assessing glycemic control on NAP, compared to the 
original UMPC algorithm, which includes two sessions studied in a supervised hotel 
setting:  
1) using NAP – a neural net implementation of UMPC, and 
2) using the original UMPC without modifications (see IDE G200206). 
Number of Sites 
One 
Endpoint 
The primary outcome will be time in range 70-180 mg/dL for an 18-hour period, 6 
PM to 12 PM on the next day, including dinner and breakfast meals.  
Population 
Key Inclusion Criteria 
• 
Age ≥18 years of age 
• 
Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at 
least 1 year  
• 
Currently using insulin for at least six months 
• 
Currently using the Control-IQ (CIQ) automated insulin delivery (AID) 
system. 
Sample Size  
Up to 20 participants 
Treatment Groups 
Randomized crossover: Participants will be randomized to two groups differing by 
the order of controller use: Group A: NAP first followed by UMPC; Group B: 
UMPC followed by NAP.   
Participant Duration 
Up to 6 weeks: Participants will be studied at a local hotel or rental house to test 
two algorithms, approximately 20 hours per each test. Prior to each hotel session, 
participants will passively collect CIQ data for a week. The two hotel sessions can 
be performed sequentially during the same hotel stay or in two hotel stays 
separated up to 28 days.  
Protocol 
Overview/Synopsis 
Following enrollment, 1 week of AID data will be downloaded from the 
participants’ pumps or t:connect accounts and will be used to establish a baseline 
and initialize the control algorithms. Participants will be then studied at a hotel for 
20 hours, including an 18-hour experiment, randomly receiving either NAP or 
UMPC.  Participants will then receive the opposite intervention either sequentially 
during the same hotel stay, or in a second hotel stay up to 28 days following the 
first hotel stay (Figure 1).  

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STUDY VISITS AND PROCEDURES SCHEDULE  
 
Screening 
Hotel Session 1 
Hotel Session 2 
 
 
Pre-Session 
Check-In 
Hotel Session 
1 
Post-Session 
Check-In* 
Pre-Session 
Check-In** 
Hotel Session 
2 
Post-Session 
Check-In 
Location 
In person or 
Remote 
Phone/ Email/ 
Text 
Hotel/ Rental 
House 
Phone/ Email/ 
Text 
Phone/ Email/ 
Text 
Hotel/ Rental 
House 
Phone/ Email/ 
Text 
Visit 
1 
2 
3 
4 
5 
6 
7 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
Pregnancy test (if applicable) 
 
 
X 
 
 
X*** 
 
Physical Exam 
X 
 
 
 
 
 
 
Vital Signs (height/weight) 
X 
 
X 
 
 
X*** 
 
Demographic Survey 
X 
 
 
 
 
 
 
Baseline data download 
(1 week of AID data) 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
NAP / UMPC use 
 
 
X 
 
 
X 
 
Review diabetes management 
and AEs 
 
X 
 
X 
X 
 
X 
* Post-session check-in Visit 4 will not occur, if the two hotel sessions are done sequentially  
** Pre-session check-in Visit 5 will not occur, if the two hotel sessions are done sequentially 
*** Pregnancy test and vital signs recheck will not occur during Hotel Session 2 if the two hotel sessions are done sequentially.

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TABLE OF CONTENTS 
1 
Chapter 1 Background and Synopsis ........................................................................................ 10 
2 
1.1 Introduction ........................................................................................................................ 10 
3 
1.2 Objective and Primary Outcome ........................................................................................ 11 
4 
1.3 Study Design ...................................................................................................................... 11 
5 
1.4 Study Hardware/Software .................................................................................................. 12 
6 
1.5 Hotel Sessions .................................................................................................................... 12 
7 
1.6 Device Download ............................................................................................................... 12 
8 
1.7 Potential Study System Issues ............................................................................................ 12 
9 
Chapter 2 Study Devices ............................................................................................................ 14 
10 
2.1 Insulin Pump ...................................................................................................................... 14 
11 
2.2 Continuous Glucose Monitor ............................................................................................. 14 
12 
2.3 Blood Glucose Meter and Strips ........................................................................................ 14 
13 
2.4 Ketone Meter and Strips .................................................................................................... 14 
14 
2.5 Study Devices Accountability Procedures ......................................................................... 14 
15 
Chapter 3 Screening ................................................................................................................... 15 
16 
3.1 Clinical Sites ...................................................................................................................... 15 
17 
3.2 Participant Recruitment and Enrollment ............................................................................ 15 
18 
3.3 Prescreening Procedures .................................................................................................... 15 
19 
3.4 Informed Consent and Authorization Procedures .............................................................. 15 
20 
3.5 Inclusion Criteria ................................................................................................................ 15 
21 
3.6 Exclusion Criteria............................................................................................................... 16 
22 
3.7 Screening Procedures ......................................................................................................... 17 
23 
3.8 Demographic Data Survey ................................................................................................. 18 
24 
Chapter 4 Randomization .......................................................................................................... 20 
25 
Chapter 5 Pre-Hotel Schedule ................................................................................................... 21 
26 
5.1 Pre-Hotel Check-In ............................................................................................................ 21 
27 
5.2 Other Issues ........................................................................................................................ 21 
28 
Chapter 6 Hotel Session.............................................................................................................. 22 
29 
6.1 Qualifications and Role of the Staff ................................................................................... 22 
30 
6.2 Session Check-In ................................................................................................................ 22 
31 
6.3 Glycemic Treatment Guidelines during the Hotel Portion of the Study ............................ 23 
32 
6.4 Study Meals ........................................................................................................................ 24 
33 
6.5 Hotel Activities .................................................................................................................. 24 
34 
6.6 Hotel Discharge .................................................................................................................. 24 
35 
6.7 Post Hotel Check-In Visit .................................................................................................. 24 
36 
Chapter 7 Medical Monitor Review .......................................................................................... 26 
37 
Chapter 8 Testing Procedures ................................................................................................... 27 
38 
8.1 HbA1c ................................................................................................................................ 27 
39 

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8.2 Pregnancy Test ................................................................................................................... 27 
40 
Chapter 9 Risks Associated with Clinical Trial ....................................................................... 28 
41 
9.1 Potential Risks and Benefits .............................................................................................. 28 
42 
9.2 General Considerations ...................................................................................................... 31 
43 
Chapter 10 Adverse Events, Device Issues, and Stopping Rules ............................................ 32 
44 
10.1 Definitions ........................................................................................................................ 32 
45 
10.2 Reportable Events ............................................................................................................ 33 
46 
10.3 Relationship of AE to Study Device ................................................................................ 34 
47 
10.4 Intensity of AE ................................................................................................................. 34 
48 
10.5 Coding of AEs .................................................................................................................. 35 
49 
10.6 Outcome of AEs ............................................................................................................... 35 
50 
10.7 Reportable Device Issues ................................................................................................. 36 
51 
10.8 Timing of Event Reporting .............................................................................................. 36 
52 
10.9 Stopping Criteria .............................................................................................................. 37 
53 
10.10 Independent Safety Oversight ........................................................................................ 37 
54 
10.11 Definition of a Data Breach ........................................................................................... 37 
55 
Chapter 11 Miscellaneous Considerations................................................................................ 38 
56 
11.1 Prohibited Medications, Treatments, and Procedures ...................................................... 38 
57 
11.2 Participant Withdrawal..................................................................................................... 38 
58 
11.3 Confidentiality ................................................................................................................. 38 
59 
Chapter 12 Statistical Consideration ........................................................................................ 39 
60 
12.1 Design and Randomization .............................................................................................. 39 
61 
12.2 Sample Size ...................................................................................................................... 39 
62 
12.3 Outcome Measures ........................................................................................................... 39 
63 
12.4 Criteria for Success .......................................................................................................... 40 
64 
12.5 CGM data treatment ......................................................................................................... 40 
65 
12.6 Safety Analyses and Participant Feedback ...................................................................... 40 
66 
12.7 Baseline Descriptive Statistics ......................................................................................... 40 
67 
Chapter 13 Data Collection and Monitoring ............................................................................ 42 
68 
13.1 Case Report Forms and Device Data ............................................................................... 42 
69 
13.2 Study Records Retention .................................................................................................. 42 
70 
13.3 Protocol Deviations .......................................................................................................... 42 
71 
Chapter 14 Ethics/Protection of Human Participants ............................................................. 43 
72 
14.1 Ethics Standard................................................................................................................. 43 
73 
14.2 Institutional Review Boards ............................................................................................. 43 
74 
14.3 Informed Consent Process ............................................................................................... 43 
75 
Chapter 15 References ................................................................................................................ 45 
76 
 
77 
 
 
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Chapter 1  Background and Synopsis 
79 
 
80 
The National Institutes of Health’s Strategic Plan for Fiscal Years 2021–2025 “outlines NIH’s 
81 
vision for biomedical research direction, capacity, and stewardship, by articulating the highest 
82 
priorities of NIH over the next 5 years.” 1 The Plan also highlights key accomplishments in the past 
83 
5 years. On page 13, under the heading “Giving the Right Treatment to the Right Patient at the 
84 
Right Time,” the Plan recognized the UVA CDT (Center for Diabetes Technology) for its research 
85 
resulting in the clinical translation of innovative automated insulin delivery (AID) technology.1 
86 
Indeed, the blueprint of the UVA-AID was created by our team over a decade ago2-5 and, after a 
87 
number of clinical trials, culminated in two large studies, part of the International Diabetes Closed-
88 
Loop (iDCL) Trial, grant UC4DK108483, led by our team and published in the New England 
89 
Journal of Medicine.6,7 As a result, FDA cleared Control-IQ (Tandem Inc.), derived from the 
90 
UVA-AID, as “the first inter-operable, automated insulin dosing controller designed to allow more 
91 
choices for patients looking to customize their individual diabetes management device system.”8 
92 
Control-IQ is now launched in over 24 countries and has over 400,000 users worldwide. 
93 
With the first-generation UVA-AID translated to routine clinical practice, we have developed a 
94 
next-generation controller – University of Virginia’s model-predictive control algorithm (UMPC) 
95 
– which was approved by the FDA for investigational use with IDE G20020638  and was then tested 
96 
successfully in a randomized controlled clinical trial (NCT04545567), published in Diabetes Care.9 
97 
Two other pilot studies tested glycemic disturbance anticipation (IDE #G21005139, 
98 
NCT04877730) and automated priming bolus (IDE #G220204,40 NCT05528770). Most recently, 
99 
in a grant application funded by the NIDDK (RO1 DK 133148-01, corresponding PI Kovatchev), 
100 
we  proposed using the data and experience amassed in our previous studies to design and test a 
101 
new class of AID algorithms – Adaptive Motif-Based Control (AMBC), which blends Data 
102 
Science methods with artificial pancreas (AP) control engineering. 
103 
The concept of AMBC is to enable a pathway towards adaptive AP algorithms which are capable 
104 
of learning from a person’s CGM and insulin delivery patterns, and from the patterns of others 
105 
stored in databases. The first step towards this concept of the future, is translating a well-
106 
established AP control algorithm, e.g., UMPC into a Data Science “environment,” i.e., creating a 
107 
Neural Net adaptation of a model-predictive controller. This protocol intends to test such an 
108 
adaptation – a Neural Net AP (NAP) – in a brief study in a well-controlled environment. Studies 
109 
to follow will expand this concept further and will add elements of controller adaptation based on 
110 
data accumulated in databases, labelled by prefixed “motifs” – a recently established structure of 
111 
daily CGM profiles.10 The latter would allow a finite table-lookup approach to real-time AP control 
112 
adaptation; but, this is a subject of future studies. Now we focus on the first step only – translating 
113 
a controller into a neural-net environment.  
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Thus, the only new AID algorithm tested in this study is NAP – a neural-net implementation of the 
115 
UMPC – which produces insulin adjustment commands identical (within a small tolerance) to the 
116 
original UMPC (see Appendix A-1: Algorithm Description). We should also emphasize that the 
117 
two experimental algorithms used in this study, UMPC and NAP, modulate only the basal rate of 
118 
insulin delivery. The other components, the Adaptive Bolus Priming System, the Hyperglycemia 
119 
Mitigation System, and the Safety System Module dedicated to prevention of hypoglycemia – 
120 
remain unchanged from previous studies and are described in IDE # G220204. In particular, the 
121 
Safety System has been reviewed by the Agency in virtually all IDEs in the reference list.15-36 The 
122 
Safety System Module has also been tested for its ability to prevent hypoglycemia in pivotal trials 
123 
[IDE#G180053 and IDE#G180053] and in millions of days of routine home use, as part of the 
124 
commercial Control-IQ AID device system.37 
125 
 
126 
Pilot test the safety and feasibility of a NAP implementation of an established AP controller – 
127 
UMPC – in a crossover study. The primary outcome is percent TIR (70 to 180 mg/dL) on NAP vs 
128 
UMPC. Secondary outcomes include frequency of hypoglycemia (TBR) and hyperglycemia 
129 
(TAR), as well as other safety and control metrics. We will analyze non-inferiority of NAP 
130 
compared to UMPC, but this pilot feasibility study is not powered to formally test noninferiority.    
131 
 
132 
We will consent up to 20 participants, ages ≥18.0, with a goal to have 15 participants complete the 
133 
trial. The study randomized crossover design is presented in Figure 1 below, and includes 
134 
screening, randomization, and two 18-hour hotel/rental house study sessions (heretofore referred 
135 
to as “hotel”). The first hotel session will be preceded by a download of 1-week AID data:  
136 
 
137 
Figure 1:  Timeline and randomized order of the hotel sessions. Group A will proceed 
138 
with NAP first; Group B will use UMPC first; then the two groups will cross over after 
139 
0-4 week time period. In particular, the two hotel sessions can be combined into one, 
140 
with two 18-hour periods alternating NAP vs UMPC.  
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142 
The study will involve CIQ users who will continue to use their CIQ systems, except during the 
143 
hotel sessions, which will use the DiAs prototyping platform (described in device master file MAF 
144 
2109), connected to a Tandem t:AP research pump and a Dexcom G6 sensor, and implementing 
145 
NAP or UMPC.  The study sensor will be the same sensor used by CIQ – it will be disconnected 
146 
from CIQ and connected to DiAs.   
147 
 
148 
The participants will arrive to hotel and the experimental system will be set up and started within 
149 
approximately two hours before dinner: participant’s CIQ will be replaced by a Tandem research 
150 
pump connected to the DiAs platform and their Dexcom G6 Transmitter will be linked with DiAs. 
151 
The research pump will be programmed based on the individual’s usual insulin parameters. Once 
152 
started, the participants will have their blood sugar managed through this system during 18 hours 
153 
of the time at hotel. A pre-meal bolus using the participant’s normal insulin-to-carbohydrate ratio 
154 
(ICR) will occur for dinner and breakfast after initiating the experimental system. Each participant 
155 
will have two of these sessions: one on NAP and one on UMPC, in random order, separated by 0-
156 
28 days. In particular, the two hotel sessions can be combined into one, with two 18-hour periods 
157 
alternating NAP vs UMPC.  (see Figure 1). 
158 
During these 18-hour hotel sessions participants will be followed to compare blood glucose control 
159 
on NAP vs. UMPC. The study meals and activities will be kept the same between study sessions. 
160 
Study staff who will be present will include nursing and technical staff; a study physician/nurse 
161 
practitioner/physician’s assistant will be available either on-site or nearby off-site. Hyperglycemia 
162 
and hypoglycemia treatment protocols will be followed per guidelines. UVa CDT study staff will 
163 
monitor CGM output continuously and manage glucose control issues. At the end of the hotel stay, 
164 
the participant will return to their home insulin management.  
165 
 
166 
Baseline data will be downloaded from the participants’ CIQ pump or t:connect account. Before 
167 
discharge from the hotel, DiAs will be turned in to study staff for device download, and the 
168 
participants will return to their usual CIQ diabetes management. If the two hotel sessions are 
169 
separated, a second CIQ pump or t:connect download will occur during Hotel Session 2. 
170 
 
171 
If the CGM signal becomes unavailable for more than 20 minutes consecutively, closed loop will 
172 
not operate to automatically adjust insulin.  If the CGM is not connected, the system will revert to 
173 
usual function of the pump and deliver insulin with the insulin dosing parameters programmed in 
174 
the system for that individual. Resumption of closed-loop control will occur automatically once 
175 
CGM signal is available again. If the study system is unable to maintain pump connectivity, the 
176 

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pump will automatically revert to pre-programmed basal insulin delivery after 30 minutes without 
177 
any need for instruction from the user. 
 
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Chapter 2  Study Devices 
179 
 
180 
The study systems will utilize the Tandem t:AP research pump connected to the UVa DiAs system 
181 
run on a dedicated external smart phone, running NAP or UMPC. 
182 
 
183 
A study Dexcom G6 CGM may be provided to study participants. . The study staff will remind the 
184 
participant approximately 2-3 days before the hotel session to replace the sensor with a new one, 
185 
so appropriate sensor warmup can occur prior to hotel session. If required, participants may use 
186 
their personal CGM during the study session. The Dexcom G6 sensor is viable for up to 10 days. 
187 
 
188 
Blood glucose levels will be measured during the hotel sessions with the use of a Bayer Contour 
189 
Next meter. The CGM device will be calibrated, if needed, using the study glucometer and strips 
190 
in accordance with the manufacturer’s labelling.  
191 
 
192 
Blood ketone levels will be measured during the hotel session with the use of the Abbott Precision 
193 
Xtra meters or Keto mojo meters and strips in accordance with the manufacturer’s labelling. The 
194 
blood glucose meter component of the ketone devices will not be used.   
195 
 
196 
Device serial numbers will be recorded, and use of equipment will be tracked. 
 
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Chapter 3  Screening  
198 
 
199 
The study will be performed at the University of Virginia, with screening procedures taking place 
200 
either virtually, at the Clinical Research Unit, or at local hotel. 
201 
 
202 
Enrollment in the study will proceed with the goal of completing up to 15 participants. Up to 20 
203 
participants may sign the consent form. 
204 
Recruitment, screening, and enrollment may be performed as an office visit, or via 
205 
telecommunication. 
206 
 
207 
Before informed consent, potential participants may be pre-screened by phone for eligibility. 
208 
During pre-screening, potential subjects will be asked the Inclusion/Exclusion Questionnaire by 
209 
study staff.  
210 
 
211 
Before completing any procedures or collecting any data that are not part of usual care, written 
212 
informed consent as described in section 14.3.1 will be obtained. Potential eligibility may be 
213 
assessed as part of a routine-care examination.   
214 
A participant is considered enrolled when the informed consent form has been signed by the 
215 
participant and the study team.  
216 
Consenting procedures and documentation are defined in section 14.3. 
217 
 
218 
The participants must meet all of the following inclusion criteria in order to be eligible to 
219 
participate in the study. 
220 
1. Age ≥18.0 at time of consent 
221 
2. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year  
222 
3. Currently using insulin for at least six months 
223 
4. Currently using the CIQ automated insulin delivery system for at least one month  
224 
5. Hemoglobin A1c ≤9% 
225 
6. Using insulin parameters such as ICR and CF consistently in order to dose insulin for meals 
226 
or corrections  
227 
7. Access to internet and willingness to upload data during the study as needed  
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8. If female of childbearing potential and sexually active, must agree to use a form of 
229 
contraception to prevent pregnancy while a participant in the study.  A negative serum or 
230 
urine pregnancy test will be required for all females of childbearing potential within 24 hours 
231 
prior to initiating the experimental algorithms. Participants who become pregnant will be 
232 
discontinued from the study. Also, participants who during the study develop and express 
233 
the intention to become pregnant within the timespan of the study will be discontinued. 
234 
9. Willingness to use the UVa DiAs system throughout study session 
235 
10. Willingness to use personal lispro (Humalog) or aspart (Novolog) during the study session.  
236 
11. Willingness not to start any new non-insulin glucose-lowering agent during the course of the 
237 
trial (including SGLT2 inhibitors, metformin/biguanides, GLP-1 receptor agonists, 
238 
pramlintide, DPP-4 inhibitors, sulfonylureas and naturaceuticals) 
239 
12. Willingness to reschedule the hotel portion of the study if placed on systemic steroids (e.g. 
240 
IV, IM, intra-articular or oral routes) 
241 
13. An understanding and willingness to follow the protocol and signed informed consent  
242 
 
243 
The participant must not have any exclusion criteria in order to be eligible for the study.  
244 
1. History of diabetic ketoacidosis (DKA) in the 12 months prior to enrollment 
245 
2. Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior to 
246 
enrollment 
247 
3. Currently pregnant or intent to become pregnant during the trial 
248 
4. Currently breastfeeding  
249 
5. Currently being treated for a seizure disorder 
250 
6. Treatment with meglitinides/sulfonylureas at the time of hotel study. 
251 
7. Use of metformin/biguanides, GLP-1 agonists, pramlintide, DPP-4 inhibitors, SGLT-2 
252 
inhibitors, or naturaceuticals intended for glycemic control with a change in dose in the past 
253 
month.  
254 
8. History of significant cardiac arrhythmia (except for benign premature atrial contractions and 
255 
benign premature ventricular contractions which are permitted or previous ablation of 
256 
arrhythmia without recurrence which may be permitted) or active cardiovascular disease 
257 
9. A known medical condition that in the judgment of the investigator might interfere with the 
258 
completion of the protocol such as the following examples: 
259 
a. Inpatient psychiatric treatment in the past 6 months  
260 
b. Presence of a known adrenal disorder 
261 
c. Uncontrolled thyroid disease (e.g. persistently abnormal TSH with hyperthyroid or 
262 
hypothyroid symptoms in participants with known thyroid disease). Stable TSH 
263 
suppression for prior thyroid cancer history for example could be enrolled.  
264 
d. End-Stage Renal Disease (e.g. CKD Stage 4 or 5) 
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10. A known medical condition that in the judgment of the investigator might interfere with the 
266 
completion of the protocol. 
267 
 
268 
After informed consent has been signed, a potential participant will be evaluated for study 
269 
eligibility through the elicitation of a medical history, performance of a physical examination 
270 
by licensed personnel to screen for exclusionary medical conditions.  A physical exam documented 
271 
in the prior 9 months can suffice for the physical exam but will not serve as an exclusionary 
272 
criterion if not available.  
273 
Up to 3 months of historical data from the participant’s CIQ system may be downloaded or 
274 
recorded. This data may be obtained through the commercial applications (e.g. t:connect). 
275 
Screening procedures will last approximately 1-2 hours. The visit may occur in-person or by 
276 
telecommunication. The following procedures may be performed/data collected/eligibility criteria 
277 
checked and documented:  
278 
1. Inclusion and Exclusion criteria assessed 
279 
2. Demographics, including: 
280 
a. Date of birth 
281 
b. Gender  
282 
c. Race 
283 
d. Ethnicity 
284 
3. Medical History, including diabetes history  
285 
a. Duration of disease (number of years) 
286 
b. Current insulin pump model 
287 
c. History of CGM use 
288 
d. Current treatment 
289 
e. Severe hypoglycemia history 
290 
f.  Severe hyperglycemia history 
291 
g. History of seizures  
292 
h. Loss of consciousness 
293 
i.  Pregnancy query 
294 
4. Basal rates 
295 
5. Carbohydrate ratios 
296 
6. Insulin sensitivity factors 
297 
7. Target glucose 
298 
8. Average daily insulin 
299 
9. Surgical history 
300 
10. Allergies 
301 
11. Concomitant medications 
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12. Physical Examination – A historical history and physical report within 9 months of 
303 
screening appointments may be used but is not required for eligibility. If vitals are not 
304 
available, may include self-reported values.  
305 
a. Weight (may be self-reported) 
306 
b. Height (may be self-reported) 
307 
c. Blood pressure 
308 
d. Temperature (if available) 
309 
e. Heart Rate 
310 
13. Labs  
311 
a. Hemoglobin A1c, (not an eligibility criteria) and can be obtained within two weeks 
312 
prior to screening and up until the start of the hotel sessions. 
313 
If needed based on medical history, investigators may include baseline chemistry panel to obtain 
314 
creatinine/eGFR to determine stage of kidney disease and thyroid stimulating hormone (lab results 
315 
within one year of screening appointment may be used). 
316 
Any labs required may be obtained at a local laboratory (e.g. LabCorp) convenient to the 
317 
participant. 
318 
This study is not meant to find out if the participant has any other disease or problem. The study 
319 
leaders will alert the participant if any of the research results are important to his/her health during 
320 
the study. The participant may have a copy of the screening tests to discuss with the personal 
321 
physician. When the blood tests are completed, any blood left over will be thrown away. It will 
322 
not be stored for any future testing. 
323 
The study physician or physician designee will have the discretion to repeat screening tests. The 
324 
participant may request a copy of any of the results from the screening evaluation to review with 
325 
their primary care provider.  
326 
If an exclusionary condition is identified, the study participant will be excluded from participation 
327 
with follow up and referral to their primary care physician as needed.  
328 
Participants may be re-screened at a later date if their clinical situation changes as determined by 
329 
the study physician. 
330 
 
331 
Research in diabetes technology has revealed significant disparities in minoritized population’s 
332 
representation in clinical trials and access to devices that improve diabetes outcomes. Collection 
333 
of detailed demographic data regarding participants in technology trials has become essential.  This 
334 
includes data on race/ethnicity, income levels and insurance status, as well as education and other 
335 
variables that describe the study population.  
336 
The Demographic Data Survey will be electronically administered once eligibility has been met.  
337 
a. Gender 
338 

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b. Race 
339 
c. Ethnicity 
340 
d. Marital status  
341 
e. Level of education 
342 
f.  Employment status  
343 
g. Household income 
344 
h. Health insurance status 
345 
i.  Monthly insulin costs 
346 

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Chapter 4  Randomization  
347 
Participants will receive the two different experimental conditions (NAP and UMPC) in random 
348 
order. Once eligibility is met and screening procedures are completed, the participant may continue 
349 
to randomization. Screening failures and dropout participants may be replaced.   
 
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Chapter 5 Pre-Hotel Schedule 
351 
Visit 2 and 4 
352 
 
353 
Participants will be contacted by the study team approximately 1-3 days prior to each hotel session 
354 
if most recent contact with the study participant exceeds 10 days. The study team will verify the 
355 
following information: 
356 
• Inquire about any changes to the participant’s medical history 
357 
• Remind the participants to place a new sensor for proper warm-up prior to session 
358 
• Verify with the subject that the goal CGM reading at time of arrival is  between 80-250 
359 
mg/dL; this may require contact with the study physician prior to arrival on the day of 
360 
the study visit  
361 
• Should any concerns regarding medical history, pump information, or unforeseen 
362 
issues arise, the session will be cancelled for that participant at the discretion of the 
363 
investigator. 
364 
 
365 
Data-driven optimization of pump settings can occur any time prior to the hotel sessions, 
366 
particularly if the participant contacts the study physician due to concerns about their pump 
367 
settings due to recurring hypo- or hyperglycemia. No pump settings changes can occur during 
368 
NAP or UMPC algorithm testing. 
 
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Chapter 6  Hotel Session 
370 
Visit 3 and 5 
371 
Each participant will have two hotel sessions. Each session will be of approximately 20 hours 
372 
duration (see Figure 1). The sessions may occur sequentially within the same hotel stay or within 
373 
28 days of each other. If the hotel sessions are sequential, it is not required that the initial hotel 
374 
check-procedures procedures be repeated.  
375 
 
376 
There will be at least two study staff present at all times at the study site, at least one of whom will 
377 
be clinical (e.g. nurse, physician, nurse practitioner, physician assistant). There will be a physician 
378 
at the hotel or nearby on call during the study. In addition, at least one engineer will be on call 
379 
during the entire session. Participants will be remotely monitored by at least one study team 
380 
member using a web-based remote monitoring system that has been previously established for 
381 
DiAs.  The web-based remote monitoring system will display real-time insulin delivery, CGM and 
382 
other system information to allow for patient safety monitoring. Study team members will be 
383 
trained in all protocol and glycemic treatment guideline procedures.  
384 
The study team will be responsible for monitoring and managing the study insulin pump during 
385 
the hotel sessions. The participants may be provided a quick overview on its functionality to 
386 
understand the equipment. The study team will assist the participant in study pump infusion site 
387 
initiation and will start the participant on the study pump. The study pump will be programmed 
388 
with the participant’s usual basal rates and pump parameters.  
389 
The participant will be instructed on charging the pump, navigation through menus, bolus 
390 
procedures including stopping a bolus, etc. The participant will be instructed to notify study staff 
391 
if they experience any issues with the study devices during the hotel session. If insulin is delivered 
392 
by any means other than the study pump (e.g. injection of subcutaneous insulin via syringe in the 
393 
event of infusion site failure), the study team will be instructed to turn off closed-loop mode for 
394 
approximately four hours. 
395 
The participant will also be asked to alert the study staff for technical issues with the Tandem 
396 
research pump and/or the DiAs system, including component disconnections.  
397 
A glucagon emergency kit will be available at the hotel once the investigational system is in place.  
398 
Glycemic Treatment Guidelines will be available for staff use during the study sessions. 
399 
 
400 
Participants will arrive at the hotel around 4PM, approximately 2 hours before dinner.  The study 
401 
team will perform vital signs and inquire about any changes to the participant’s medical history.  
402 
Any changes to medical history will be communicated to the medical physician to ensure 
403 
continued eligibility and participation.   
404 

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A urine pregnancy test will be collected for female participants of childbearing age. The test must 
405 
be negative for the participant to continue with the study.  
406 
The subject’s CGM reading, and ketone concentration will be recorded. In the event that the 
407 
participant’s CGM reading is not between 80-250 mg/dL or ketone concentration is >0.6 mmol/L 
408 
prior to initiation of DiAs, the study physician may recommend additional insulin dosing according 
409 
to the participants’ usual doses or glycemic treatments prior to initiating DiAs. Study physician 
410 
may elect to cancel participant’s participation in the hotel session if concerned about their medical 
411 
safety. This participant will not be replaced but could be rescheduled for a later hotel session per 
412 
investigator determination in the event of a modifiable factor that occurs early in the hotel session 
413 
(e.g. severe migraine at the start of the hotel session).  
414 
The participant’s CIQ will be discontinued, and the DiAs will be initiated.  The study team will 
415 
ensure the proper function of the CGM and insulin pump.  
416 
The CGM used in the study is FDA-approved for the non-adjunctive measurement of blood 
417 
glucose (i.e. the CGM reading can be used for insulin dosing decisions). The CGM readings will 
418 
be the primary source of blood glucose values. There are no protocol fingerstick blood glucose 
419 
measurements other than at times of CGM calibration (if necessary) and if directed by the study 
420 
team. Fingerstick blood glucose measurements may be taken whenever participants experience 
421 
symptoms, if the CGM glucose is suspected to be erroneous, or any time the participant would like 
422 
to be reassured.  
423 
 
424 
The study physician will suggest appropriate treatment if the participant’s CGM is <80 mg/dL or 
425 
>250 mg/dL, or ketone test is >0.6 mmol/L at the start of the hotel session prior to the initiation of 
426 
DiAs. The study subject may be initiated on DiAs at the start of the hotel study once CGM is 
427 
between 80-250 mg /dL and ketone concentration is ≤0.6 mmol/L. Once DiAs is initiated, if CGM 
428 
<60 mg/dL at any time, subjects will be given approximately 8-16 grams of fast-acting rescue 
429 
carbohydrates. Study team will monitor CGM rise and will consider treating again if CGM <80 
430 
mg/dL after approximately 15-20 minutes. Hypoglycemic treatments can occur at any time per 
431 
study physician request. Glucagon will be available at the study site and will be administered in 
432 
the event of loss of consciousness or seizure related to hypoglycemia. 
433 
The study team may request fingersticks as needed. Any fingerstick readings obtained will be 
434 
addressed the same way as the CGM values.  
435 
Once DiAs is initiated, if CGM is >250 mg/dL for more than 3 hours or >400 mg/dL at any time, 
436 
study physician will be notified, and ketones will be checked. If ketone concentration is >0.6 
437 
mmol/L, the study team will notify the study physician and check the insulin pump infusion site 
438 
and correction insulin will be administered via the subject’s insulin pump or subcutaneous as 
439 
needed. If subcutaneous injection is administered, closed-loop control  will be stopped for up to 4 
440 
hours. The study team will monitor CGM changes and ketones will be checked every 60 minutes 
441 

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until ketone concentration is ≤0.6 mmol/L. Closed-loop control using DiAs will be re-initiated 
442 
once the participant’s CGM reading is <250 mg/dL and ketones are <0.6 mmol/L. If ketone 
443 
concentration is >1.0 mmol/L with significant symptoms, the study physician will recommend the 
444 
appropriate medical treatment and the participant will be withdrawn from that portion of the study 
445 
(the participant may possibly reinitiate the hotel portion of the study at a later date if a reversible 
446 
cause) 
447 
 
448 
Participants will eat dinner and breakfast during the session, with approximately the same amount 
449 
of carbohydrate, protein, and fat for Sessions 1 and 2. Snacks with carbohydrates will not be 
450 
allowed unless for the treatment of low blood sugars. Non-carbohydrates snacks may be allowed 
451 
throughout the protocol per investigator discretion. Study staff will assist with bolusing decisions 
452 
prior to all meals.  
453 
 
454 
Generally, the daily routine of the participant will follow their usual daily routine as close as 
455 
possible. Exercise will be permitted, to the extent it is typical for the participant and feasible for 
456 
study staff to remotely monitor (e.g. would not allow a run outside). 
457 
If the hotel sessions are sequential within the same hotel stay, then the system algorithm will be 
458 
changed by study staff to the second randomized condition at approximately 1 pm on the second 
459 
day and the check-in procedures in section 6.2 do not need to be repeated. The hotel activities 
460 
during the second session will be the same as the first (i.e. identical timing and content of meals, 
461 
identical timing of activities). 
462 
 
463 
Discharge will be at approximately 1 pm. Discharge criteria is CGM value between 80-250 mg/dL 
464 
with stable trend and ketones ≤0.6 mmol/L. If the CGM values are above 250 mg/dL and ketone 
465 
values are >0.6 mmol/L, the study team will check the insulin pump infusion site and correction 
466 
insulin will be administered per study physician judgement via the subject’s insulin pump. The 
467 
participant will not be able to be discharged from the study until the discharge criteria are met. The 
468 
participant’s CIQ will be reactivated and a qualified clinical study team member (e.g. MD, NP, 
469 
PA, CDCES/RN) will assess and discuss the transition back to usual care.    
470 
Participants will be asked to continue monitoring ketone levels for 24-48 hours after the hotel 
471 
session if ketones were >0.6 mmol/L within 12 hours prior to discharge. Urine ketone supplies 
472 
may be provided for this testing. All study equipment will be returned at the time of study end. 
473 
 
474 
Visit 5 
475 

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Approximately 24-48 hours after the hotel session, the study team will contact the participant via 
476 
phone/email/text to assess adverse events, adverse device effects, and device issues.  
477 

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Chapter 7  Medical Monitor Review  
478 
The Medical Monitor will review compiled safety data at the conclusion of the trial. In addition, 
479 
the Medical Monitor will review all DKA and severe hypoglycemia irrespective of relatedness to 
480 
study device use, and all serious events (including UADEs) related to study device use as soon as 
481 
possible to the time of occurrence. The Medical Monitor also will be informed of any ADEs not 
482 
meeting criteria for a UADE if the Study PI requests the Medical Monitor review. The Medical 
483 
Monitor can request modifications to the study protocol or suspension or stoppage of the study if 
484 
deemed necessary based on the totality of safety data available. Details regarding the Medical 
485 
Monitor review will be documented in a separate document.  
 
486 

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Chapter 8  Testing Procedures 
487 
 
488 
A blood sample will be obtained to obtain a baseline hemoglobin A1c level by the start of the hotel 
489 
visit. A blood test obtained within 2 weeks prior to enrollment may be used. 
490 
HbA1c level may be measured by study team using the DCA2000, or another comparable point of 
491 
care device, at time of screening or by the start of the hotel visit.  
492 
Labs may be obtained at a local laboratory (e.g. LabCorp) convenient to the participant. 
493 
 
494 
A urine pregnancy test will be required for women of childbearing potential within 24 hours prior 
495 
to initiating the experimental algorithms during the hotel stay.  Test must be negative to continue 
496 
participation in the study.  
 
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Chapter 9 Risks Associated with Clinical Trial 
498 
 
499 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are 
500 
handled to minimize this risk. Hypoglycemia, hyperglycemia, and ketone formation are always a 
501 
risk in participants with type 1 diabetes and participants will be monitored for these symptoms.  
502 
9.1.1 Venipuncture Risks 
503 
A hollow needle/plastic tube may be placed in the arm for taking blood samples (e.g. external 
504 
HbA1c measurements for inclusion criteria). Blood draws can cause some common reactions like 
505 
pain, bruising, or redness at the sampling site.  Less common reactions include bleeding, formation 
506 
of a small blood clot or swelling of the vein and surrounding tissues, and fainting. 
507 
9.1.2 Fingerstick Risks 
508 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
509 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital laboratory 
510 
tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount of bleeding 
511 
under the skin will produce a bruise. A small scar may persist for several weeks. The risk of local 
512 
infection is less than 1 in 1000. This should not be a significant contributor to risks in this study 
513 
as finger sticks are part of the usual care for people with diabetes. 
514 
9.1.3 Subcutaneous Needle Risks (CGM) 
515 
Participants using the CGM will be at low risk for developing a local skin infection at the site of 
516 
the sensor needle placement. If a needle is left under the skin for more than 24 hours, it is possible 
517 
to get an infection where it goes into the skin, with swelling, redness, and pain.  There may be 
518 
bleeding where the needle is inserted and bleeding under the skin causes a bruise (1 in 10 risk). 
519 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
520 
leave a small portion of the needle under the skin that may cause redness, swelling, or pain. The 
521 
participants will be instructed to notify the study coordinator immediately if this occurs. 
522 
9.1.4 Risks of Hypoglycemia  
523 
As with any person having type 1 diabetes and using insulin, there is a risk of having a low blood 
524 
sugar (hypoglycemia). The frequency of hypoglycemia should be no more and possibly less than 
525 
it would be as part of daily living. Symptoms of hypoglycemia can include sweating, jitteriness, 
526 
and not feeling well.  Just as at home, there is the possibility of fainting or seizures (convulsions) 
527 
and that for a few days the participant may not be as aware of symptoms of hypoglycemia. A CGM 
528 
functioning poorly and significantly over-reading glucose values could lead to inappropriate 
529 
insulin delivery. 
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9.1.5 Risks of Hyperglycemia  
531 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
532 
extended period, e.g. if the pump or infusion set is not working properly, or a CGM functioning 
533 
poorly significantly under-estimates glucose values. 
534 
9.1.6 Risks of Device Reuse  
535 
Participant will be informed that FDA or relevant national authorities have approved the insulin 
536 
pump, CGM, glucometer and ketone meter for single use and that by using them among multiple 
537 
patients, bloodborne pathogens (i.e. Hepatitis B) may be spread through the use of multiple users. 
538 
The study CGM system is labelled for single use only. The sensor (the component of the system 
539 
that enters the skin) will be single use only. The transmitter and receiver may be reused during the 
540 
study after cleaning the device using a hospital-approved cleaning procedure. The transmitter is 
541 
attached to the sensor but does not enter the skin and the receiver, if used, is a handheld device.  
542 
The study insulin pumps are labelled for single-patient use. During the study, this device may be 
543 
reused after cleaning adhering to a hospital-approved cleaning procedure. All infusion set 
544 
equipment will be single patient use only (infusion set insertion kits, tubing, cartridges etc.).   
545 
The study blood ketone meter is labelled for single-patient use. During the study, these devices 
546 
may be reused after cleaning adhering to a hospital-approved cleaning procedure.   
547 
9.1.7 Device Cleaning Instructions 
548 
CGM cleaning instructions are provided in the Dexcom G4 Platinum (Professional) Cleaning and 
549 
Disinfection manual (current edition) and a similar approach will be applied for the G6 version 
550 
used in this study. The transmitter should be cleaned with Clorox Healthcare® Bleach Germicidal 
551 
Cleaner or any disinfectant product in a spray bottle containing a bleach solution of 6500 parts per 
552 
million with the EPA registration number 56392-7. The transmitter will be submerged in this 
553 
solution and then placed on an absorbent wipe or clean surface. Two sprays will be dispensed from 
554 
the Clorox cleaner onto each side of the transmitter. A nylon brush will be used to scrub the 
555 
transmitter on all sides for 30 seconds. The transmitter will be placed in the Clorox Cleaner 
556 
solution for one minute. Transmitter is then rinsed under flowing tap water for ten seconds. The 
557 
transmitter will then be disinfected using a disinfectant product with EPA registration number 
558 
56392-7 using similar procedures as the cleaning process.   
559 
Per the pump manufacturer, the insulin pump will be cleaned with a damp lint-free cloth. Use of 
560 
household or industrial cleaners, solvents, bleach, scouring pads, chemicals, or sharp instruments 
561 
are prohibited. The pump should never be submerged in water. If needed, use only a very mild 
562 
detergent, such as a bit of liquid soap with warm water. A soft towel will be used to dry the pump.  
563 

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The glucometer is cleaned and disinfected with two separate Super Sani-Cloths (EPA number 
564 
9480-4). The entire surface will be cleaned, making sure the surface stays wet for 2 minutes. This 
565 
step is repeated with a clean cloth for disinfecting the device.  
566 
The Precision Xtra User’s Guide suggests that healthcare professionals use 10% bleach, 70% 
567 
alcohol or 10% ammonia to clean the device.  
568 
Equipment that touches intact skin will be cleaned with ethyl or isopropyl alcohol (70-90%), 
569 
quaternary ammonium germicidal detergent (i.e. Cavicide, EPA number 46781) or household 
570 
bleach. The contact time on the surface depends on the method used to clean the equipment. 
571 
Cavicide requires three minutes on the surface of the equipment. Clorox Germicidal Bleach Wipes 
572 
require two minutes on the equipment. The surface should remain wet (i.e. slightly damp) with the 
573 
disinfectant to be considered effective though not wet enough to leave drops of liquid.  
574 
In the event a manufacturer updates cleaning procedures for their device, the study team will 
575 
adhere to the most current recommendations.  
576 
There is the risk of blood sampling collection and contamination from sampling techniques. Hand 
577 
washing with either soap & water or waterless hand sanitizer will be used prior to caring for the 
578 
study subject. Gloves will be worn during blood sample collection and processing. Medical 
579 
personnel will continue to practice hygiene for the subject’s protection (i.e. hand washing, 
580 
changing gloves frequently, disposing needles properly). Gloves will be removed, and hands 
581 
washed or sanitized prior to leaving and upon return to the subject’s room. Soiled linen will be 
582 
changed to minimize the transfer of pathogenic organisms. 
583 
9.1.8 Risk of Exercise 
584 
While there are risks associated with physical activity, during the trial the participants will engage 
585 
only in activities that are typical for them. No extra risks are added by the study protocol.  
586 
9.1.9 Other Risks  
587 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
588 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
589 
If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, 
590 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
591 
medication may be required. 
592 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump infusion 
593 
sites are inserted under the skin.  It is possible that any part that is inserted under the skin may 
594 
cause an infection.  These occur very infrequently, but, if an infection was to occur, oral and/or 
595 
topical antibiotics can be used.  The risk of skin problems could be greater if a sensor is used for 
596 
longer than it is supposed to be used. Therefore, participants will be carefully instructed about 
597 
proper use of the sensor. 
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Data downloaded from the CGM, pump, glucometer, and ketone meter will be collected for the 
599 
study as measures of diabetes self-management behaviors. Some people may be uncomfortable 
600 
with the researchers' having such detailed information about their daily diabetes habits. 
601 
9.1.10 Known Potential Benefits  
602 
It is expected that this protocol will yield increased knowledge about using a new neural-net based 
603 
automated closed-loop system to control glucose levels. The individual participant may not benefit 
604 
from study participation. 
605 
9.1.11 Risk Assessment 
606 
The risk to participants in this study are no higher than the risks associated with type 1 diabetes 
607 
and the use of CIQ under normal outpatient conditions. This assessment is based on the following 
608 
facts: (1) adults with diabetes experience mild hypoglycemia and hyperglycemia frequently as a 
609 
consequence of the disease and its management, (2) the study intervention involves automated 
610 
insulin dosing that may increase the likelihood of hypoglycemia, and automated attenuation of 
611 
insulin delivery that may increase the likelihood of hyperglycemia, (3) however, mitigations are 
612 
in place that limit the likelihood of excessive insulin dosing or prolonged withdrawal of insulin, 
613 
and (4) rapid reversal of hypoglycemia and hyperglycemia can be achieved. 
614 
 
615 
The study is being conducted in compliance with the policies described in the study policies 
616 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
617 
protocol described herein, and with the standards of Good Clinical Practice (GCP). 
618 
Whenever possible, data will be directly collected in electronic case report forms, which will be 
619 
considered the source data. 
620 
The protocol is considered a significant risk device study, due to the fact that the NAP and UMPC 
621 
systems are experimental. Therefore, an investigational device exemption (IDE) from the U.S. 
622 
Food and Drug Administration (FDA) is required to conduct the study. 
623 
The study team will adhere to any CDC and local guidelines in effect at the time of the study. 
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Chapter 10 Adverse Events, Device Issues, and Stopping Rules 
625 
 
626 
10.1.1 Adverse Events (AE) 
627 
Any untoward medical occurrence in a study participant, irrespective of the relationship between 
628 
the adverse event and the device(s) under investigation (section 10.2) for reportable adverse events 
629 
for this protocol). 
630 
Positive pregnancy test will not be considered an adverse event.  
631 
10.1.2 Serious Adverse Event (SAE) 
632 
 Any untoward medical occurrence that: 
633 
• Results in death. 
634 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
635 
have become life-threatening, is not necessarily considered a serious adverse event). 
636 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
637 
• Results in persistent or significant disability/incapacity or substantial disruption of the 
638 
ability to conduct normal life functions (life threatening). 
639 
• Is a congenital anomaly or birth defect. 
640 
• Is considered a significant medical event by the investigator based on medical judgment 
641 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
642 
prevent one of the outcomes listed above). 
643 
10.1.3 Unanticipated Adverse Device Effect (UADE) 
644 
Any serious adverse effect on health or safety or any life-threatening problem or death caused by, 
645 
or associated with, a device, if that effect, problem, or death was not previously identified in nature, 
646 
severity, or degree of incidence in the investigational plan or application (including a 
647 
supplementary plan or application), or any other unanticipated serious problem associated with a 
648 
device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
649 
10.1.4 Adverse Device Effect (ADE) 
650 
Any untoward medical occurrence in a study participant which the device may have caused or to 
651 
which the device may have contributed. 
652 
10.1.5 Device Complaints and Malfunctions 
653 
A device complication or complaint is something that happens to a device or related to device 
654 
performance, whereas an adverse event happens to a participant. A device complaint may occur 
655 
independently from an AE, or along with an AE. An AE may occur without a device complaint or 
656 
there may be an AE related to a device complaint.  A device malfunction is any failure of a device 
657 

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to meet its performance specifications or otherwise work as intended.  Performance specifications 
658 
include all claims made in the labelling for the device.  The intended performance of a device 
659 
refers to the intended use for which the device is labelled or marketed. (21 CFR 803.3).   
660 
 
661 
For this protocol, a reportable adverse event includes any untoward medical occurrence that meets 
662 
one of the following criteria: 
663 
• A SAE, as defined in section 10.1.2 
664 
• An ADE, as defined in section 10.1.4, unless excluded from reporting in section 10.7 
665 
• An AE, as defined in section 10.1.1 occurring in association with a study procedure 
666 
• An AE, as defined in section 10.1.1 which leads to discontinuation of a study device 
667 
for 2 or more hours 
668 
• Hypoglycemia meeting the definition of severe hypoglycemia as defined in section 
669 
10.2.1  
670 
• DKA, as defined in section 10.2.2 or in the absence of DKA, a hyperglycemic or ketosis 
671 
event meeting the criteria below 
672 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
673 
events unless associated with an ADE. Skin reactions from sensor placement are only reportable 
674 
if severe and/or requiring treatment. 
675 
10.2.1 Hypoglycemia Event 
676 
Hypoglycemia not associated with an ADE is only reportable as an AE when the following 
677 
definition for severe hypoglycemia is met:   
678 
• The event required assistance of another person due to altered consciousness, and 
679 
required another person to actively administer carbohydrate, glucagon, or other 
680 
resuscitative actions 
681 
• Impaired cognitively to the point that he/she was unable to treat himself/herself, was 
682 
unable to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or 
683 
experienced seizure or coma. These episodes may be associated with sufficient 
684 
neuroglycopenia to induce seizure or coma 
685 
• If plasma glucose measurements are not available during such an event, neurological 
686 
recovery attributable to the restoration of plasma glucose to normal is considered 
687 
sufficient evidence that the event was induced by a low plasma glucose concentration 
688 
10.2.2 Hyperglycemia Events/Diabetes Ketoacidosis 
689 
Hyperglycemia not associated with an ADE is only reportable as an AE when one of the following 
690 
criteria is met:  
691 
• The event involved DKA, as defined by the DCCT and described below  
692 

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• Treatment was obtained at a health care provider facility for an acute event involving 
693 
hyperglycemia or ketosis 
694 
Blood ketone level ≥1.0 mmol/L at any time during the study Hyperglycemic events are classified 
695 
as DKA if the following are present: 
696 
• Symptoms such as polyuria, polydipsia, nausea, or vomiting 
697 
• Serum ketones ≥1.5 mmol/L or large/moderate urine ketones 
698 
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15 
699 
• Treatment provided in a health care facility 
700 
All reportable AEs—whether volunteered by the participant, discovered by study personnel during 
701 
questioning, or detected through physical examination, laboratory test, or other means—will be 
702 
reported on an AE form online.  Each AE form is reviewed by the study investigator to verify the 
703 
coding and the reporting that is required. 
704 
 
705 
The study investigator will assess whether any AE is related or unrelated by determining if there 
706 
is a reasonable possibility that the adverse event may have been caused by the study device. 
707 
To ensure consistency of adverse event causality assessments, investigators should apply the 
708 
following general guideline when determining whether an adverse event is: 
709 
• Related: There is a plausible temporal relationship between the onset of the adverse 
710 
event and the study intervention, and the adverse event cannot be readily explained by 
711 
the participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
712 
adverse event follows a known pattern of response to the study intervention; and/or the 
713 
adverse event abates or resolves upon discontinuation of the study intervention or dose 
714 
reduction and, if applicable, reappears upon rechallenge. 
715 
• Unrelated: Evidence exists that the adverse event has an etiology other than the study 
716 
intervention (e.g., pre-existing medical condition, underlying disease, intercurrent 
717 
illness, or concomitant medication); and/or the adverse event has no plausible temporal 
718 
relationship to study intervention. 
719 
 
720 
The intensity of an AE will be rated on a three-point scale: (1) mild, (2) moderate, or (3) severe. It 
721 
is emphasized that the term severe is a measure of intensity: thus, a severe AE is not necessarily 
722 
serious. For example, itching for several days may be severe, but may not be clinically serious. 
723 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
724 
participant’s daily activities. 
725 

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• MODERATE: Usually causes a low level of inconvenience or concern to the 
726 
participant and may interfere with daily activities but is ameliorated by simple 
727 
therapeutic measures. 
728 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires 
729 
systemic drug therapy or other treatment. 
730 
 
731 
AEs will be coded per the UVA IRB website instructions (i.e. mild, moderate, severe).  AEs that 
732 
continue after the participant’s discontinuation or completion of the study will be followed until 
733 
their medical outcome is determined or until no further change in the condition is expected. 
734 
 
735 
The outcome of each reportable AE will be classified by the investigator as follows: 
736 
• RECOVERED/RESOLVED – The participant recovered from the AE/SAE without 
737 
sequelae.  Record the AE/SAE stop date. 
738 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had 
739 
stabilized without change in the event anticipated.  Record the AE/SAE stop date. 
740 
• FATAL – A fatal outcome is defined as SAE resulting in death. Only the event that 
741 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing prior 
742 
to death, however, were not the cause of death, will be recorded as “resolved” at the 
743 
time of death. 
744 
• NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is 
745 
defined as the event was ongoing with an undetermined outcome. 
746 
• An ongoing outcome will require follow-up by the site in order to determine the final 
747 
outcome of the AE/SAE. 
748 
• The outcome of an ongoing event at the time of death that was not the cause of death, 
749 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
750 
date. 
751 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant 
752 
or the participant’s records to determine outcome (e.g., a participant lost to follow-up). 
753 
All clinically significant abnormalities of clinical laboratory measurements or AEs occurring 
754 
during the study and continuing at study termination should be followed by the participant’s 
755 
physician and evaluated with additional tests (if necessary) until diagnosis of the underlying cause, 
756 
or resolution. Follow-up information should be recorded on source documents. 
757 
If any reported AEs are present when a participant completes the study, or if a participant is 
758 
withdrawn from the study due to an AE, the participant will be contacted for re-evaluation within 
759 
2 weeks.  If the AE has not resolved, additional follow-up will be performed as appropriate.  Every 
760 
effort should be made to contact the participant until the AE has resolved or stabilized. 
761 

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762 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
763 
whether an AE occurred, except in the following circumstances. 
764 
The following device issues are anticipated and will not be reported but will be reported as an AE 
765 
if the criteria for AE reporting described above are met: 
766 
• Component disconnections 
767 
• CGM sensors lasting fewer than the number of days expected per CGM labelling 
768 
• CGM tape adherence issues 
769 
• Pump infusion set occlusion not leading to ketosis 
770 
• Battery lifespan deficiency due to inadequate charging or extensive wireless 
771 
communication 
772 
• Intermittent device component disconnections/communication failures not leading to 
773 
system replacement 
774 
• Device issues clearly addressed in the user guide manual that do not require additional 
775 
troubleshooting 
776 
• Skin reactions from CGM sensor placement or pump infusion set placement that do not 
777 
meet criteria for AE reporting. 
778 
 
779 
• UADEs must be reported within 10 working days to the FDA after the sponsor first 
780 
receives notice of the adverse effect. 
781 
• Other reportable AEs, device malfunctions (with or without an AE) and device 
782 
complaints should be reported promptly, but there is no formal required reporting 
783 
period. 
784 
• The IDE Sponsor will investigate the UADE and if indicated, report the results of the 
785 
investigation to the Medical Monitor, IRBs, and FDA within 10 working days of the 
786 
study team becoming aware of the UADE per 21CFR 812.46(b) (2).  
787 
• The Medical Monitor will determine if the UADE presents an unreasonable risk to 
788 
participants. If so, the Sponsor must ensure that all investigations, or parts of 
789 
investigations presenting that risk, are terminated as soon as possible but no later than 
790 
5 working days after the Medical Monitor makes this determination and no later than 
791 
15 working days after first receipt notice of the UADE. 
792 
• In the case of a device system component malfunction (e.g. pump, CGM, control 
793 
algorithm), information will be forwarded to the responsible manufacturer by the study 
794 
personnel. 
795 

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796 
10.9.1 Participant Discontinuation  
797 
Rules for discontinuing investigational device use are described below. 
798 
• The investigator believes it is unsafe for the participant to continue the intervention.  
799 
This could be due to the development of a new medical condition or worsening of an 
800 
existing condition; or participant behavior contrary to the indications for use of the 
801 
device that imposes on the participant’s safety. 
802 
• The participant requests that the treatment be stopped. 
803 
• The participant tests positive for COVID-19 within 14 days of a hotel session. 
804 
• Any diagnosis of DKA meeting the definition in section 10.2.2 of the protocol.  
805 
• Any severe hypoglycemia event meeting the definition in section 10.2.1 of the protocol. 
806 
• Any ketone level >1.0 mmol/L with significant symptoms (e.g. nausea, vomiting, 
807 
abdominal pain). The participant may be studied at a later date if due to a reversible 
808 
cause (e.g. infusion site failure) 
809 
10.9.2 Suspending/Stopping Overall Study 
810 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
811 
hyperglycemia event (as defined in section 10.2.2), use of the study device system will be 
812 
suspended while the problem is diagnosed. 
813 
In the event that two distinct episodes of DKA, two distinct severe hypoglycemia events, or one 
814 
distinct DKA episode and one distinct severe hypoglycemia episode, as defined in section 10.2 
815 
occur, the overall study would be suspended while the underlying conditions are determined.   
816 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
817 
study device requires stoppage of device use for safety reasons (e.g. product recall). The affected 
818 
study activities may resume if the underlying problem can be corrected by a protocol or system 
819 
modification that will not invalidate the results obtained prior to suspension. The Medical Monitor 
820 
may request suspension of study activities or stoppage of the study if deemed necessary based on 
821 
the safety data available. 
822 
 
823 
Detailed in Chapter 7.  
824 
 
825 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, 
826 
access, or use of protected health information (PHI) that compromises the security or privacy of 
827 
such information.  
828 
 
 
829 

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Chapter 11 Miscellaneous Considerations  
830 
 
831 
Participants using insulins other than lispro and aspart at the time of enrollment will be asked to 
832 
contact their personal physician to change their prescribed personal insulin to lispro or aspart for 
833 
the hotel sessions of the trial. 
834 
The study devices (study insulin pump, study CGM) must be removed before Magnetic Resonance 
835 
Imaging (MRI), Computed Tomography (CT) or diathermy treatment. Participants may continue 
836 
in the trial after temporarily discontinuing use if requiring one of the treatments above. 
837 
 
838 
Participation in the study is voluntary. Participant may withdraw at any time.  For participants who 
839 
do withdraw from the study, the study team will determine if their data will be used in analysis.  
840 
 
841 
For security and confidentiality purposes, subjects will be assigned an identifier that will be used 
842 
instead of their name.  De-identified subject information may also be provided to collaborators 
843 
involved in the study after the appropriate research agreement has been executed. 
 
844 

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Chapter 12 Statistical Consideration 
845 
 
846 
This is an early study intending to pilot test the safety and feasibility of a NAP implementation of 
847 
an established AP controller – UMPC – in a crossover design (Figure 1).  
848 
The randomization list will use a sequence of computer-generated pseudorandom Bernoulli trials 
849 
and will aim to balance age/gender and match groups by baseline HbA1c. The two groups will 
850 
follow two different sequences of AID approaches: NAP followed by UMPC or UMPC followed 
851 
by NAP.   
852 
 
853 
We use pilot trials to introduce new technologies, test system component interoperability, and 
854 
support regulatory approval of larger subsequent studies. Depending on the traceability of the 
855 
system to previous established technology or components, the pilots can range from a small 5-
856 
person 3-day trial, such as the one we used to enable the pivotal trial of Control-IQ,11 to a multi-
857 
center test of pump configurations.12 In this study, NAP is directly traceable to UMPC in terms of 
858 
its functionality; however, its implementation is qualitatively new. Thus, based on our experience, 
859 
we estimate that the completion of N=15 (and recruitment of up to 20) CIQ users who will test 
860 
NAP vs UMPC during two 18-hour hotel sessions, will be feasible, in terms of first regulatory 
861 
approval, and sufficient to test the translation of the existing UMPC into neural-net framework.   
862 
 
863 
The main purpose of this trial is initial system testing and receiving feedback form the participants 
864 
regarding system functionality. Thus, we will observe, record, and tabulate any NAP errors that 
865 
would inform us whether system fixes would be needed prior to deployment in a subsequent larger 
866 
study. We will tabulate technical performance metrics including: 
867 
• Malfunctions requiring study team contact and other reported device issues; 
868 
• Percent time in closed-loop and any other relevant operational modes; 
869 
• Rate of relevant NAP and UMPC failure events and alarms per 24 hours; 
870 
In addition, descriptive glycemic analyses for certain efficacy measures recommended by a review 
871 
written by the sponsor of this study13 and by the International Consensus on Time-in-Range (TIR), 
872 
to which we contributed,14 will be tabulated for each subject based on CGM data, including: 
873 
• TIR, 70-180 mg/dL (primary outcome) 
874 
• percentage of readings in other ranges, including TBR, TAR, and 70-140 mg/dl; 
875 
• mean glucose; glucose variability measured by coefficient of variation;  
876 
• percentage of readings <54 mg/dl (i.e., level 2 hypoglycemia14) 
877 
• percentage of readings >250 and >300 mg/dl (i.e., level 2 hyperglycemia14) 
878 

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The technical performance, errors, and glycemic analyses will be also split by time of the day: 
879 
daytime vs. night-time. 
880 
 
881 
The success criteria will include no critical system errors and the following performance criteria, 
882 
which factor in likely inter-day variability for each participant and are consistent with the 
883 
recommendations of the International Consensus on TIR:   
884 
• Difference in TIR between NAP and UMPC < 8 percentage points; 
885 
• Difference in TBR between NAP and UMPC < 3 percentage points; 
886 
• Difference in TAR between NAP and UMPC < 8 percentage points; 
887 
Formal power analysis is not applicable to this pilot study – 5-percent noninferiority hypothesis of 
888 
NAP vs UMPC will be tested, but with this sample size a statistically significant result is not 
889 
expected. The point of the study is to show feasibility of a neural-net implementation of an 
890 
automated insulin delivery algorithm which, if shown, will open possibilities for control strategies 
891 
based on machine-learning and artificial intelligence methods.  
892 
 
893 
• Saturated CGM values “High” and “Low” will be replaced by 401mg/dL and 39mg/dL 
894 
respectively.  
895 
• CGM data during recorded occlusion event will be removed from analysis as follows: 
896 
any measurement less than 2h before or after the time of record will be removed. 
897 
• CGM data following a pump/DiAs communication interruption >1h but less than 2h 
898 
will be removed. 
899 
 
900 
We will assess NAP functionality, including the ability of the system to run its code without error 
901 
(deliver insulin safely, as planned), as well as its ability to avoid hypo- and hyperglycemia. 
902 
Participants feedback will be informal, in the format of contrasting their experience with the 
903 
commercial CIQ vs. the experimental NAP and UMPC.  
904 
 
905 
Baseline demographic and clinical characteristics of the cohort of all randomized participants will 
906 
be summarized in a table using summary statistics appropriate to the distribution of each variable. 
907 
The following descriptive statistics will be displayed overall and by treatment group: 
908 
• Age 
909 
• HbA1c 
910 
• Gender 
911 
• Race/ethnicity 
912 
• Diabetes duration 
913 

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• BMI 
914 
• Total Daily Insulin 
 
915 

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Chapter 13  Data Collection and Monitoring 
916 
 
917 
Data is collected through a combination of case report forms (electronic and paper) and electronic 
918 
device data files obtained from the software and individual hardware components. These electronic 
919 
device files and electronic CRFs are considered the primary source documentation. Records will 
920 
be maintained in accordance with ICH E6 and institutional regulatory requirements for the 
921 
protection of confidentiality of participants. 
922 
 
923 
Study documents should be retained for a minimum of 6 years after the study completion, or until 
924 
at least 2 years have elapsed since the formal discontinuation of development of the investigational 
925 
product. Documents should be retained for a longer period, if required by local regulations. No 
926 
records will be destroyed without the written consent of the sponsor. It is the responsibility of the 
927 
sponsor to inform the investigator when these documents no longer need to be retained. 
928 
 
929 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
930 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
931 
the study staff. In response to protocol deviations, corrective actions may be required and 
932 
implemented as appropriate. Major deviations will be reported to the IRB within 7 calendar days 
933 
of when the study team becomes aware of the event.  
 
934 

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Chapter 14  Ethics/Protection of Human Participants 
935 
 
936 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
937 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
938 
CFR Part 56, and/or the ICH E6. 
939 
 
940 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
941 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
942 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
943 
require review and approval by the IRB before the changes are implemented to the study.  All 
944 
changes to the consent form will be IRB approved; a determination will be made regarding whether 
945 
previously consented participants need to be re-consented. 
946 
 
947 
14.3.1 Consent Procedures and Documentation 
948 
Informed consent is a process that is initiated prior to an individual’s agreement to participate in 
949 
the study and continues throughout the individual’s study participation. Consent forms will be IRB 
950 
approved, and the participant will be asked to read and review the document. The investigator or 
951 
delegate will explain the study to the participant and answer any questions that may arise. All 
952 
participants will receive verbal explanation in terms suited to their comprehension of the purposes, 
953 
procedures, and potential risks of the study and of their rights as research participants. Extensive 
954 
discussion of risks and possible benefits of participation will be provided. The participant will sign 
955 
the informed consent document prior to any procedures being done specifically for the study.  
956 
The potential participant will be provided a short overview of the study including its study goals, 
957 
study procedures, and study timeline. If the potential participant remains interested, they will be 
958 
asked permission to review inclusion/exclusion criteria to assess if they are eligible to participate 
959 
in the study. If permission is granted, the study team will review the Inclusion/Exclusion 
960 
Questionnaire. If eligible, the study team member will provide a copy of the informed consent 
961 
form (e.g. in person, email, fax, or mail) to the potential participant for their review. Potential 
962 
participants may also elect to review the informed consent form prior to discussing pre-screening 
963 
questions.  
964 
The consenting process will involve discussing the study at length in a phone call/HIPAA 
965 
compliant telecommunication method for consenting that is not face to face. The potential 
966 
participant will be given an opportunity to ask the study team questions or may speak directly with 
967 
the study physician. The potential participant’s understanding of the information, presented in the 
968 
process of consent will be assessed by asking open-ended questions.  
969 

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The consent form may be signed electronically with the use of the Part 11 compliant version of 
970 
DocuSign for both in-person and telecommunication screening visits. Note: For potential 
971 
participants who are not able to use DocuSign, email, fax, or mail will be an option for receipt of 
972 
the signed consent. A HIPAA compliant video conferencing tool will be utilized during the 
973 
consenting process of the telecommunication screening visit to facilitate the FDA part 11 
974 
compliant process of verification of reviewing two forms of identification if signing electronically 
975 
off site. A copy of the informed consent document will be given to the participant for their records. 
976 
Study procedures may begin once the consent has been signed by the participant and a member of 
977 
the study team.  
978 
The rights and welfare of the participants will be protected by emphasizing to them that the quality 
979 
of their medical care will not be adversely affected if they decline to participate in this study. 
980 
 Participant
981 
The study monitor, representatives of the IRB or device company supplying study product may 
982 
inspect all documents and records required to be maintained by the investigator, including but not 
983 
limited to, medical records (office, clinic, or hospital) for the participants in this study.   
984 
The study participant’s contact information will be securely stored at the clinical site for internal 
985 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
986 
for as long a period as dictated by local IRB and Institutional regulations. 
987 
Participants’ research data, which is for the purposes of statistical analysis and scientific reporting, 
988 
will be transmitted to and stored at the UVA CDT. The study data entry and study management 
989 
systems used by research staff will be secured and password protected.  At the end of the study, 
990 
all study databases may be de-identified and archived at the UVA CDT. 
 
991 

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Chapter 15 References  
992 
1. 
https://www.nih.gov/about-nih/nih-wide-strategic-plan 
993 
2. 
Kovatchev BP, Patek SD, Dassau E, Doyle FJ III, Magni L, De Nicolao G, Cobelli C. 
994 
Control-to-range for diabetes: functionality and modular architecture. J Diabetes Sci 
995 
Technol. 2009; 3: 1058-1065. PMCID: PMC2769910 
996 
3. 
Hughes CS, Patek SD, Breton MD, Kovatchev BP. Hypoglycemia prevention via pump 
997 
attenuation and red-yellow-green “traffic” lights using continuous glucose monitoring 
998 
and insulin pump data. J Diabetes Sci Technol. 2010; 4: 1146-1155. PMCID: 
999 
PMC2956822 
1000 
4. 
Patek SD, Magni L, Dassau E, Karvetski CH, Toffanin C, DeNicolao G, Del Favero S, 
1001 
Breton M, Dalla Man C, Renard E, Zisser H, Doyle FJ III, Cobelli C, Kovatchev BP. 
1002 
Modular closed-loop control of diabetes. Transactions on Biomedical Engineering. 2012; 
1003 
29: 2986-99. PMCID: PMC4607512 
1004 
5. 
Keith Hynes P, Guerlain S, Mize LB, Hughes Karvetski C, Khan M, McElwee Malloy M, 
1005 
Kovatchev BP. DiAs user interface: a patient-centric interface for mobile artificial 
1006 
pancreas systems. J Diabetes Sci Technol. 2013; 7: 1416–1426. PMCID: PMC3876320 
1007 
6. 
Brown SA, Kovatchev BP, Raghinaru D, et al, for the iDCL Trial Research Group. 6-
1008 
month randomized multicenter trial of closed-loop control in type 1 diabetes. N Engl J 
1009 
Med. 2019; 381: 1707-17. PMID: 31618560 PMCID: PMC7076915 
1010 
7. 
Breton MD, Kanapka LG, Beck RW, et al, for the iDCL Trial Research Group. A 
1011 
Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes. N Engl J 
1012 
Med. 2020; 383:836-845. PMID: 32846062; PMCID: PMC7920146. 
1013 
8. 
U.S. Food & Drug Administration: FDA authorizes first interoperable, automated insulin 
1014 
dosing controller designed to allow more choices for patients looking to customize their 
1015 
individual diabetes management device system. https://www.fda.gov/news-events/press-
1016 
announcements/fda-authorizes-first-interoperable-automated-insulin-dosing-controller-
1017 
designed-allow-more-choices.  
1018 
9. 
Garcia-Tirado J, Diaz JL, Esquivel-Zuniga R, Koravi CLK, Corbett JP, Dawson M, 
1019 
Wakeman C, Barnett CL, Oliveri MC, Myers H, Krauthause K, Breton MD, DeBoer MD. 
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Advanced Closed-Loop Control System Improves Postprandial Glycemic Control 
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Compared With a Hybrid Closed-Loop System Following Unannounced Meal. Diabetes 
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Care. 2021 Aug 15:dc210932. doi: 10.2337/dc21-0932. Epub ahead of print. PMID: 
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Lobo B, Farhy L, Shafiei M, Kovatchev B. A data-driven approach to classifying daily 
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continuous glucose monitoring (CGM) time series. IEEE Trans Biomed Eng. 2021 Aug 
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Brown S, Raghinaru D, Emory E, Kovatchev BP. First look at control-IQ: a new-
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dc181249, PMID: 30305346; PMCID: PMC6245207 
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12. 
Anderson SM, Dassau E, Raghinaru D, Lum J, Brown SA, Pinsker JE, Church MM, 
1031 
Levy C, Lam D, Kudva YC, Buckingham B, Forlenza GP, Wadwa RP, Laffel L, Doyle 
1032 
FJ 3rd, DeVries JH, Renard E, Cobelli C, Boscari F, Del Favero S, Kovatchev BP. The 
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international diabetes closed-loop study: testing artificial pancreas component 
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interoperability. Diabetes Technol Ther. 2019; 21: 73-80. PMCID: PMC6354594 
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Kovatchev BP. Metrics for glycaemic control: from HbA1c to continuous glucose 
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monitoring. Nature Reviews Endocrinology. 2017; 13: 425-436. PMID: 28304392 
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14. 
Battelino T, Danne T, Bergenstal RM, Amiel SA, et al. for the International Time-in-
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Range Consensus. Clinical targets for continuous glucose monitoring data interpretation: 
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recommendations from the international consensus on time in range. Diabetes Care. 
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2019; 42: 1593-1603. PMID: 31177185.  
1041 
15. 
IDE #G110095: Feasibility study of closed loop control in type 1 diabetes using heart rate 
1042 
monitoring as an exercise marker, approved 10/08/2011. 
1043 
16. 
IDE #G120032: Early feasibility (pilot) study of outpatient control-to-range; 3/2/2012. 
1044 
17. 
IDE #G120210: Early feasibility study 2 of outpatient control-to-range; 10/12/2012. 
1045 
18. 
IDE #G130118: DiAs control-to-range nocturnal closed-loop camp study; 6/19/2013. 
1046 
19. 
IDE #G130121: Optimizing closed-loop control of type 1 diabetes mellitus in 
1047 
adolescents; 6/19/2013; 05/01/13. 
1048 
20. 
IDE# G130142: Closed loop control in adolescents using heart rate as exercise indicator; 
1049 
7/16/2013. 
1050 
21. 
IDE #G130143: Early feasibility study of adaptive advisory/automated (AAA) control of  
1051 
type 1 diabetes; 7/19/2013. 
1052 
22. 
IDE #G140066: Full day and night closed-loop with DiAs platform; 5/9/2014. 
1053 
23. 
IDE #G140068: Unified Safety System (USS) Virginia Closed Loop versus sensor 
1054 
augmented pump therapy overnight in type 1 diabetes; 5/14/2014. 
1055 
24. 
IDE #G140119: Outpatient control-to-range: Safety and efficacy with day-and-night in-
1056 
home use; 6/6/2014. 
1057 
25. 
IDE #G140169: Unified Safety System (USS) Virginia Closed-Loop versus Sensor 
1058 
Augmented Pump (SAP) therapy for hypoglycemia reduction in type 1 diabetes; 
1059 
10/3/2014. 
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26. 
IDE #G150221: Reducing risks and improving glucose control during extended exercise 
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in youth with T1DM: The AP Ski Camp; 11/09/2015. 
1062 
27. 
IDE #G150240: Project Nightlight: Efficacy and system acceptance of dinner/night vs. 24 
1063 
hr closed loop control; 11/12/2015. 
1064 
28. 
IDE #G160047: Closed-loop in young children 5-8 years old using DiAs platform; 
1065 
03/29/2016. 
1066 
29. 
IDE #G160097: Clinical Acceptance of the Artificial Pancreas: the International Diabetes 
1067 
Closed-Loop (iDCL) Trial/Research Site Training Protocol; 06/03/2016. 
1068 
30. 
IDE#G160181: PROTOCOL 1 for “Clinical Acceptance of the Artificial Pancreas: The 
1069 
International Diabetes Closed Loop (iDCL) Trial; 09/21/2017. 
1070 
31. 
IDE#G170255: Protocol 3 for “Pilot Trial of t:slim X2 with Control-IQ 
1071 
Technology”;11/16/17 and IDE#G170255/S001 Protocol 3 for “Training Study of t:slim 
1072 
X2 with Control-IQ Technology”; 11/16/2017. 
1073 
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IDE#G170267 : “Real-Time Monitoring and Glucose Control During Winter-Sport 
1074 
Exercise in Youth with Type 1 Diabetes: The AP Ski Camp Continued”; Three 48-hour 
1075 
winter ski camps trial T1D participants; one site enrolled 13-18 years old participants in 
1076 
January 2018. The other two sites enrolled participants aged 6-12 years old. At the 
1077 
conclusion of these ski camps, subjects continued with the study device for 72 hours use 
1078 
at home; 11/21/17 & 01/10/18. 
1079 
33. 
IDE#150240/S008: Project Nightlight: Efficacy and system acceptance of dinner/night 
1080 
vs. 24 hr closed loop control (Tandem t:slim insulin pump with Control-IQ Technology); 
1081 
02/02/2018. 
1082 
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IDE#G180279: “Safety and Efficacy of Initializing the Control-IQ Artificial Pancreas 
1083 
System Using Total Daily Insulin.” A safety and efficacy of using the Control-IQ 
1084 
artificial pancreas system using MyTDI in a randomized controlled trial; 12/19/2018. 
1085 
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IDE#G190205: “Safety of the Tandem t:slim X2 with Control-IQ Automated Insulin 
1086 
Delivery System in Preschoolers, age 2-6 Years Old”; 09/06/2019. 
1087 
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IDE#G190250: “SGLT2 Inhibitor Adjunctive Therapy to Closed Loop Control in Type 1 
1088 
Diabetes”; 10/02/2019. 
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Kovatchev BP, Singh H, Mueller L, Gonder-Frederick LA. Biobehavioral Changes 
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Following Transition to Automated Insulin Delivery: A Large Real-life Database 
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36126177. 
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IDE # G200206: Fully Automated Closed Loop Control in Adolescents with Type 1 
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Diabetes (RocketAP). 08/20/2020. 
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39. 
IDE#210051: “Diabetes Closed-Loop Project 6 (DCLP6): Fully Automated Closed-Loop 
1096 
Control in Type 1 Diabetes Using Meal Anticipation”, 03/18/2021.  
1097 
40. 
IDE#220204: “Evaluation of The Postprandial Impact of Automated Priming Bolus for 
1098 
Full Closed Loop Insulin Delivery”, 08/29/2022.  
1099