Adaptive Biobehavioral Control (ABC) of Automated Insulin Delivery: A Randomized, Controlled Pilot Study
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Sponsor: University of Virginia

UVA CENTER FOR DIABETES TECHNOLOGY 
Adaptive Biobehavioral Control (ABC) of 
Automated Insulin Delivery: A Randomized, 
Controlled Pilot Study 
NCT04784637
Version Number: v1.3 
30-Jun-2021

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

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PROTOCOL VERSION HISTORY 
Version 
Number 
Author(s) 
Approver 
Effective Date Revision Description 
1.0 
Jon Olson,  
Mary Oliveri 
Sue Brown 
17-Nov-2020 
Original Protocol 
1.1 
Jon Olson 
 
Mary Oliveri 
20-Nov-2020 
FDA modifications 
• 
Added “Participants will be 
notified that eA1c is for 
informational purposes only 
and not to be used for short-
term changes to insulin 
settings (section 5.3).   
• 
Modified 
study 
stopping 
criteria to include three 
severe hypoglycemia events 
or three DKA events (section 
9.9.2) 
1.2 
Jon Olson 
Sue Brown 
11-Jan-2020 
IRB Pre-Review 
• 
Corrected visit numbering 
(section 6.7) 
1.3 
Mary Oliveri 
Sue Brown 
30-Jun-2021 
Study Team 
• Modified use of personal CGM 
equipment (Section 3.2 & 5.1) 
• Added 
Participant 
Compliance 
definitions (section 6.5) 
 
 

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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title:  Adaptive Biobehavioral Control (ABC) of Automated Insulin Delivery: A 
Randomized, Controlled Pilot Study 
 
Protocol Version/Date: v1.3/30-Jun-2021I have read the protocol specified above.  In my formal 
capacity as a Site Principal Investigator, my duties include ensuring the safety of the study 
participants enrolled under my supervision.  It is understood that all information pertaining to 
the study will be held strictly confidential and that this confidentiality requirement applies to all 
study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as required 
by the following: United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training.  Further, 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
Investigator’s Signature ___________________________Date: _____ / _____ / _____ 
Investigator’s Name:  _____________________________________________________ 
Site Name:  University of Virginia 
 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ABC 
Adaptive Biobehavioral Control 
AID 
Automated Insulin Delivery Device  
ATM 
Auto Titration Module 
ADRR 
Average Daily Risk Range 
AP 
Artificial Pancreas 
APG 
Ambulatory Glucose Profile 
API 
Application Programming Interface 
AWS 
Amazon Web Services 
BAM 
Behavioral Anticipation Module 
BG 
Blood Glucose 
BT/BTLE 
Bluetooth, Bluetooth low energy 
CF 
Insulin sensitivity factor 
CGM 
Continuous Glucose Monitoring 
CLC 
Closed-Loop Control 
Control-IQ 
Tandem t:slim X2 Insulin Pump with Control-IQ Technology 
CR 
Carbohydrates Ratios Profile 
CSII 
Continuous Subcutaneous Insulin Injection 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data Safety Monitoring Board 
eA1c 
Estimated Hemoglobin A1c 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBGI 
High Blood Glucose Index  
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
LBGI 
Low Blood Glucose Index  
NIH 
National Institutes of Health 
O/P 
Office Visit / Phone Visit 
POC 
Point-of-Care 
SAP 
Sensor-Augmented Insulin Pump  
QC 
Quality Control 

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UI 
User Interface 
WIT 
Web Information Tool 
WST 
Web Simulation Tool 
 
 

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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION  
Title 
Adaptive Biobehavioral Control (ABC) of Automated Insulin Delivery: A 
Randomized, Controlled Pilot Study 
Investigational Device 
Web Information Tool (WIT) - A web-based software providing additional 
information regarding glucose variability, estimated A1c, risks for hypo- and 
hyperglycemia, and potential changes of insulin pump parameters, to users of the 
Control-IQ system. The WIT is the clinical implementation of the ABC concept, 
which includes the following modules:  
• 
Behavioral Anticipation Module (BAM) - an app running on a smart 
phone which provides on-demand information to the participant 
primarily on glycemic risks. 
• 
Auto Titration Module (ATM) that provides recommendations to the 
participant to periodically update insulin parameters. 
• 
Web Simulation Tool (WST) - is intended to allow users of the Control-IQ 
system replay treatment scenarios in computer simulation, thereby 
allowing user training with carbohydrate and insulin action. 
Investigational Medication 
None 
Objectives 
Assess the safety and feasibility of two modules (BAM and ATM / WST) used in 
conjunction with an FDA approved automated insulin delivery system (t:slim X2 
with Control-IQ technology) 
Study Design 
Randomized parallel group trial. 
Number of Sites 
1 
Endpoint 
Primary Outcome: Safety assessment of ATM / WST and BAM modules. 
Secondary Outcomes: 
• 
Percent of readings in the target ranges of 70-180 and 70-140 md/dL 
• 
Other CGM-based metrics; 
• 
Questionnaires addressing BAM and participant preferences for 
system/technology use. 
Population 
Key Inclusion Criteria 
• Age 18-70, inclusive, with Type 1 Diabetes for at least one year 
• Current user of t:slim X2 insulin pump with Control-IQ Technology 
Key Exclusion Criteria 
• Recent severe hypoglycemic event or DKA during the past one year 
Sample Size 
 Recruit up to 45 participants of Control-IQ with the objective of randomizing 30 
subjects 
Treatment Groups 
• Group 1: Control-IQ + Auto Titration Module (ATM) and Web Simulation Tool 
(WST) for 6 weeks 
• Group 2: Control-IQ + Auto Titration Module (ATM) and Web Simulation Tool 
(WST) +Behavioral Adaptation Module (BAM) for 6 weeks 
Participant Duration 
8 weeks 

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Protocol Overview/Synopsis 
Two-week baseline use of personal Control-IQ system followed by randomization 
1:1 into two groups. Group 1 will use their personal Control-IQ system and add an 
auto titration module ATM) and web simulation tool (WST) in which insulin 
parameters may be adjusted on a weekly basis. Group 2 will use their personal 
Control-IQ system and add the ATM / WST on a weekly basis as well as a 
behavioral adaptation module (BAM). The BAM will consist of information 
modules in which information only is given to participants (e.g. hypoglycemic risks, 
daily glycemic profiles, eA1c, and variability tracker).  
 

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Table 1 Schedule of Study Visits and Procedures 
 
Visit Name 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Description 
Screening 
Visit 
Device 
Training & 
Run-In 
Randomiza
tion 
Weekly 
Check-In 
Weekly 
Check-In 
Weekly 
Check-In 
Weekly 
Check-In 
Weekly 
Check-In 
Final 
Visit  
Timing 
-8 to -2 
weeks 
-28 to -14 
days 
Day 1 
Day 7±3 
Day 
14±3 
Day 
21±3 
Day 
28±3 
Day 
35±3 
Day 
42±3 
Location 
O/P 
O/P 
O/P 
O/P 
O/P 
O/P 
O/P 
O/P 
O/P 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
HbA1c  
X 
 
 
 
 
 
 
 
X 
Screening Blood 
Testing: CMP, TSH if 
applicable 
X 
 
 
 
 
 
 
 
 
Pregnancy test (if 
applicable) 
X 
X 
X 
 
 
 
 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
Vital Signs (including 
height/weight) 
X 
 
 
 
 
 
 
 
 
Training on Relevant 
Devices or Modules 
 
X 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
Questionnaires  
 
 
X 
 
 
 
 
 
X 
Review diabetes 
management and AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Table of Contents 
1 
Chapter 1:  Background ....................................................................................................... 14 
2 
1.1 Introduction ........................................................................................................................ 14 
3 
1.2 Description of the Equipment ............................................................................................. 18 
4 
1.3 Description of the Information Modules ............................................................................ 19 
5 
Chapter 2: Study Description ............................................................................................... 22 
6 
2.1 Study Objective ................................................................................................................... 22 
7 
2.2 Study Design........................................................................................................................ 22 
8 
2.3 Purpose/Objectives of Clinical Study .................................................................................. 23 
9 
2.4 Study Participants ............................................................................................................... 23 
10 
2.5 Clinical Sites ........................................................................................................................ 23 
11 
2.6 Primary Specific Aim ........................................................................................................... 23 
12 
2.7 Secondary Specific Aim ....................................................................................................... 23 
13 
Chapter 3: Study Devices ..................................................................................................... 24 
14 
3.1 Insulin Pump ....................................................................................................................... 24 
15 
3.2 Continuous Glucose Monitor .............................................................................................. 24 
16 
3.3 Blood Glucose Meter and Strips ......................................................................................... 24 
17 
3.4 Ketone Meter and Strips ..................................................................................................... 24 
18 
3.5 Study Devices Accountability Procedures........................................................................... 24 
19 
Chapter 4: Study Screening .................................................................................................. 25 
20 
4.1 Participant Recruitment and Enrollment ............................................................................ 25 
21 
4.2 Informed Consent and Authorization Procedures .............................................................. 25 
22 
4.3 Screening Procedures ......................................................................................................... 25 
23 
4.4 Participant Inclusion Criteria............................................................................................... 26 
24 
4.5 Participant Exclusion Criteria .............................................................................................. 26 
25 
4.6 Screening Procedures ......................................................................................................... 27 
26 
Chapter 5: Study Equipment Training ................................................................................... 30 
27 

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5.1 CGM Training ...................................................................................................................... 30 
28 
5.2 Insulin Pump Training ......................................................................................................... 30 
29 
5.3 Training on the Investigational Applications ...................................................................... 31 
30 
5.4 Ancillary Device Training ..................................................................................................... 32 
31 
5.5 Blood Glucose Training ....................................................................................................... 33 
32 
5.6 Blood Ketone Training......................................................................................................... 33 
33 
Chapter 6: Study Procedures ................................................................................................ 34 
34 
6.1 Run-In Phase (Visit 2) .......................................................................................................... 34 
35 
6.2 Randomization Visit (Visit 3) ............................................................................................... 34 
36 
6.3 Optimization of Insulin Pump Settings ............................................................................... 35 
37 
6.4 Check-In Visits (Visit 4-8) .................................................................................................... 35 
38 
6.5 Participant Study Compliance ............................................................................................. 35 
39 
6.6 Study System Issues ............................................................................................................ 35 
40 
6.7 Repeating Visits & Unscheduled Visits ............................................................................... 36 
41 
6.8 Final Visit (Visit 9) ................................................................................................................ 36 
42 
6.9 Post-Study Check-In Visit .................................................................................................... 36 
43 
6.10 Early Withdraw ................................................................................................................. 36 
44 
Chapter 7: Testing Procedures ............................................................................................. 37 
45 
7.1 Laboratory / Point of Care Testing ...................................................................................... 37 
46 
7.2 Questionnaires .................................................................................................................... 37 
47 
Chapter 8: Risks Associated with Clinical Trial ...................................................................... 39 
48 
8.1 Potential Risks and Benefits of the Investigational Device ................................................. 39 
49 
8.2 General Considerations....................................................................................................... 41 
50 
Chapter 9: Adverse Events, Device Issues, and Stopping Rules .............................................. 42 
51 
9.1 Definitions ........................................................................................................................... 42 
52 
9.2 Reportable Events ............................................................................................................... 43 
53 
9.3 Relationship of Adverse Event to Study Device .................................................................. 44 
54 

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9.4 Intensity of Adverse Event .................................................................................................. 45 
55 
9.5 Coding of Adverse Events ................................................................................................... 45 
56 
9.6 Outcome of Adverse Events................................................................................................ 45 
57 
9.7 Reportable Device Issues .................................................................................................... 46 
58 
9.8 Timing of Event Reporting .................................................................................................. 47 
59 
9.9 Stopping Criteria ................................................................................................................. 47 
60 
Chapter 10: Miscellaneous Considerations ........................................................................... 49 
61 
10.1 Prohibited Medications, Treatments, and Procedures .................................................... 49 
62 
10.2 Participant Withdrawal ..................................................................................................... 49 
63 
10.3 Confidentiality ................................................................................................................... 49 
64 
Chapter 11: Statistical Consideration ................................................................................... 50 
65 
11.1 Design and Randomization ............................................................................................... 50 
66 
11.2 Sample Size ....................................................................................................................... 50 
67 
11.3 Outcome Measures ........................................................................................................... 50 
68 
11.4 Safety Analyses ................................................................................................................. 51 
69 
11.5 Baseline Descriptive Statistics ........................................................................................... 52 
70 
11.6 Device Issues ..................................................................................................................... 52 
71 
11.7 Analysis of Secondary CGM-based Outcomes .................................................................. 52 
72 
Chapter 12: Data Collection and Monitoring ........................................................................ 54 
73 
12.1 Case Report Forms and Device Data ................................................................................. 54 
74 
12.2 Study Records Retention .................................................................................................. 54 
75 
12.3 Protocol Deviations ........................................................................................................... 54 
76 
Chapter 13: Ethics/Protection of Human Participants ........................................................... 55 
77 
13.1 Ethics Standard ................................................................................................................. 55 
78 
13.2 Institutional Review Boards .............................................................................................. 55 
79 
13.3 Informed Consent Process ................................................................................................ 55 
80 
Chapter 14: References ........................................................................................................ 57 
81 

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82 
 
 
83 

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Chapter 1:  Background 
84 
 
85 
Large-scale artificial pancreas studies, including two multi-center pivotal trials recently 
86 
completed by our team, have established the current capabilities of closed-loop control (CLC) 
87 
and identified its deficiencies, e.g. inferior control during the day due to slow insulin response to 
88 
fast biobehavioral perturbations. We therefore propose to pilot test elements of a next-
89 
generation CLC system – Adaptive Biobehavioral Control (ABC) based on the novel concept of 
90 
human-machine co-adaptation – which uses a stochastic-process approximation of the day-to-
91 
day variation in human physiology and behavior to individualize and optimize CLC. The ABC 
92 
concept recognizes both the necessity for the control algorithm to adapt to changes in human 
93 
physiology and the necessity for the person to adapt to CLC action. This pilot-feasibility study is 
94 
intended to test the Web Information Tool (WIT), a web-based software that provides additional 
95 
information regarding glucose variability, estimated A1c, risks for hypo- and hyperglycemia, and 
96 
potential changes of insulin pump parameters, to users of the Control-IQ system (Tandem 
97 
Diabetes Care, San Diego, CA). 
98 
The ABC concept was conceived during our extensive studies carried under NIH/NIDDK project 
99 
UC4DK108483 “Clinical Acceptance of the Artificial Pancreas: the International Diabetes Closed 
100 
Loop (iDCL) Trial.” The iDCL Trial became most successful study funded by NIDDK under RFA-DK-
101 
14-024 “Advanced Clinical Trials to test Artificial Pancreas Device Systems in Type 1 Diabetes 
102 
(UC4).” We completed three clinical protocols, DCLP1, DCLP3, and DCLP5, which became three 
103 
of the largest closed-loop control studies attempted to date: 
104 
1) Protocol 1 (DCLP1, NCT02985866, IDE#G160181) established that a mobile Artificial Pancreas 
105 
(AP) system using a smart phone as a computational hub running the control algorithm, is a 
106 
viable treatment for T1D. This protocol was executed at seven U.S. sites and was coordinated 
107 
by the Jaeb Center for Health Research. DCLP1 recruited N=127 subjects randomized to AP 
108 
vs. sensor-augmented pump (SAP). The results were published in Diabetes Care, showing that 
109 
the study met its predefined criteria for success.1  
110 
2) Protocol 3 (DCLP3, NCT03563313, IDE #G180053) was a pivotal trial which, responding to the 
111 
requirements of RFA-DK-14-024, aimed at regulatory clearance of Control-IQ – a system that 
112 
includes a Dexcom G6 sensor and a t:slim pump (Tandem Diabetes Care). This system is based 
113 
on a control algorithm developed at the University of Virginia under the NIDDK-funded grant 
114 
RO1 DK 085623. DCLP3 randomized N=168 participants to Control-IQ vs. SAP, all of whom 
115 
completed the 6-month trial and then continued with a 12-month study extension. DCLP3 
116 
met all of its predefined primary and secondary outcomes. The results were published in the 
117 
New England Journal of Medicine.2 As a result, the Control-IQ system received FDA clearance 
118 
for clinical use by children and adults ages 14 and up. 
119 

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3) Protocol 5 (DCLP5, NCT03844789, IDE #G180053/S008) was also a pivotal trial, which aimed 
120 
at regulatory clearance of Control-IQ in children ages 6-13 years old. DCLP5 randomized 
121 
N=101 participants to Control-IQ vs. SAP, and met all of its predefined primary and secondary 
122 
outcomes. The results were also published in the New England Journal of Medicine.3 As a 
123 
result, the Control-IQ system received FDA clearance for clinical use by children ages 6-13 
124 
years old as well. 
125 
Defining the ABC Process: The ABC process consists of interacting cycles developing on different 
126 
time scales: 4 (1) First, it is initialized by individual characteristics, such as HbA1c, history of severe 
127 
hypoglycemia, or hypoglycemia unawareness that sets the stage for further control adaptation; 
128 
this initialization is slow, develops over months or years, and can be favorable or unfavorable to 
129 
CLC (e.g. individuals at overall good vs. poor control would fare differently using CLC;2 (2) Natural 
130 
variation in a person’s metabolic parameters occurs within a day (e.g. circadian rhythms) and 
131 
between days; slower changes are possible, e.g. due to illness; (3) Behavioral perturbations 
132 
challenge the metabolic system with meals or physical activity, which may trigger low BG events 
133 
and escalate to recurrent hypoglycemia; this cycle includes significant randomness and is 
134 
therefore best described by a stochastic process (dotted lines–clockwise cycles in Figure 1). This 
135 
bio-behavioral interplay amplifies or attenuates the BG fluctuations of a person and is detected 
136 
as degree of GV by CGM and/or other signals. (4) In this context, the control co-regulation 
137 
objective is two-fold: gradual and safe stabilization of the metabolic system by adapting control 
138 
parameters to the specifics and physiological variation of the metabolic system, and fast 
139 
response to biobehavioral challenges that may require behavioral adaptation by the user, e.g. 
140 
around meals and exercise (solid lines–counterclockwise cycles in Figure 1).  
141 

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142 
Figure 1: Main premise, signals, time scales, and control action of the recursive ABC 
143 
process: initialization with routine T1D treatment parameters; behavioral and 
144 
physiological perturbations monitored through CGM and other signals, and human-
145 
machine co-adaptation using pattern/risk information presented to the user and to the 
146 
control algorithm. Clockwise cycles indicate system disturbances; Counterclockwise 
147 
cycles indicate adaptation. 
148 
Monitoring the ABC Process: Observed in time, the compounded effect of the recurrent 
149 
processes presented in Figure 1 is a stochastic process of glycemic variation5 governed by 
150 
transition probabilities from one CGM daily profile to the next. We introduced this concept in 
151 
February 2019, in two consecutive presentations at the international ATTD conference, focusing 
152 
on its applications to patient decision support6 and adaptation of automated control built upon 
153 
a virtual image of the patient (VIP).7 These two applications will be used in the proposed study to 
154 
enable: (i) behavioral co-adaptation through pattern/risk information provided to the user and 
155 
intended to provoke thoughts and prompt, but not suggest or require, adaptive behavioral 
156 
reaction, and (ii) adaptation of the insulin pump parameters used by control algorithm, which 
157 
will be proposed to the user, but not implemented automatically in this pilot phase of research.  
158 
Initialization:
Baseline A1c;
History of severe 
hypoglycemia;
Hypoglycemia 
unawareness.
TIME SCALE:
Years/Months
Behavior:
Physical activity;
Missed meals;
Excessive insulin.
TIME SCALE:
Days/Hours/Minutes
Physiology:
Endogenous glucose 
production; Insulin 
action; Insulin sensitivity.
TIME SCALE:
Weeks/Days/Hours
Treatment:
Adaptive 
Biobehavioral 
Control (ABC).
TIME SCALE: 
Minutes
Clockwise: 
Disturbances
Counterclock
wise: Control
Data: Real-time CGM; body sensors; Psychometrics; Diabetes treatment parameters;
Information Flow: To algorithm: every few minutes; To User: episodic, on demand.

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Pattern Recognition, Clustering, and Classification: At the core of the ABC technology is an 
159 
innovative method for pattern-based therapy optimization. In this approach, the collection of all 
160 
possible daily patterns, i.e. the state space of the ABC process, is defined by machine-learning 
161 
classification of CGM profiles into clusters derived from our library of over 50,000 CGM daily 
162 
profiles accumulated in our studies. To illustrate how this works, we use data from the 
163 
International Diabetes Closed-Loop (iDCL) Trial Protocol 1, NCT02985866. This study yielded 
164 
~9,000 CGM daily profiles, which allowed performing the following steps: (1) CGM daily profiles 
165 
are classified into identifiable clusters; (2) Over time, each person transitions through a sequence 
166 
of clusters, which are approximated by a stochastic Markov chain identified by an individual 
167 
transition probability matrix; (3) Treatment adaptation is then assisted by presenting pattern/risk 
168 
predictions to the patient and to the control algorithm, aiming to maximize the probabilities of 
169 
favorable daily transitions. For illustrative purposes, Figure 2 shows results for a 3-cluster 
170 
solution. Clusters are color coded according to their clinical interpretation: Cluster 1: Tight 
171 
Control/Intensive Treatment; Cluster 2: Hyperglycemic exposure; Cluster 3: Intermediate/ 
172 
Average Control.  
173 
Each cluster is associated with a specific level of glucose control, and over time each person 
174 
transitions through a sequence of clusters, each describing this person’s glycemic control for 
175 
one day.  
176 
The color-coded profiles in Figure 2 present the daily stochastic transitions of two participants in 
177 
the iDCL Protocol 1 using sensor-augmented pump (SAP) and CLC, respectively. Underneath, we 
178 
present a set of glycemic control metrics that reflect the state of each person when s/he was in 
179 
each one of the 
180 
three clusters. By 
181 
cluster 
design, 
182 
despite the marked 
183 
differences in the 
184 
overall control of 
185 
these 
subjects, 
186 
their 
glycemic 
187 
characteristics are 
188 
very similar when 
189 
they are in the 
190 
same cluster. For 
191 
example, both had 
192 
mean glucose of 
193 
151-152mg/dL 
194 
when in a blue 
195 
 
 
Figure 2: Daily transitions, cluster assignment, and transition 
probability for two representative participants in iDCL Protocol 1.  
CL
mean
SD
CV
LBGI
HBGI
<70
70-180
>180
#Days
1
151.29
51.48
34.34
0.52
5.55
1.97
71.88
26.16
3
2
236.85
85.66
37.02
0.84
22.03
3.76
24.17
72.07
39
3
180.68
68.17
38.95
1.21
11.14
5.28
47.39
47.33
41
total
206.01
75.78
37.88
1.01
16.05
4.45
37.36
58.19
83
Control Subject
Days
1
10
20
30
40
50
60
70
80
CL
1
2
3
1
0.00
0.00
1.00
2
0.00
0.58
0.42
3
0.07
0.41
0.51
Transition Probabilities
CL
mean
SD
CV
LBGI
HBGI
<70
70-180
>180
#Days
1
152.49
49.02
32.10
0.51
5.61
1.53
72.66
25.81
44
2
234.89 108.77
46.31
0.04
22.25
0.00
43.10
56.90
1
3
185.69
76.14
41.09
0.28
11.84
0.59
55.58
43.83
23
total
164.93
59.07
35.35
0.43
7.96
1.19
66.45
32.36
68
Experimental Subject
Days
1
10
20
30
40
50
60
70
80
CL
1
2
3
1
0.67
0.00
0.33
2
1.00
0.00
0.00
3
0.57
0.04
0.39
Transition Probabilities

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cluster for the day, or 237-235mg/dL when in a red cluster. The major difference between these 
196 
two study participants is the time they spent in each cluster type, e.g., 44 days in the blue cluster 
197 
for the CLC Subject and only 3 days for the SAP Subject (Figure 2). Further, each person’s 
198 
stochastic transitions from one day to the next are approximated by a Markov chain5 governed 
199 
by individual transition probability matrices presented in Figure 2. For example, the probability 
200 
is zero for the control subject to remain in tight control for two consecutive days (blue-to-blue), 
201 
while this probability is 67% for the Experimental Subject. We therefore conclude that: (i) A library 
202 
of clinically-relevant clusters describes the possible one-day glycemic profiles for each person; (ii) 
203 
When in the same cluster, the glycemic metrics for different people are similar; (iii) However, each 
204 
person transitions through a different sequence of daily profiles, governed by individual transition 
205 
probability matrices; (iv) This allows each person’s ABC process to be encoded in a Markov chain 
206 
of consecutive daily profiles; (v) This encoding results in estimates of the probabilities for 
207 
upcoming events, i.e. the chances from transition to a particular cluster tomorrow, which informs 
208 
a person’s treatment decisions and the control algorithm’s adaptation. 
209 
With this conceptual description in mind, the overall objective of the ABC strategy is to enable a 
210 
new generation of artificial pancreas technologies which will: (i) Provide information to the user 
211 
to inform user’s adaptation to the CLC system, and (ii) Adapt automatically the action of the 
212 
control algorithm to follow daily changes in physiology and behavior. To the best of our 
213 
knowledge, such bi-directional human-machine co-adaptation has not been attempted before, 
214 
partially due to underestimation of the behavioral challenges related to CLC use, and partially 
215 
due to the relative immaturity of CLC systems, which until recently could not sustain long-term 
216 
use without facing significant technical problems or requiring extensive user involvement.  
217 
In this IDE application, we make the case that we are now equipped with well-established CLC 
218 
technology (Control-IQ, Tandem Diabetes Care), with which we have very extensive experience. 
219 
We will rely on our extensive track record of behavioral interventions concerning technology,8 
220 
and on one of the largest CLC databases collected to date. Thus, we can confidently propose to 
221 
pilot test and evaluate the ability of an adaptive CLC system to optimize metabolic control in the 
222 
context of behavioral management and response to such technology. In this first pilot study, the 
223 
feedback to the patient will be limited to information about relevant glycemic parameters and 
224 
risks. No prescription will be given for behavioral changes or adaptation. Similarly, adjustment of 
225 
the control parameters, will be proposed to the user and will be accompanied by an option to 
226 
replay treatment scenarios via computer simulation, but will not be implemented automatically.  
227 
 
228 
Closed-Loop Control System:  
229 
Trade/Device Name: Control-IQ Technology   
230 

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Regulation Name: Interoperable automated glycemic controller  
231 
System components include:  
232 
• t:slim X2 insulin pump with Control-IQ technology, and  
233 
• Dexcom G6 continuous glucose monitor (CGM).  
234 
The CLC system and its components are approved by the FDA for clinical use in children and adults 
235 
ages 6 years old or older.  
236 
 
237 
The WIT is the clinical implementation of the ABC concept, which includes: 
238 
• A Behavioral Adaptation Module (BAM); 
239 
• An Auto Titration Module (ATM), and  
240 
• A Web Simulation Tool (WST). 
241 
The three information modules BAM, ATM, and WST will be provided to users of the t:slim X2 
242 
with Control-IQ closed-loop system in a Web-based interactive format via a website that allows 
243 
for unique login. These modules will provide the user with potentially useful recommendations, 
244 
but will not interfere automatically with the functioning of the CLC system. The primary purpose 
245 
of this pilot trial is safety testing and receiving feedback from the participants regarding module 
246 
functionality and user interface.  
247 
Briefly, the WIT presents daily updates by the BAM first, and allows the user to navigate to other 
248 
modules. Details for all algorithm modules are provided in Appendix A-2. 
249 
BAM uses the concept described in the Introduction under “Monitoring the ABC Process” and 
250 
well-established metrics of glycemic control computed daily: 
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Measure  
Computed From  
Estimated A1c   
14 days of CGM data plus lab HbA1c calibration10  
Low/High BG [Risk] Indices 
(LBGI/HBGI) – measures of risk for 
hypo- or hyperglycemia  
Previous day of CGM data8  
Average Daily Risk Range (ADRR) – a 
measure of glucose variability  
Computed as the average of the HRRs (Hourly Risk 
Range) for the previous day8  
Forecast-today  
8 days of CGM data, plus today’s readings by 6AM   
Table 2: Glycemic metrics used by the BAM  
252 
Results will be presented every morning, e.g. at 7AM. All Variability and Risk metrics are mapped 
253 
to the interval [0-11] as follows: 0 is mapped to 0; 99th percentile of the metric is mapped to 11.  
254 
ATM is a set of optimization algorithms designed to use the participants’ data and provide weekly 
255 
updates for their default insulin pump parameters: basal rate profile, insulin to carbohydrates 
256 
ratios profile (CR), and insulin sensitivity factors profile (CF). The module is derived from the 
257 
optimization already used in G200122 and is largely identical but for one key element: the CR and 
258 
CF profiles are not using fixed timestamps (e.g. 3am-11am and 11am-3am), but automatically 
259 
determined in concert with the basal profile so as to ensure no more than 12 segments for the 
260 
combinations of the daily profiles. As the timing of each CR/CF profile segments is not fixed, the 
261 
algorithm has been modified to use all historical boluses for each profile segments (vs using only 
262 
boluses that fell in the segment specific time interval) with appropriate weighing (a historical 
263 
bolus at 1pm has a much larger influence on a noon-3pm segment than a historical 11pm bolus).  
264 
WST is a simulation infrastructure that allows individuals to interact with their data in a novel 
265 
way: each user can not only see their historical CGM/insulin/meal data streams, summary 
266 
indices, and summary graphical representation (in a format similar to an ambulatory glucose 
267 
profile, AGP), but can also modify their insulin treatment strategies, play “what-if” scenarios, and 
268 
observe the predicted glycemic impact. For example, a user could observe an early morning 
269 
hypoglycemia tendency (from the summary graphical representation), reduce the underlying 
270 
basal rate (say 3am-6am) by 10%, and see if such change would have limited the hypoglycemic 
271 
exposure and/or increase late morning hyperglycemia. Therefore, WST can be considered an 
272 
advanced education tool for people with T1D to leverage their own data and experience and gain 
273 
insight in possible behavioral/therapeutic changes they may want to consider with their care 
274 
team. This module is based on our replay simulation technology11-13 and is supported by a 
275 
transfer of data from the user devices (in the case of this study, an automated transmission of 
276 

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the t:slim X2 data to the Tandem phone app and then to the t:connect web system, with a 
277 
frequent (every 6h) pull triggered by our AWS infrastructure of the t:connect data via a Tandem 
278 
API) (Application Programming Interface). 
 
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Chapter 2: Study Description 
280 
 
281 
The purpose of this pilot study is to test the safety and feasibility of using two or three research 
282 
modules in conjunction with an approved automated insulin delivery device (AID) (t:slim X2 
283 
insulin pump with Control-IQ technology, Tandem Diabetes Care). 
284 
This concept is implemented in the Adaptive Biobehavioral Control (ABC) system – ABC will use 
285 
human-machine co-adaptation of CLC, recognizing both the necessity for the control algorithm 
286 
to adapt to changes in human physiology, and the necessity for the person to adapt to CLC action. 
287 
ABC will be implemented on the Web Information Tool (WIT) platform/system and includes the 
288 
following modules to be used alongside the automated insulin delivery device: 
289 
• Behavioral Adaptation Module (BAM) – a behavioral intervention deployed in a mobile 
290 
app to assist a person’s adaptation to automated insulin delivery by information and risk 
291 
assessment primarily regarding glycemic risks, and 
292 
• Auto Titration Module (ATM) — a web-based tool with an automated procedure to track 
293 
risk status and changes in the participant’s metabolic profile. This module will present 
294 
updated insulin control parameters (e.g. basal rate, carb ratio, correction factor) to the 
295 
user once a week using a web-based format accessible to the participant. These adjusted 
296 
parameters are not able to directly update the pump automatically, so the participant will 
297 
then need to manually enter the suggested changes directly onto their insulin pump.  
298 
• Web-based Simulation Tool (WST) --a web-based education tool for participants to 
299 
interact with their data to visualize and replay various scenarios to understand the impact 
300 
of insulin parameter changes. 
301 
 
302 
This is a safety and feasibility study with a randomized two-arm parallel group trial in which both 
303 
groups will use the AID (Control-IQ) plus ATM and WST. The difference between the two groups 
304 
will be the behavioral module. One group will be randomized to add BAM and one group will not 
305 
use BAM. This is illustrated in Figure 2: 
306 

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307 
Figure 3: Study Diagram 
308 
 
309 
This pilot study is intended to test a Web-based Information Tool (WIT) software providing 
310 
additional information regarding glucose variability, estimated A1c, risks for hypo- and 
311 
hyperglycemia, and potential changes of insulin pump parameters, to users of the Control-IQ 
312 
system.  
313 
 
314 
Enrollment in the study will proceed with the goal of completing approximately 30 subjects.  
315 
Study duration is between 8-10 weeks.  
316 
Up to 45 participants may sign the consent form.  
317 
 
318 
The study will be performed at the University of Virginia. 
319 
 
320 
The primary outcome will be a safety assessment using all 6 weeks of treatment data in terms of 
321 
incidence of DKA or severe hypoglycemia.  
322 
 
323 
The secondary outcome of interest will be primarily CGM-based metrics using the last two weeks 
324 
of the treatment data and the two-week baseline to compare: 
325 
• ATM / WST vs. Baseline 
326 
• ATM / WST + BAM vs. Baseline 
327 
• Group 1 vs. Group 2: ATM / WST vs. ATM / WST + BAM.  
 
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Chapter 3: Study Devices 
329 
 
330 
Participants will use their personal FDA-approved Tandem t:slim X2 with Control-IQ Technology 
331 
which will be used without modifications.   
332 
 
333 
Participants will be provided a study provided CGM that includes Dexcom G6 transmitter and 
334 
sensors while using the Tandem t:slim X2 insulin pumps. The CGM sensor is viable for 10 days. 
335 
All participants will be provided a Dexcom G6 system by the study team as needed. This system 
336 
will be used without modifications. The CGM device will be calibrated, if needed, using the 
337 
glucometer in accordance with the manufacturer’s labeling. The participant may elect to 
338 
continue use of their personal CGM during the study. The study will provide CGM supplies, as 
339 
necessary. As a previously noted, data may be obtained through the commercial applications 
340 
(e.g. t:connect and Dexcom G6).  
341 
 
342 
Blood glucose levels will be measured using the participant’s personal glucometer.  
343 
 
344 
Blood ketone levels will be measured using the Abbott Precision Xtra meters and strips in 
345 
accordance with the manufacturer’s labeling. The blood glucose meter component of the 
346 
Precision Xtra Device will not be used.  
347 
 
348 
Device serial numbers will be recorded and use of equipment will be tracked.  
 
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Chapter 4: Study Screening 
350 
 
351 
Enrollment in the study will proceed with the goal of completing approximately 30 subjects.  
352 
Up to 45 participants may sign the consent form.  
353 
Recruitment, screening, and enrollment may be performed as an office visit, or via 
354 
telecommunication. 
355 
 
356 
Before consent has been obtained, participants will be asked inclusion/exclusion criteria 
357 
questions during pre-screening to determine study eligibility. Before completing any procedures 
358 
or collecting any data that are not part of usual care, written informed consent will be obtained. 
359 
Potential eligibility may be assessed as part of a routine-care examination.   
360 
A participant is considered enrolled when the informed consent form has been signed by the 
361 
participant and the study team. 
362 
Consenting procedures and documentation is defined in section 13.3. 
363 
Telecommunicated study visits may take the place of all in-person study visits as deemed feasible 
364 
by the study team.  
365 
 
366 
After informed consent has been signed, a potential participant will be evaluated for study 
367 
eligibility through the elicitation of a medical history, performance of a physical examination 
368 
by licensed study personnel or using a historical exam within 12 months if the visit is done 
369 
remotely, and pregnancy testing (if applicable) to screen for exclusionary medical conditions. 
370 
Once all results of the screening evaluations are available, a decision will be made to determine 
371 
the participant’s eligibility for the study, or if one or more parts of the screening will have to be 
372 
repeated. These may be repeated at the discretion of the Principal Investigator 
373 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
374 
date per investigator discretion.  
375 

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376 
The participants must meet all the following inclusion criteria in order to be eligible to participate 
377 
in the study. 
378 
1. Age ≥18.0 and ≤70 years old at time of consent 
379 
2. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one 
380 
year  
381 
3. Currently using insulin pump for at least six months  
382 
4. Currently using insulin for at least six months 
383 
5. Currently using or anticipated to be using the t:slim X2 insulin pump with Control-IQ 
384 
technology at the start of the run-in phase (Visit 1). 
385 
6. Using or willing to use insulin parameters such as carbohydrate ratio and correction 
386 
factors consistently on their pump in order to dose insulin for meals or corrections  
387 
7. Access to internet and willingness to upload data during the study as needed  
388 
8. Willing to use an app on a smart phone during the study. 
389 
9. For females, not currently known to be pregnant or breastfeeding 
390 
10. If female, sexually active, and of childbearing potential, must agree to use a form of 
391 
contraception to prevent pregnancy while a participant in the study.  A negative serum or 
392 
urine pregnancy test will be required for all females of childbearing potential. Participants 
393 
who become pregnant will be discontinued from the study. Also, participants who during 
394 
the study develop and express the intention to become pregnant within the timespan of 
395 
the study will be discontinued. 
396 
11. Willingness to use only insulin analogs approved for use in the t:slim X2 pump such as 
397 
lispro (Humalog) or as part (Novolog) and not use ultra-rapid acting insulin analogs (e.g. 
398 
FiAsp) during the study 
399 
12. Total daily insulin dose (TDD) at least 10 units per day 
400 
13. Willingness not to start any new non-insulin glucose-lowering agent during the course of 
401 
the trial (including metformin, GLP-1 agonists, pramlintide, DPP-4 inhibitors, biguanides, 
402 
and sulfonylureas) 
403 
14. An understanding and willingness to follow the protocol and signed informed consent  
404 
 
405 
The participant must not have any exclusion criteria in order to be eligible to participate in the 
406 
study.  
407 
1. Concurrent use of any non-insulin glucose-lowering agent other than metformin 
408 
(including GLP-1 agonists, pramlintide, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas) 
409 

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2. A condition, which in the opinion of the investigator or designee, would put the 
410 
participant at risk or interfere with the completion of the protocol.  
411 
3. History of diabetic ketoacidosis (DKA) in the 12 months prior to enrollment 
412 
4. Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior 
413 
to enrollment 
414 
5. Currently being treated for a seizure disorder 
415 
6. Hemophilia or any other bleeding disorder 
416 
7. Planned surgery during study duration  
417 
8. Participation in another pharmaceutical or device trial at the time of enrollment or during 
418 
the study  
419 
9. Having a direct supervisor at place of employment who is also directly involved in 
420 
conducting the clinical trial (e.g. study investigator, coordinator, etc.); or having a first-
421 
degree relative who is directly involved in conducting the clinical trial. 
422 
 
423 
The participant will be evaluated for study inclusion and exclusion eligibility after the informed 
424 
consent form has been signed by the participant and the study team.  
425 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
426 
date per investigator discretion. 
427 
Screening procedures will last approximately 1-2 hours. The visit may occur in-person or by 
428 
telecommunication. The following procedures may be performed/data collected/eligibility 
429 
criteria checked and documented:  
430 
• Inclusion and exclusion criteria assessed 
431 
• Demographics (date of birth, gender, race and ethnicity, and socioeconomic indicators) 
432 
• Contact information 
433 
• Diabetes history including severe hypoglycemia history  
434 
• Medical history  
435 
• Concomitant Medications  
436 
• Physical examination to include (a physical exam report within last 52 weeks may be 
437 
substituted): 
438 
• Weight, height (may be self-reported) 
439 
• Vital signs including measurement of blood pressure and pulse (may use medical record 
440 
within 6 months or self-report) 
441 
• Urine or serum pregnancy test for all females of child-bearing potential (this test can be 
442 
done remotely with results sent to the study team) 
443 
• HbA1c level measured using the DCA Vantage or similar point of care device or local lab  
444 

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• If needed based on medical history, investigators may include baseline chemistry panel, 
445 
liver function tests, hematocrit and thyroid stimulating hormone (lab results within one 
446 
year of screening appointment may be used) 
447 
• Diabetes Management Information: We will record the participant’s average total daily 
448 
insulin use, carbohydrate ratio, correction factor (insulin sensitivity factor), and insulin 
449 
infusion basal rate profile. Up to 6 months of historical data from the participant’s 
450 
personal insulin pump, glucometer, or continuous glucose monitor may be downloaded 
451 
or recorded. 
452 
• Data will be obtained from the participant’s personal insulin pump and CGM. This data 
453 
may be obtained through the commercial applications (e.g. t:connect and Dexcom G6).  
454 
• If participants are on-site, the participant’s glucometer may be uploaded to ensure that 
455 
the participant can successfully upload the equipment.  
456 
• Any labs required may be obtained at a local laboratory (e.g. LabCorp) convenient to the 
457 
participant. 
458 
This study is not meant to find out if the participant has any other disease or problem. The study 
459 
leaders will alert the participant if any of the research results are important to his/her health 
460 
during the study. The participant may have a copy of the screening tests to discuss with the 
461 
personal physician. When the blood tests are completed, any blood left over will be thrown away. 
462 
It will not be stored for any future testing. 
463 
Participants travelling from a distance or participants wishing to be pre-screened for eligibility 
464 
may elect to have the consent read and explained by study staff by phone. Once all questions 
465 
have been answered, the signed consent will be sent to study personnel and the participant may 
466 
then have pre-screening with labs performed locally (e.g. LabCorp) prior to Visit 1.  
467 
The study physician or physician designee will have the discretion to repeat screening tests. The 
468 
repeat screening tests may be conducted locally (e.g. LabCorp). The participant may request a 
469 
copy of any of the results from the screening evaluation to review with their primary care 
470 
provider.  
471 
If an exclusionary condition is identified, the study participant will be excluded from participation 
472 
with follow up and referral to their primary care physician as needed.  
473 
If the study participant is pregnant, the study physician will discuss the results of the blood test 
474 
with the participant and the participant will be asked to seek confirmation of the test and the 
475 
appropriate medical care.  
476 

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Participants may be re-screened at a later date if their clinical situation changes as determined 
477 
by the study physician.  
 
478 

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Chapter 5:  Study Equipment Training 
479 
Equipment training relevant to the study visit may begin immediately after screening eligibility 
480 
has been met or may be deferred for a maximum of 30 days.  
481 
All participants will be asked to use their personal t:slim X2 insulin pump with Control-IQ 
482 
Technology and study Dexcom G6 CGM throughout the study period from Run-In Visit through 
483 
the Final Study Visit. Study supplied phones will be available upon request.  
484 
Study contact information will be provided to the participant. The study team will be available by 
485 
phone as needed throughout the study duration. 
486 
All study training may be performed as an office visit, or via telecommunication. 
487 
 
488 
A Dexcom G6 CGM will be provided to all participants at the training session. The participants 
489 
may choose to use their personal CGM equipment or will be provided with study CGM 
490 
equipment.  Participants will be instructed to use the study CGM on a daily basis. If the participant 
491 
has prior use of the CGM, re-training will be specific to the individual. The study team may elect 
492 
to 
have 
less 
frequent 
CGM 
users 
watch 
the 
Dexcom 
online 
training 
videos 
493 
(https://www.dexcom.com/training-videos) to assist in the training session.    
494 
The participants will be asked to perform fingerstick blood glucose measurements (if needed) in 
495 
accordance with the labeling of the CGM device.  
496 
 
497 
Participants are current users of Control-IQ and therefore do not require training on the pump. 
498 
The participant will be instructed on how to use the system if insulin is delivered by any means 
499 
other than the Control-IQ pump (e.g. injection of subcutaneous insulin via syringe in the event of 
500 
infusion site failure). If insulin is delivered by any means other than the study pump, the 
501 
participant will be instructed to turn off Control-IQ for approximately four hours. 
502 
The participant will be provided with contact information and will be asked to call the study 
503 
clinical staff during periods of illness with an elevated temperature >101.5 degrees Fahrenheit 
504 
(38.6 degrees Celsius), periods of significant illness, or during periods of use of medications such 
505 
as epinephrine for the emergency treatment of a severe allergic reaction or asthma attack in 
506 
addition to use of oral or injectable glucocorticoids to determine if automated insulin delivery 
507 
should be temporarily discontinued. 
508 
The participant will be provided Glycemic Treatment Guidelines (Appendix A-11) to use at home. 
509 

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 Optimization of Insulin Pump Settings  
510 
Throughout the study, study clinicians will refrain from adjusting insulin pump settings beyond 
511 
the once-weekly Auto-titration adjustments. However, data-driven optimization of pump 
512 
settings can occur at any time during the study for safety reasons, particularly if the participant 
513 
contacts the study team due to concerns about their pump settings due to recurring hypo- or 
514 
hyperglycemia. 
515 
 Autotitration of Insulin Pump Settings 
516 
Participants will receive recommendations via email for adjustments to insulin parameters 
517 
derived from the WIT once a week. Participants will be asked to implement those parameters as 
518 
suggested and will manually change the settings on their personal pump. Participants may 
519 
contact the study clinicians to discuss concerns they may have with the suggested settings.  The 
520 
study clinician will then evaluate and may alter the implementation of some or all of the 
521 
parameters if deemed a significant safety concern.  
522 
 
523 
All participants in both groups will be trained on the WIT application.  
524 
Autotitration / WST training consists of: 
525 
• Review of how to access the web-based application (e.g. on a smart phone, iPAD or 
526 
computer).  
527 
• Review of menus of the application. 
528 
• Review of actual parameters being adjusted (e.g. basal rates, correction factors) 
529 
• Review of frequency of parameter updates (i.e. once weekly) 
530 
• Participants will be instructed to contact the study team to review parameters updates at 
531 
any time if they are concerned about appropriateness of adjustments 
532 
• Participants will be instructed to contact the study team to confirm the institution of 
533 
parameter adjustments  
534 
• Participants will be instructed to how to run a simulation and interrupt the results 
535 
displayed on the screen 
536 
Participants who are randomized to Group 2 will also receive BAM training and will generally 
537 
consist of the following: 
538 
• Review of how to access the BAM application components and troubleshooting. 
539 
• Hands-on training of identification of information modules components and how to 
540 
access the information modules and an explanation of those modules  
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• Hands-on training of how to access prescriptive modules on demand and an explanation 
542 
of those modules 
543 
• Participants will be notified that eA1c is for informational purposes only and not to be 
544 
used for short-term changes to insulin settings 
545 
Information Modules will include:  
546 
i. 
Hypoglycemia Risk Indicator based on pattern recognition and risk assessment;  
547 
ii. 
Daily glycemic profile forecast;  
548 
iii. 
Estimated A1c (eA1c) which will assist with tracking average glycemia and goal setting, 
549 
and  
550 
iv. 
Variability tracker highlighting glycemic patterns related to behavioral challenges such 
551 
as meals and exercise.  
552 
Study staff will be available 24/7 to assist the participant and troubleshoot the BAM and auto-
553 
titration modules.  
554 
 
555 
Participants will have the option to receive a study-owned smartphone or to use their personal 
556 
smartphone in order to collect the data from the CGM and insulin pump devices and stream it to 
557 
respective cloud servers. The chosen phone will also allow the participant to access the WIT 
558 
application. 
559 
If participants choose the study-owned smartphone option, they will be provided a study phone 
560 
with a data plan, an anonymous email account, the Dexcom G6 app, the Tandem t:connect 
561 
Mobile App, and access to the WIT system for the duration of the study. The Dexcom app will 
562 
allow the participant to monitor the CGM values and alerts in real-time and stream CGM data to 
563 
the Dexcom Clarity cloud. The Tandem t:connect Mobile App will be downloaded to their phone 
564 
in order allow the participant to stream insulin pump data to the Tandem t:connect cloud. Study 
565 
staff will register a subject account and login so that the subject can access the WIT system via 
566 
the smartphone.  
567 
If the participant elects to use a personal smartphone, the Dexcom G6 app and the Tandem 
568 
t:connect Mobile App will be downloaded to their phones if they are not already installed. 
569 
In both cases, the participant will have the option of using their personal Dexcom and their 
570 
personal Tandem t:connect accounts or anonymous, study-provided accounts. Participants who 
571 
do not wish to use their personal accounts, or do not have personal accounts and do not wish to 
572 
create one, will be provided an anonymous account created by study staff.  
573 

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Participants who elect to use a study phone will be trained on the basic functioning of the phone 
574 
(e.g. charging, password entry, accessing apps). All participants will be asked to verify successful 
575 
installation of apps (where applicable) and account access.  
576 
 
577 
Participants will use their personal home glucometer.  
578 
The study team may inquire about glucometer readings if the study visits are performed 
579 
remotely. If visits are done in person, the glucometer may be uploaded. Participants will be 
580 
reminded to use the same blood glucose meter for all fingerstick BGs during the study. 
581 
 
582 
Participants will be provided with a study blood ketone meter and test strips to be used at home 
583 
per manufacturer guidelines. 
584 
All study blood ketone meters will be QC tested by study staff with at least two different 
585 
concentrations of control solution, if available.  A tested meter will not be used in a study if it 
586 
does not read within the target range at each concentration per manufacturer labeling.   
587 
Participants will be instructed to perform blood ketone testing as described in Glycemic 
588 
Treatment Guidelines (see Participant Manual). A home glucagon emergency kit is considered 
589 
standard of care. Participants who currently do not have one will be asked to obtain a 
590 
prescription for the glucagon emergency kit. 
591 
The study team may inquire about ketone readings if the study visits are performed remotely. If 
592 
visits are done in person, the glucometer may be uploaded. 
 
593 

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Chapter 6: Study Procedures  
594 
 
595 
After eligibility is confirmed, participants will undergo a run-in phase. This visit may occur on the 
596 
same day as the screening visit and should be completed within 30 days once screening elements 
597 
are completed and eligibility determined.  This visit may occur as an in-person office visit or via 
598 
telecommunication. For visits occurring remotely, these relevant devices will be shipped to the 
599 
participant. 
600 
The purpose of the run-in phase is to obtain about 14 days of baseline data while the participant 
601 
is following their usual care with their personal t:slim X2 study pump and Dexcom G6 CGM. The 
602 
study team may elect to allow the participant to repeat the run-in phase as needed.   
603 
At Visit 2, participants will be trained on the CGM and insulin pump, if relevant, as described in 
604 
section 5.1 and 4.2. Participants will also be trained on blood glucose meter if relevant and the 
605 
ketone meter as described in section 5.5 and 4.6. 
606 
A pregnancy test will be repeated as needed if more than 30 days has elapsed since the 
607 
prior pregnancy test.  
608 
Study clinicians may optimize insulin pump settings if needed during this visit. Participants will 
609 
be allowed to make insulin dosing decisions per their usual care but will be asked to avoid 
610 
changing insulin pump settings during the two-week run-in.   
611 
 
612 
 Randomization Criteria 
613 
After the completion of at least 2 weeks of run-in data, participants will have a randomization 
614 
visit. This visit can occur between 14-28 days from Visit 2. This visit can be conducted either in-
615 
person office visit or as a remote visit.   
616 
Screening failures and study dropout participants may be replaced.  
617 
This visit may be performed as an office visit, or via telecommunication. 
618 
 Participants 
619 
Participants will be randomized 1:1 to either: 
620 
• Group 1: Use of AID and ATM / WST for 6 weeks 
621 

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• Group 2: Use of AID,  ATM / WST, and BAM for 6 weeks 
622 
The randomization scheme will be completed prior to the first study participant and will be done 
623 
by a study team member who is not involved with enrollment.   
624 
 
625 
Insulin pump optimization will occur during the study as described in Section 4.2.1. 
626 
 
627 
These visits will occur either as in-person office visits or remote visits. These visits will occur 
628 
weekly (+/- 3 day). Prior to each phone visit, participants will be asked to download any relevant 
629 
devices if applicable (i.e. not using a shared web-based app for data such as the t:connect mobile 
630 
app or G6 mobile app). During these visits, the study team will:  
631 
• Answer any questions and inquire about any device complaints.  
632 
• Inquire about new medications, updates to medical conditions, adverse events, and 
633 
whether the adverse event was related to study device use. 
634 
• Inquire about ketone readings (a ketone meter download will not be required)  
635 
• Review the downloaded/uploaded data to assess completeness. 
636 
 
637 
The study team may contact the study participant as needed to ensure study compliance.  
638 
Group 1 will be asked to have a minimum of weekly interaction to review and implement weekly 
639 
parameter settings.  
640 
Group 2 will be asked to have a minimum of weekly interaction to review and implement weekly 
641 
parameter settings. Participants engaging in the BAM module will be asked to have daily contact 
642 
with that module. 
643 
The study team will determine if non-compliance should result in additional study weeks or 
644 
discontinuation from the study.   
645 
 
646 
The study team will be available to troubleshoot with the investigational WIT, BAM, and ATM / 
647 
WST.  
648 
The AID system will used per approved use without modification.  
649 

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650 
Participants may have unscheduled visits during the study period if required for additional device 
651 
training or other unanticipated needs per the study investigator discretion. 
652 
 
653 
The following procedures will be performed in both groups at the final study visit: 
654 
• Adverse events, adverse device effects, and device issues  
655 
• All devices will be downloaded (i.e. insulin pump, CGM, glucometer, ketone meter) 
656 
• Study team or participant may download the study equipment 
657 
• Questionnaires will be completed electronically when possible 
658 
• Blood will be drawn for HbA1c (which can be done on-site or locally) 
659 
• Pregnancy test (if applicable) 
660 
• Equipment may be returned in person or via Federal Express 
661 
Study participants will be instructed on how to transition back to the home insulin regimen. 
662 
Subjects will be informed that there may be a risk of severe hypoglycemia and/or severe 
663 
hyperglycemia during the transition back to the subject’s usual home insulin parameters. The 
664 
study physician will be available for consultation during this transition period.   
665 
All study devices will be returned except the study glucometers or ketone meters may be retained 
666 
by the study participant after download is completed. 
667 
 
668 
Approximately 48 hours after the participant completes the home use of the equipment portion 
669 
of the study, the study team will contact the participant via phone/email/text to assess: 
670 
• Adverse events  
671 
• Confirm HbA1c completed 
672 
• Equipment returned in person or via Federal Express  
673 
 
674 
Participants who withdraw from the study will be asked to complete the Final and Post Study 
675 
Check-In Visit requirements. 
 
676 

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Chapter 7: Testing Procedures 
677 
 
678 
 HbA1c  
679 
• A blood sample will be obtained at screening to obtain a baseline hemoglobin A1c level. 
680 
Blood test obtained within 2 weeks prior to enrollment may be used. 
681 
• HbA1c level may be measured by study team using the DCA2000, a comparable point of 
682 
care device, at time of screening  
683 
• Labs may be obtained at a local laboratory convenient to the participant. 
684 
 Comprehensive Metabolic Panel/TSH/Hematocrit 
685 
• A blood sample may be obtained at screening to assess kidney and liver functioning, 
686 
thyroid function or hematocrit.  
687 
• Labs may be obtained at a local laboratory convenient to the participant. 
688 
 Pregnancy Test 
689 
• A serum or urine pregnancy test will be required for women of childbearing potential at 
690 
the screening visit, prior to each study equipment training session and at the end of the 
691 
study.  Test must be negative to participate in the study.  
692 
 
693 
Questionnaires are completed as noted below for all participants.  
694 
 Questionnaire Schedule 
695 
Screening:  
696 
• ABC Pilot Study Baseline: This questionnaire has 5 open-ended questions for baseline 
697 
assessment of expectations for the investigational system. 
698 
Administration time is approximately 5 minutes. 
699 
• INSPIRE Survey: The INSPIRE (Insulin Delivery Systems: Perceptions, Ideas, Reflections and 
700 
Expectations) survey was developed to assess various aspects of a user’s experience 
701 
regarding automated insulin delivery. The surveys include various topics important to 
702 
patients with type 1 diabetes based upon >200 hours of qualitative interviews and focus 
703 
groups. The adult survey includes 31 items. Response options for all surveys include a 5-
704 
point Likert scale from strongly agree to strongly disagree, along with an N/A option.  
705 

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Administration time is approximately 5 minutes. 
706 
Final Visit: 
707 
• ABC Pilot Study Follow-up: This questionnaire has 5 open-ended questions for post-study 
708 
assessment of experience with investigational system that are similar to the baseline 
709 
questionnaire. 
710 
Administration time is approximately 5 minutes. 
711 
• INSPIRE Survey: Similar survey administered at Screening Visit.  
712 
Administration time is approximately 5 minutes.     
 
713 

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Chapter 8:  Risks Associated with Clinical Trial 
714 
 
715 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are 
716 
handled to minimize this risk.  Hypoglycemia, hyperglycemia and ketone formation are always a 
717 
risk in participants with type 1 diabetes and participants will be monitored for these symptoms.  
718 
 Venipuncture Risks 
719 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws can 
720 
cause some common reactions like pain, bruising, or redness at the sampling site.  Less common 
721 
reactions include bleeding from the sampling site, formation of a small blood clot or swelling of 
722 
the vein and surrounding tissues, and fainting. 
723 
 Fingerstick Risks 
724 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
725 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital 
726 
laboratory tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount 
727 
of bleeding under the skin will produce a bruise.  A small scar may persist for several weeks.  The 
728 
risk of local infection is less than 1 in 1000.  This should not be a significant contributor to risks in 
729 
this study as finger sticks are part of the usual care for people with diabetes. 
730 
 Subcutaneous Catheter Risks (CGM) 
731 
Participants using the CGM will be at low risk for developing a local skin infection at the site of 
732 
the sensor needle placement.  If a catheter is left under the skin for more than 24 hours it is 
733 
possible to get an infection where it goes into the skin, with swelling, redness and pain.  There 
734 
may be bleeding where the catheter is put in and bleeding under the skin causes a bruise (1 in 10 
735 
risk). 
736 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
737 
leave a small portion of the sensor under the skin that may cause redness, swelling, or pain at 
738 
the insertion site.  The participant should be further instructed to notify the study coordinator 
739 
immediately if this occurs. 
740 
 Risks of Hypoglycemia  
741 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a low 
742 
blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and possibly less 
743 
than it would be as part of daily living.  Symptoms of hypoglycemia can include sweating, 
744 

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jitteriness, and not feeling well.  There is the possibility of fainting or seizures (convulsions) and 
745 
that for a few days the participant may not be as aware of symptoms of hypoglycemia.  A CGM 
746 
functioning poorly and significantly over-reading glucose values could lead to inappropriate 
747 
insulin delivery. 
748 
 Risks of Hyperglycemia  
749 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
750 
extended period or if the pump or infusion set is not working properly.  A CGM functioning poorly 
751 
and significantly under-reading glucose values could lead to inappropriate suspension of insulin 
752 
delivery. 
753 
 Hb1Ac Risk 
754 
An NGSP Point of Care analyzer (i.e. DCA Vantage Analyzer) may be utilized at the research site 
755 
to obtain the subject’s HbA1c level. 
756 
 Other Risks  
757 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
758 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
759 
If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, 
760 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
761 
medication may be required. 
762 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump infusion 
763 
sites are inserted under the skin.  It is possible that any part that is inserted under the skin may 
764 
cause an infection.  These occur very infrequently, but, if an infection was to occur, oral and/or 
765 
topical antibiotics can be used.  The risk of skin problems could be greater if you use a sensor for 
766 
longer than it is supposed to be used.  Therefore, participants will be carefully instructed about 
767 
proper use of the sensor. 
768 
Data downloaded from the CGM, pump, and glucose and ketone meter will be collected for the 
769 
study as measures of diabetes self-management behaviors.  Some people may be uncomfortable 
770 
with the researchers' having such detailed information about their daily diabetes habits. 
771 
 Known Potential Benefits  
772 
It is expected that this protocol will yield increased knowledge about using an automated insulin 
773 
delivery system with anticipatory action to control glucose levels.  The individual participant may 
774 
not benefit from study participation. 
775 

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 Risk Assessment 
776 
Based on the facts that (1) adults and adolescents with diabetes experience mild hypoglycemia 
777 
and hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
778 
intervention involves periodic automated insulin dosing that may increase the likelihood of 
779 
hypoglycemia, and periodic automated attenuation of insulin delivery that may increase the 
780 
likelihood of hyperglycemia, (3) mitigations are in place, and have been tested in prior studies 
781 
using the investigational device system in the home setting, that limit the likelihood of excessive 
782 
insulin dosing or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and 
783 
hyperglycemia can be achieved, it is the assessment of the investigators that this protocol falls 
784 
under DHHS 46.405 which is a minor increase over minimal risk. In addition, it is the belief of the 
785 
investigators that this study also presents prospect of direct benefit to the participants and 
786 
general benefit to others with diabetes. 
787 
 
788 
The study is being conducted in compliance with the policies described in the study policies 
789 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
790 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
791 
Whenever possible, data will be directly collected in electronic case report forms, which will be 
792 
considered the source data. 
793 
The protocol is considered a significant risk device study, due to the fact that investigational 
794 
modules of BAM and ATM / WST are experimental.  Therefore, an investigational device 
795 
exemption (IDE) from the U.S. Food and Drug Administration (FDA) is required to conduct the 
796 
study. 
 
797 

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Chapter 9:   Adverse Events, Device Issues, and Stopping Rules 
798 
 
799 
 Adverse Events (AE) 
800 
Any untoward medical occurrence in a study participant, irrespective of the relationship between 
801 
the adverse event and the device(s) under investigation (section 9.2) for reportable adverse 
802 
events for this protocol). 
803 
 Serious Adverse Event (SAE) 
804 
 Any untoward medical occurrence that: 
805 
• results in death. 
806 
• is life-threatening; (a non-life-threatening event which, had it been more severe, might 
807 
have become life-threatening, is not necessarily considered a serious adverse event). 
808 
• requires inpatient hospitalization or prolongation of existing hospitalization. 
809 
• results in persistent or significant disability/incapacity or substantial disruption of the 
810 
ability to conduct normal life functions (life threatening). 
811 
• is a congenital anomaly or birth defect. 
812 
• is considered a significant medical event by the investigator based on medical judgment 
813 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
814 
prevent one of the outcomes listed above). 
815 
 Unanticipated Adverse Device Effect (UADE) 
816 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
817 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
818 
nature, severity, or degree of incidence in the investigational plan or application (including a 
819 
supplementary plan or application), or any other unanticipated serious problem associated with 
820 
a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
821 
 Adverse Device Effect (ADE) 
822 
Any untoward medical occurrence in a study participant which the device may have caused or to 
823 
which the device may have contributed. 
824 
 Device Complaints and Malfunctions 
825 
A device complication or complaint is something that happens to a device or related to device 
826 
performance, whereas an adverse event happens to a participant.  A device complaint may occur 
827 

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independently from an AE, or along with an AE.  An AE may occur without a device complaint or 
828 
there may be an AE related to a device complaint.  A device malfunction is any failure of a device 
829 
to meet its performance specifications or otherwise perform as intended.  Performance 
830 
specifications include all claims made in the labeling for the device.  The intended performance 
831 
of a device refers to the intended use for which the device is labeled or marketed. (21 CFR 803.3).   
832 
 
833 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
834 
meets one of the following criteria: 
835 
• a serious adverse event as defined in section 9.1.2 
836 
• an adverse device effect as defined in section 9.1.4, unless excluded from reporting in 
837 
section 9.7 
838 
• an adverse event as defined in section 9.1.4 occurring in association with a study 
839 
procedure 
840 
• an ae as defined in section 9.1.1 which leads to discontinuation of a study device for 2 or 
841 
more hours 
842 
• hypoglycemia meeting the definition of severe hypoglycemia as defined in section 9.2.1  
843 
• diabetic ketoacidosis (DKA) as defined in section 9.2.2 or in the absence of DKA, a 
844 
hyperglycemic or ketosis event meeting the criteria defined below 
845 
• hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as 
846 
adverse events unless associated with an Adverse Device Effect.  Skin reactions from 
847 
sensor placement are only reportable if severe and/or required treatment. 
848 
 Hypoglycemia Event 
849 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
850 
when the following definition for severe hypoglycemia is met:   
851 
• the event required assistance of another person due to altered consciousness, and 
852 
required another person to actively administer carbohydrate, glucagon, or other 
853 
resuscitative actions;  
854 
• impaired cognitively to the point that he/she was unable to treat himself/herself, was 
855 
unable to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or 
856 
experienced seizure or coma.  These episodes may be associated with sufficient 
857 
neuroglycopenia to induce seizure or coma; 
858 

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• if plasma glucose measurements are not available during such an event, neurological 
859 
recovery attributable to the restoration of plasma glucose to normal is considered 
860 
sufficient evidence that the event was induced by a low plasma glucose concentration. 
861 
 Hyperglycemia Events/Diabetes Ketoacidosis 
862 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
863 
event when one of the following four criteria is met:  
864 
• the event involved DKA, as defined by the Diabetes Control and Complications Trial 
865 
(DCCT) and described below 
866 
• evaluation or treatment was obtained at a health care provider facility for an acute event 
867 
involving hyperglycemia or ketosis 
868 
• blood ketone level ≥1.5 mmol/L and communication occurred with a health care provider 
869 
at the time of the event 
870 
• blood ketone level ≥3.0 mmol/L, even if there was no communication with a health care 
871 
provider 
872 
Hyperglycemic events are classified as DKA if the following are present: 
873 
• symptoms such as polyuria, polydipsia, nausea, or vomiting; 
874 
• serum ketones ≥1.5 mmol/l or large/moderate urine ketones; 
875 
• treatment provided in a health care facility 
876 
• all reportable Adverse Events—whether volunteered by the participant, discovered by 
877 
study personnel during questioning, or detected through physical examination, 
878 
laboratory test, or other means—will be reported on an adverse event form online.   
879 
 
880 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
881 
by determining if there is a reasonable possibility that the adverse event may have been caused 
882 
by the study device. 
883 
To ensure consistency of adverse event causality assessments, investigators should apply the 
884 
following general guideline when determining whether an adverse event is related: 
885 
• There is a plausible temporal relationship between the onset of the adverse event and 
886 
the study intervention, and the adverse event cannot be readily explained by the 
887 
participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
888 
adverse event follows a known pattern of response to the study intervention; and/or the 
889 

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adverse event abates or resolves upon discontinuation of the study intervention or dose 
890 
reduction and, if applicable, reappears upon re-challenge. 
891 
• Evidence exists that the adverse event has an etiology other than the study intervention 
892 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
893 
concomitant medication); and/or the adverse event has no plausible temporal 
894 
relationship to study intervention. 
895 
 
896 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or 
897 
(3) severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 
898 
event is not necessarily serious.  For example, itching for several days may be rated as severe, 
899 
but may not be clinically serious. 
900 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
901 
participant’s daily activities. 
902 
• MODERATE: Usually causes a low level of inconvenience or concern to the participant and 
903 
may interfere with daily activities, but is usually ameliorated by simple therapeutic 
904 
measures. 
905 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic 
906 
drug therapy or other treatment. 
907 
 
908 
Adverse events will be coded per the UVA IRB website instructions (i.e. mild, moderate, severe).   
909 
Adverse events that continue after the participant’s discontinuation or completion of the study 
910 
will be followed until their medical outcome is determined or until no further change in the 
911 
condition is expected. 
912 
 
913 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
914 
• RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae.  
915 
Record the AE/SAE stop date. 
916 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized without 
917 
change in the event anticipated.  Record the AE/SAE stop date. 
918 
• FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event that 
919 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the 
920 

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time of death; however, were not the cause of death, will be recorded as “resolved” at 
921 
the time of death. 
922 
• NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as the 
923 
event was ongoing with an undetermined outcome. 
924 
• An ongoing outcome will require follow-up by the site in order to determine the final 
925 
outcome of the AE/SAE. 
926 
• The outcome of an ongoing event at the time of death that was not the cause of death, 
927 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
928 
date. 
929 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant or 
930 
the participant’s records to determine the outcome (for example, a participant that was 
931 
lost to follow-up). 
932 
All clinically significant abnormalities of clinical laboratory measurements or adverse events 
933 
occurring during the study and continuing at study termination should be followed by the 
934 
participant’s physician and evaluated with additional tests (if necessary) until diagnosis of the 
935 
underlying cause, or resolution.  Follow-up information should be recorded on source 
936 
documents. 
937 
If any reported adverse events are present when a participant completes the study, or if a 
938 
participant is withdrawn from the study due to an adverse event, the participant will be 
939 
contacted for re-evaluation within 2 weeks.  If the adverse event has not resolved, additional 
940 
follow-up will be performed as appropriate.  Every effort should be made by the Investigator or 
941 
delegate to contact the participant until the adverse event has resolved or stabilized. 
942 
 
943 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
944 
whether an adverse event occurred, except in the following circumstances. 
945 
The following device issues are anticipated and will not be reported but will reported as an 
946 
Adverse Event if the criteria for AE reporting described above are met: 
947 
• Component disconnections 
948 
• CGM sensors lasting fewer than the number of days expected per CGM labeling 
949 
• CGM tape adherence issues 
950 
• Pump infusion set occlusion not leading to ketosis 
951 
• Battery lifespan deficiency due to inadequate charging or extensive wireless 
952 
communication 
953 

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• Intermittent device component disconnections/communication failures not leading to 
954 
system replacement 
955 
• Device issues clearly addressed in the user guide manual that do not require additional 
956 
troubleshooting 
957 
• Skin reactions from CGM sensor placement or pump infusion set placement that do not 
958 
meet criteria for AE reporting 
959 
 
960 
• UADEs must be reported within 10 working days to the FDA after the sponsor first 
961 
receives notice of the adverse effect. 
962 
• Other reportable adverse events, device malfunctions (with or without an adverse event) 
963 
and device complaints should be reported promptly, but there is no formal required 
964 
reporting period. 
965 
• The IDE Sponsor will investigate the UADE and if indicated, report the results of the 
966 
investigation to the IRBs and FDA, within 10 working days of the study team becoming 
967 
aware of the UADE per 21CFR 812.46(b) (2).  
968 
• In the case of a device system component malfunction (e.g. pump, CGM, control 
969 
algorithm), information will be forwarded to the responsible manufacturer by the study 
970 
personnel. 
971 
 
972 
 Participant Discontinuation  
973 
Rules for discontinuing study device use are described below. 
974 
• The investigator believes it is unsafe for the participant to continue on the intervention.  
975 
This could be due to the development of a new medical condition or worsening of an 
976 
existing condition; or participant behavior contrary to the indications for use of the device 
977 
that imposes on the participant’s safety 
978 
• The participant requests that the treatment be stopped 
979 
• Two distinct episodes of DKA 
980 
• Two distinct severe hypoglycemia events as defined in section 9.2.1. 
981 
 Suspending/Stopping Overall Study 
982 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
983 
hyperglycemia event (as defined in section 9.2), use of the study device system will be suspended 
984 
while the problem is diagnosed. 
985 

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In addition, study activities could be similarly suspended if the manufacturer of any constituent 
986 
study device requires stoppage of device use for safety reasons (e.g. product recall).  The affected 
987 
study activities may resume if the underlying problem can be corrected by a protocol or system 
988 
modification that will not invalidate the results obtained prior to suspension. Definition of a Data 
989 
Breach. 
990 
The study must also stop if there are three severe hypoglycemia events or three DKA events. 
991 
After further medical/safety review of the events, the study may resume if the events are 
992 
determined to be unrelated to an unanticipated system malfunction. 
993 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, access, 
994 
or use of protected health information (PHI) that compromises the security or privacy of such 
995 
information.  
 
996 

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Chapter 10: Miscellaneous Considerations  
997 
 
998 
Participants using non-approved insulins at the time of enrollment will be asked to contact their 
999 
personal physician to change their prescribed personal insulin to a rapid-acting insulin approved 
1000 
for use in the t:slim X2 pump (e.g. lispro or aspart) for the duration of the trial. 
1001 
The devices (insulin pump, CGM) must be removed before Magnetic Resonance Imaging (MRI), 
1002 
Computed Tomography (CT) or diathermy treatment. Participants may continue in the trial after 
1003 
temporarily discontinuing use if requiring one of the treatments above. 
1004 
 
1005 
Participation in the study is voluntary. Participant may withdraw at any time.  For participants 
1006 
who do withdraw from the study, the study team will determine if their data will be used in 
1007 
analysis.  
1008 
 
1009 
For security and confidentiality purposes, subjects will be assigned an identifier that will be used 
1010 
instead of their name.  Protected health information gathered for this study may be shared with 
1011 
the third party collaborators.  De-identified subject information may also be provided to 
1012 
collaborators involved in the study after the appropriate research agreement has been executed. 
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Chapter 11: Statistical Consideration 
1014 
The intent of this pilot-feasibility study is to introduce and initially test elements of two modules 
1015 
to be included in a future Adaptive Biobehavioral Control (ABC) system: (1) A Behavioral 
1016 
Adaptation Module (BAM) and (2) An Auto Titration Module (ATM) and a Web Simulation Model 
1017 
(WST). BAM and ATM / WST will be provided to users of the t:slim X2 with Control-IQ closed-loop 
1018 
system. The only purpose of this trial is safety testing and receiving feedback from the 
1019 
participants regarding system functionality and user interface.   
1020 
 
1021 
1022 
The study will recruit current users of the Control-IQ system. Following a 2-week baseline using 
1023 
Control-IQ only, the participants will be randomized 1:1 to Control-IQ + ATM / WST vs Control IQ 
1024 
+ ATM / WST + BAM and will be followed for 6 weeks. The randomization list will use a sequence 
1025 
of computer-generated pseudorandom Bernoulli trials. The 6 weeks of active trial will be used 
1026 
for assessment of the safety and usability of ATM / WST and BAM. The baseline data and the last 
1027 
2 weeks of the active trial will be used for secondary comparisons of CGM-based metrics of 
1028 
glycemic control. 
1029 
 
1030 
We intend to recruit up to 45 users of Control-IQ, with the objective to randomize N=30 subjects. 
1031 
The number of participants is a convenience sample not based on statistical principles. This 
1032 
sample will provide ~180 weeks of data for the assessment of the safety and utility of the ATM 
1033 
and up to 90 weeks for assessment of the safety and utility of the BAM. 
1034 
 
1035 
 Primary Efficacy Endpoint  
1036 
Safety assessment of ATM / WST and BAM. 
1037 
 Secondary Outcome 
1038 
CGM-based metrics and user experience (UX) questionnaires, including: 
1039 

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• Percentage of readings in the target ranges of 70-180 and 70-140 mg/dl;  
1040 
• Mean glucose; 
1041 
• Glucose variability measured by standard deviation and coefficient of variation;  
1042 
• Percentage of readings <70, 60, and 54 mg/dl;  
1043 
• Low blood glucose index (LBGI)10  
1044 
• Percentage of readings >180, 250, and 300 mg/dl;  
1045 
• High blood glucose index (HBGI)10 
1046 
• ABC Pilot Pre and Post Study Questionnaire 
1047 
• INSPIRE 
1048 
 
1049 
All randomized participants will be included in these analyses and the circumstances of all 
1050 
reportable cases of the following will be summarized and tabulated by treatment group: 
1051 
• Severe hypoglycemia; 
1052 
• Diabetic ketoacidosis (DKA); 
1053 
• Ketone events defined as a calendar day with ketone level >1.0 mmol/L; 
1054 
• Serious adverse events (SAE) with a possible or greater relationship to a study device 
1055 
(including anticipated and unanticipated adverse device effects); 
1056 
• Other serious adverse events not related to a study device, and  
1057 
• Adverse device effects (ADE) that do not meet criteria for SAE. 
1058 
Criteria for Success have been discussed with FDA during the submission of our previous pilot 
1059 
study (IDE G170255, “A Pilot Test of t:slim X2 with Control-IQ Technology”), which was used to 
1060 
introduce Control-IQ and enable a subsequent pivotal trial.  These criteria included system safety 
1061 
checks and CGM-based performance criteria consistent with the recommendations of the 
1062 
International Consensus on Time-in-Range.  Because these criteria are well established, we will 
1063 
keep them to gauge the success of the pilot evaluation of the new modules ATM / WST and BAM:  
1064 
• No critical ATM / WST or BAM errors; 
1065 
• No SAE or ADE related to the use of ATM / WST or BAM; 
1066 
• Percent time in the range 70-180 mg/dL: mean 71% ±11; 
1067 
• Percent time <70 mg/dL: median <5%.  
1068 
• Percent time >250 mg/dL: median <10%.  
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1070 
Baseline demographic and clinical characteristics of the cohort of all randomized participants will 
1071 
be summarized in a table using summary statistics appropriate to the distribution of each 
1072 
variable. Descriptive statistics will be displayed overall and by treatment group, and will include: 
1073 
• Demographics (e.g. age, duration of diabetes, and other); 
1074 
• Baseline HbA1c, and 
1075 
• CGM-based metrics from the 2-week baseline use of Control-IQ: 
1076 
o Percentage of readings in the target ranges of 70-180 and 70-140 mg/dl;  
1077 
o Mean glucose; 
1078 
o Glucose variability measured by standard deviation and coefficient of variation;  
1079 
o Percentage of readings <70, 60, and 54 mg/dl;  
1080 
o Low blood glucose index (LBGI) ;10 
1081 
o Percentage of readings >180, 250, and 300 mg/dl;  
1082 
o High blood glucose index (HBGI).10 
1083 
 
1084 
The following tabulations and analyses will be performed by treatment group to assess device 
1085 
issues: 
1086 
• Device malfunctions requiring study team contact and other reported device issues 
1087 
• Sensor performance metrics (difference, absolute relative difference, and International 
1088 
Organization for Standardization criteria) – if applicable, by sensor version. 
1089 
• % time CGM data available - overall and by month 
1090 
• % time in different operational modes per week - overall and by month 
1091 
 
1092 
The study design includes repeated measures (baseline vs last 2 weeks of study) on all secondary  
1093 
CGM and UX outcomes (Figure 1); thus, we will use a linear mixed-effect model that corresponds 
1094 
well to this structure5,6 (e.g. Linear Mixed Models in SPSS.7), with “Subject” as a random factor 
1095 
and “Group” as a fixed factor. The models will adjust for age and HbA1c as fixed effects.  We 
1096 
should note that similar results may be generated by repeated measures ANOVA, but mixed 
1097 
models handle missing data better (e.g. ANOVA only uses listwise deletion, which could reduce 
1098 
power and introduce bias towards study completers).8,9 
1099 
The general principles that will be followed during analysis are: 
1100 
• The analysis will follow an Intention-to-treat (ITT) approach;  
1101 

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• All randomized participants will be included in the primary safety analysis and in the 
1102 
secondary analyses of CGM metrics.  
1103 
• All covariates obtained on a continuous scale will be entered into the models as 
1104 
continuous variables, unless it is determined that a variable does not have a linear 
1105 
relationship with the outcome. In such a case, categorization and/or transformation will 
1106 
be explored. All p-values will be two-sided. 
1107 
• Standard residual diagnostics will be performed for all analyses. If values are highly 
1108 
skewed, then an alternate transformation or nonparametric methods will be used. 
1109 
Previous experience suggests that no transformation or nonparametric analyses will be 
1110 
necessary for TIR 70-180 mg/dL, TIR above 180 mg/dL, mean glucose, or HbA1c.Other 
1111 
outcomes, such as TIR below 70 mg/dL are typically skewed. 
 
1112 

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Chapter 12: Data Collection and Monitoring 
1113 
 
1114 
The study data are collected through a combination of case report forms (electronic and paper) 
1115 
and electronic device data files obtained from the software and individual hardware 
1116 
components.  These electronic device files and electronic CRFs are considered the primary source 
1117 
documentation. 
1118 
When data are directly collected in electronic case report forms, this will be considered the 
1119 
source data.  Records will be maintained in accordance with ICH E6 and institutional regulatory 
1120 
requirements for the protection of confidentiality of participants. 
1121 
 
1122 
Study documents should be retained for a minimum of 2 years after the last approval of a 
1123 
marketing application in an ICH region and until there are no pending or contemplated marketing 
1124 
applications in an ICH region or until at least 2 years have elapsed since the formal 
1125 
discontinuation of clinical development of the investigational product.  These documents should 
1126 
be retained for a longer period, however, if required by local regulations.  No records will be 
1127 
destroyed without the written consent of the sponsor, if applicable.  It is the responsibility of the 
1128 
sponsor to inform the investigator when these documents no longer need to be retained. 
1129 
 
1130 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practices 
1131 
(GCP), or procedure requirements.  The noncompliance may be either on the part of the 
1132 
participant, the investigator, or the study site staff.  As a result of deviations, corrective actions 
1133 
may be developed by the site and implemented as appropriate.  Major deviations will be reported 
1134 
to the IRB-HSR within 7 calendar days of when the study team becomes aware of the event.  
1135 

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Chapter 13: Ethics/Protection of Human Participants 
1136 
 
1137 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1138 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
1139 
CFR Part 56, and/or the ICH E6. 
1140 
 
1141 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1142 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1143 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1144 
require review and approval by the IRB before the changes are implemented to the study.  All 
1145 
changes to the consent form will be IRB approved; a determination will be made regarding 
1146 
whether previously consented participants need to be re-consented. 
1147 
 
1148 
 Consent Procedures and Documentation 
1149 
Informed consent is a process that is initiated prior to an individual’s agreement to participate in 
1150 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
1151 
risks and possible benefits of participation will be provided.  Consent forms will be IRB approved 
1152 
and the participant will be asked to read and review the document.  The investigator or their 
1153 
delegate will explain the research study to the participant and answer any questions that may 
1154 
arise.  All participants will receive a verbal explanation in terms suited to their comprehension of 
1155 
the purposes, procedures, and potential risks of the study and of their rights as research 
1156 
participants.  Participant will have the opportunity to carefully review the written consent form 
1157 
and ask questions prior to signing. 
1158 
The participant will sign the informed consent document prior to any procedures being done 
1159 
specifically for the study. A copy of the informed consent document will be given to the 
1160 
participant for their records.  The rights and welfare of the participants will be protected by 
1161 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
1162 
decline to participate in this study. 
1163 
 Participant and Data Confidentiality 
1164 
The study monitor, representatives of the IRB or device company supplying study product may 
1165 
inspect all documents and records required to be maintained by the investigator, including but 
1166 
not limited to, medical records (office, clinic, or hospital) for the participants in this study.   
1167 

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The study participant’s contact information will be securely stored at the clinical site for internal 
1168 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
1169 
location for as long a period as dictated by local IRB and Institutional regulations. 
1170 
Study participant research data, which is for purposes of statistical analysis and scientific 
1171 
reporting, will be transmitted to and stored at the University of Virginia Center for Diabetes 
1172 
Technology.  The study data entry and study management systems used by research staff will be 
1173 
secured and password protected.  At the end of the study, all study databases may be de-
1174 
identified and archived at the University of Virginia Center for Diabetes Technology. 
1175 

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Chapter 14: References  
1176 
1. Kovatchev BP, Anderson SM, Raghinaru D, et al, for the iDCL Trial Research Group. 
1177 
Randomized Controlled Trial of Mobile Closed-Loop Control. Diabetes Care. 2020; 43:607-
1178 
615. PMID: 31937608 
1179 
2. Brown SA, Kovatchev BP, Raghinaru D, et al, for the iDCL Trial Research Group. 6-month 
1180 
randomized multicenter trial of closed-loop control in type 1 diabetes. N Engl J Med. 2019; 
1181 
381: 1707-17. PMID: 31618560. 
1182 
3. Breton MD, Kanapka LG, Beck RW, et al, for the iDCL Trial Research Group. A Randomized 
1183 
Trial of Closed-Loop Control in Children with Type 1 Diabetes. N Engl J Med. 2020; 383:836-
1184 
845. PMID: 32846062. 
1185 
4. Kovatchev BP, Cobelli C.  Glucose variability: timing, risk analysis, and relationship to 
1186 
hypoglycemia in diabetes. Diabetes Care. 2016; 39: 502-510. PMCID: PMC4806774 
1187 
5. Ching Ng W-K, Ching MK W. Markov Chains. Springer-Verlag; 2006. 
1188 
6. Kovatchev BP. Decision Support System for Patients with Diabetes: Concept, Goals, and 
1189 
Feasibility. Advanced Technologies and Treatments for Diabetes (ATTD), Berlin, Germany, 
1190 
2019. 
1191 
7. Kovatchev BP. Building a Virtual Image of a Patient – the VIP Approach to Precision Medicine 
1192 
for Diabetes. Advanced Technologies and Treatments for Diabetes (ATTD), Berlin, Germany, 
1193 
2019 
1194 
8. Kovatchev BP, Mendosa P, Anderson SM, Hawley JS, Ritterband LM, Gonder-Frederick L. 
1195 
Effect of automated bio-behavioral feedback on the control of type 1 diabetes. Diabetes Care. 
1196 
2011; 34: 302-307. PMCID: PMC3024338 
1197 
9. Fabris C, Heinemann L, Beck RW, Cobelli C, Kovatchev B. Estimation of Hemoglobin A1c From 
1198 
Continuous Glucose Monitoring Data in Individuals With Type 1 Diabetes: Is Time in Range All 
1199 
We Need? Diabetes Technol Ther. 2020 doi: 10.1089/dia.2020.0236 
1200 
10. Kovatchev BP. Metrics for glycaemic control: from HbA1c to continuous glucose monitoring. 
1201 
Nature Reviews Endocrinology. 2017; 13: 425-436. PMID: 28304392 
1202 
11. Patek SD, Lv D, Ortiz EA, Hughes-Karvetski C, Kulkarni S, Zhang Q, Breton MD. Empirical 
1203 
representation of blood glucose variability in a compartmental model. InPrediction Methods 
1204 
for Blood Glucose Concentration 2016 (pp. 133-157). Springer, Cham. 
1205 
12. Colmegna P, Wang K, Garcia-Tirado J, Breton MD. Mapping data to virtual patients in type 1 
1206 
diabetes. Control Engineering Practice. 2020 Oct 1;103:104605. 
1207 
13. Hughes J, Gautier T, Colmegna P, Fabris C, Breton MD, Replay Simulations with Personalized 
1208 
Metabolic Model for Treatment Design and Evaluation in Type 1 Diabetes. Journal of Diabetes 
1209 
Technology and Therapeutics, 2020 In Press 
1210 

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14. Brown S, Raghinaru D, Emory E, and Kovatchev BP. First Look at Control-IQ: A New-
1211 
Generation Automated Insulin Delivery System. Diabetes Care 2018; 41:2634-2636, PMID: 
1212 
30305346 
1213 
15. Kovatchev BP, Kollar L, Anderson SM, Barnett C, Breton MD, Carr K, Gildersleeve R, Oliveri 
1214 
MC, Wakeman CA, Brown SA. Evening and overnight closed-loop control versus 24/7 
1215 
continuous closed-loop control for type 1 diabetes: a randomized crossover trial. Lancet 
1216 
Digital Health 2020; 2: e64-e73.  
1217 
16. Ekhlaspour L, Forlenza GP, Chernavvsky D, Maahs DM, Wadwa RP, DeBoer MD, Messer LH, 
1218 
Town M, Pinnata J, Kruse G, Kovatchev BP, Buckingham BA, Breton MD. Closed Loop Control 
1219 
in Adolescents and Children During Winter Sports: Use of the Tandem Control-IQ AP System. 
1220