Efficacy of inControl Advice: A Decision Support System (DSS) for Diabetes
Phase: NA
Conditions: Type1 Diabetes Mellitus
Sponsor: University of Virginia

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx 
Efficacy of inControl Advice:  A Decision Support System (DSS) 
for Diabetes 
A Randomized Clinical Trial to Assess the Efficacy of CGM+DSS versus CGM to Improve 
Glucose Control in Subjects with T1DM on MDI Therapy 
Version 1.3 
August 31, 2017 
Universal Trial Number (UTN): U1111-1191-3911 
ALL INFORMATION & ANY ATTACHMENTS CONTAINED IN THIS PROTOCOL ARE 
CONFIDENTIAL INFORMATION. 
NCT03093636

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1 
 
2 
 
3 
Protocol Chair: 
4 
Stacey Anderson, MD 
5 
University of Virginia 
6 
 
7 
 
8 
Participating Institutions: 
9 
University of Virginia, Charlottesville, VA 
10 
Stanford University, California 
11 
Mount Sinai School of Medicine, New York City 
12 
 
13 
 
14 
Project Principal Investigator: 
15 
Boris Kovatchev, Ph.D. 
16 
University of Virginia 
17 
 
18 
 
19 
Principal Investigator – Stanford Site: 
20 
Bruce Buckingham, MD 
21 
Stanford University 
22 
 
23 
 
24 
Principal Investigator – Mount Sinai Site: 
25 
Carol Levy, MD 
26 
Icahn School of Medicine at Mount Sinai 
27 
 
28 
 
 
29 

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TABLE OF CONTENTS 
30 
 
31 
1 
INTRODUCTION ...................................................................................................................... 1-7 
32 
1.1 
Background ............................................................................................................................ 1-7 
33 
1.2 
Preliminary Studies ................................................................................................................ 1-7 
34 
1.3 
Synopsis of Study Protocol .................................................................................................. 1-10 
35 
1.3.1 
Study Objective ............................................................................................................. 1-10 
36 
1.3.2 
Study Design .................................................................................................................. 1-11 
37 
1.3.3 
Major Eligibility Criteria ............................................................................................... 1-11 
38 
1.3.4 
Sample Size ................................................................................................................... 1-11 
39 
1.3.5 
Main Study Treatment Groups ...................................................................................... 1-11 
40 
1.3.6 
Main Study Visit and Phone Contact Schedule ............................................................. 1-11 
41 
1.3.7 
Endpoints ....................................................................................................................... 1-15 
42 
1.4 
General Considerations ........................................................................................................ 1-15 
43 
2 
SUBJECT SCREENING AND ENROLLMENT .................................................................. 2-17 
44 
2.1 
Study Population .................................................................................................................. 2-17 
45 
2.2 
Eligibility and Exclusion Criteria ........................................................................................ 2-17 
46 
2.2.1 
Eligibility ....................................................................................................................... 2-17 
47 
2.2.2 
Exclusion ....................................................................................................................... 2-17 
48 
2.3 
Authorization Procedures ..................................................................................................... 2-18 
49 
2.4 
Screening and Enrollment Visit Logistics ........................................................................... 2-19 
50 
2.4.1 
Data Collection and Testing .......................................................................................... 2-20 
51 
3 
PILOT TESTING OF DSS ...................................................................................................... 3-21 
52 
3.1 
Pilot Testing Overview ........................................................................................................ 3-21 
53 
4 
2-WEEK BLINDED CGM ....................................................................................................... 4-21 
54 
4.1 
2-Week Blinded CGM Overview ........................................................................................ 4-21 
55 
4.1.1 
Blinded CGM Use Assessment ..................................................................................... 4-22 
56 
5 
RANDOMIZED TRIAL .......................................................................................................... 5-23 
57 
5.1 
Randomization Visit ............................................................................................................ 5-23 
58 
5.1.1 
CGM Training ............................................................................................................... 5-24 
59 
5.1.2 
Randomization ............................................................................................................... 5-24 
60 
5.1.3 
CGM Data Downloads .................................................................................................. 5-25 
61 
5.2 
Procedures for the CGM+DSS Group ................................................................................. 5-25 
62 
5.2.1 
DSS Training ................................................................................................................. 5-25 
63 
5.3 
Procedures for the CGM Group ........................................................................................... 5-25 
64 
5.4 
Follow-up Phone Contacts for Both Groups ........................................................................ 5-26 
65 
5.4.1 
Phone Contacts .............................................................................................................. 5-26 
66 
5.4.2 
Study Conclusion Visit .................................................................................................. 5-26 
67 
5.5 
Follow-up Phone Contacts for Both Groups: Post-study ..................................................... 5-27 
68 
6 
QUESTIONNAIRES ................................................................................................................ 6-28 
69 
6.1 
Introduction .......................................................................................................................... 6-28 
70 
6.2 
Diabetes Specific Personality Questionnaire ....................................................................... 6-28 
71 
6.3 
Clarke’s Hypoglycemia Awareness Scale ........................................................................... 6-28 
72 
6.4 
Hypoglycemia Fear Survey (HFS-II) / Low Blood Sugar Survey ....................................... 6-28 
73 
6.5 
Hyperglycemia Avoidance Survey (HAS) / High Blood Sugar Survey .............................. 6-29 
74 
6.6 
Diabetes Distress Scale ........................................................................................................ 6-29 
75 
6.7 
Technology Expectation and Technology Acceptance Surveys .......................................... 6-29 
76 
7 
SAFETY MEASURES ............................................................................................................. 7-30 
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7.1 
Safety Measures ................................................................................................................... 7-30 
78 
7.1.1 
CGM Calibration ........................................................................................................... 7-30 
79 
7.1.2 
Safety Measures ............................................................................................................. 7-30 
80 
8 
ADVERSE EVENTS, DEVICE ISSUES, POTENTIAL RISKS, AND STOPPING RULES 8-
81 
31 
82 
8.1 
Adverse Event Definition..................................................................................................... 8-31 
83 
8.2 
Recording of Adverse Events .............................................................................................. 8-31 
84 
8.3 
Reporting Serious Adverse Events, Unexpected Adverse Device Effects, Serious Adverse 
85 
Reactions (SAR) and Serious Adverse Drug Reaction (SARD) .................................................... 8-32 
86 
8.4 
Device Issues........................................................................................................................ 8-34 
87 
8.5 
Potential Risks and Side Effects .......................................................................................... 8-34 
88 
8.5.1 
Venipuncture Risks ........................................................................................................ 8-35 
89 
8.5.2 
Fingerstick Risks ........................................................................................................... 8-35 
90 
8.5.3 
Subcutaneous Catheter Risks (CGM) ............................................................................ 8-35 
91 
8.5.4 
Risk of Hypoglycemia ................................................................................................... 8-35 
92 
8.5.5 
Risk of Hyperglycemia .................................................................................................. 8-35 
93 
8.5.6 
Risk of Device Reuse ..................................................................................................... 8-35 
94 
8.5.7 
Psychosocial Questionnaires ......................................................................................... 8-36 
95 
8.5.8 
Other Risks .................................................................................................................... 8-36 
96 
8.6 
Study Stopping Criteria ........................................................................................................ 8-36 
97 
8.6.1 
Subject Discontinuation of Study Treatment ................................................................. 8-36 
98 
8.6.2 
Criteria for Suspending/Stopping Overall Study ........................................................... 8-36 
99 
9 
MISCELLANEOUS CONSIDERATIONS ............................................................................ 9-37 
100 
9.1 
Benefits ................................................................................................................................ 9-37 
101 
9.2 
Subject Compensation.......................................................................................................... 9-37 
102 
9.3 
Subject Withdrawal .............................................................................................................. 9-37 
103 
9.4 
Confidentiality ..................................................................................................................... 9-37 
104 
9.5 
Drug Accountability and Storage ......................................................................................... 9-37 
105 
10 STATISTICAL CONSIDERATIONS .................................................................................. 10-39 
106 
10.1 Sample Size ........................................................................................................................ 10-39 
107 
10.2 Primary Endpoints Analyses .............................................................................................. 10-39 
108 
10.3 Secondary Efficacy Analyses ............................................................................................. 10-39 
109 
10.4 Questionnaires .................................................................................................................... 10-39 
110 
10.5 Primary Safety Analyses .................................................................................................... 10-40 
111 
10.6 Additional Tabulations ....................................................................................................... 10-40 
112 
10.7 Interim Analysis ................................................................................................................. 10-40 
113 
11 DATA COLLECTION AND MONITORING ..................................................................... 11-41 
114 
11.1 Case Report Forms and Device Data ................................................................................. 11-41 
115 
11.2 Document Storage and Retention ...................................................................................... 11-41 
116 
12 PUBLICATION POLICY ...................................................................................................... 12-42 
117 
13 REFERENCES ....................................................................................................................... 13-43 
118 
 
119 
120 

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TABLE OF ACRONYMS 
121 
 
122 
Acronym 
Abbreviation For 
ADA 
American Diabetes Association 
AP 
Artificial Pancreas 
ATTD 
Advanced Technologies & Treatments for Diabetes 
AUC 
Area Under the Curve 
BG 
Blood Glucose 
BRM 
Basal Rate Modulator 
BT 
Bluetooth 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
CLC 
Closed-Loop Control 
CSII 
Continuous Subcutaneous Insulin Infusion 
CTR 
Control-to-Range 
DSS 
Decision Support System 
DiAs 
Diabetes Assistant 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
EC 
European Commission 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAS 
Hyperglycemia Avoidance Survey 
HbA1c 
Hemoglobin A1c 
HCT 
Helmsley Charitable Trust 
HFS-II 
Hypoglycemia Fear Survey 
HMS 
Hyperglycemia Mitigation System 
ID 
Identification 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
IQR 
Interquartile Range 
JDRF 
Juvenile Diabetes Research Foundation 
MDI 
Multiple Daily Injections 
NFC 
Near Field Communication 
NIH 
National Institutes of Health 
OS 
Operating System 
POC 
Point-of-Care 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled/Clinical Trial 
RMB 
Risk-Based Monitoring 
 

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Acronym 
Abbreviation For 
 
 
SADE 
Serious Adverse Device Event 
SAE 
Serious Adverse Event 
SAP 
Sensor-Augmented Pump 
SD 
Standard Deviation 
SFPQ 
Six Factor Personality Questionnaire 
SH 
Severe Hypoglycemia 
SI 
Insulin Sensitivity 
SII 
Subcutaneous Insulin Injection 
SMBG 
Self-Monitoring of Blood Glucose 
SSL 
Secure Sockets Layer 
SSM 
Safety Supervision Module 
T1DM 
Type 1 Diabetes Mellitus 
T2DM 
Type 2 Diabetes Mellitus 
UADE 
Unanticipated Adverse Device Effect 
UI 
User Interface 
UVA 
University of Virginia 
 
 
123 

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1 
INTRODUCTION 
124 
 
125 
1.1 Background  
126 
Behavioral Challenges to the Control of Type 1 Diabetes Mellitus (T1DM): Regular meals, exercise, 
127 
and even a strict daily regiment are interrupted by generally random behavioral events (e.g. insulin 
128 
overdose, missed food, or excessive exercise [1,2]). A formal description of the process of self-
129 
treatment behavior in T1DM and its potential to generate network challenges is critical for the 
130 
engineering of any system relying on interaction with human behavior. We have created the Stochastic 
131 
Model of Self-Regulation Behavior which gives a probabilistic interpretation of the pattern: internal 
132 
condition  perception/awareness  appraisal  self-regulation decision [2,3] and approximates 
133 
behavioral self-regulation of T1DM with a stochastic process quantifying the probability for extreme 
134 
events, such as severe hypoglycemia or major hyperglycemia. The parameters of this process are 
135 
specific to each individual. We have shown that such an approach was particularly useful for 
136 
understanding the causes of severe hypoglycemia [1,4]; the approach was employed by well-
137 
established behavioral interventions, such as BGAT (Blood Glucose Awareness Training) [5,6].  
138 
 
139 
1.2 Preliminary Studies 
140 
The Effects of Automated Decision Support: We have also shown that automated behavioral feedback 
141 
delivered in the field by a portable device can optimize glycemic control by simultaneously reducing 
142 
HbA1c and occurrence of severe hypoglycemia [7]. This study tested the effect of an automated 
143 
system providing real-time 
144 
HbA1c estimates of, 
145 
glucose variability, and 
146 
risk for hypoglycemia 
147 
(Figure 1). For one year, 
148 
120 adults with type 1 
149 
diabetes, 69/51 
150 
female/male, age = 39.1 
151 
(±14.3) years, duration of 
152 
diabetes 20.3 (±12.9) 
153 
years, HbA1c=8.0 (±1.5) 
154 
%, performed self-
155 
monitoring of blood 
156 
glucose (SMBG) and 
157 
received feedback at three 
158 
increasingly complex 
159 
levels, each continuing for 
160 
3 months: Level 1 - 
161 
routine SMBG; Level 2 - 
162 
adding estimated HbA1c, 
163 
hypoglycemia risk, and 
164 
glucose variability; Level 
165 
3 - adding estimates of symptoms potentially related to hypoglycemia. 
166 
The subjects were randomized to feedback sequences of either Levels 1-2-3 or Levels 2-3-1. HbA1c, 
167 
symptomatic hypoglycemia, and blood glucose awareness, were evaluated at baseline and at the end of 
168 
each level.  
169 
 
Figure 1: Results from 1-year automated decision-support intervention based 
on SMBG data, with 3 levels of feedback to the patient: Level 1 – SMBG only; 
Level 2 – aggregate glycemic characteristics based on SMBG; Level 3 – 
adding perceived symptom ratings [7] 
5
6
7
8
9
10
Baseline
Level 1
Level 2
Level 3
Baseline A1c < 8.0
Baseline A1c >= 8.0
A: HbA1c Throughout the Study
0
0.1
0.2
0.3
0.4
0.5
Baseline
Level 1
Level 2
Level 3
No history of SH
History of SH
B: Severe Hypoglycemia
(episodes/subject/month)
P=0.001
P<0.005
n.s.
P<0.001
n.s.
P<0.05

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For all subjects, this decision-support intervention reduced HbA1c from 8.0 to 7.6 from baseline to the 
170 
end of study, p=0.001. This effect was confined to subjects with baseline HbA1c above 8.0 (from 9.3 
171 
to 8.5, p<0.001). Incidence of symptomatic moderate/severe hypoglycemia was reduced from 5.72 to 
172 
3.74 episodes/person per month (p=0.019), more prominently for subjects with history of severe 
173 
hypoglycemia (from 7.20 to 4.00 episodes, p=0.008) and for those who were hypoglycemia unaware 
174 
(from 6.44 to 3.71 episodes, p=0.045). The subjects’ ratings of the feedback were positive, with up to 
175 
89% approval of the provided features. We have therefore concluded that feedback of SMBG data and 
176 
summary SMBG-based measures resulted in improvement in average glycemic control and reduction 
177 
in moderate/severe hypoglycemia. As summarized in Figure 1, these effects were most prominent in 
178 
subjects who were at highest risk at the baseline [7]: 
179 
The system used in this study was an early prototype of the Decision Support System proposed here; it 
180 
included advisory modules assessing the risk for hypoglycemia, HbA1c, and BG variability, all 
181 
estimated from self-monitoring data (see [7]-online appendix). 
182 
Closed-Loop Control (CLC): In the past 5 years, our CLC (artificial pancreas, AP) studies have 
183 
progressed from short-term 2-day trials in controlled outpatient environment to 6-month free-living 
184 
studies. These studies used the first portable AP platform – the Diabetes Assistant (DiAs) introduced 
185 
by our UVA group in 2011. DiAs was built using an Android smart phone as a computational hub and 
186 
included AP user interface (UI) designed for the patient [8-12] and a Cloud-based remote monitoring 
187 
and automated alert system [11]. The defining characteristic of DiAs is its ability to switch smoothly 
188 
between different modes of operation, depending on patient preference and signal availability [8,12].  
189 
To date, 475 patients with T1DM have tested DiAs for over 230,000 hours of outpatient use. These 
190 
studies were conducted at several centers in the U.S. and overseas. We can therefore affirm that 
191 
reliable technology has been developed and sufficient data have been accumulated to warrant the 
192 
transition of this system to user modes that go beyond closed-loop control - most importantly for this 
193 
project - Decision Support for diabetes using closed-loop control technology.  
194 
In addition to a stable, well tested platform, the AP project developed key technologies that are at the 
195 
core of the proposed DSS, namely: (i) the state estimation and modelling powering the treatment 
196 
adaptation and insulin sensitivity tracking, and (ii) glycemic forecast modules that now enable the 
197 
exercise adviser system, the nighttime adviser system, and the hypoglycemia prediction system. 
198 
inControl Advice, inControl-AP, Cloud Database, Notifications/Alerts, and Remote Monitoring:  
199 
Our DiAs platform [8-12] has now matured into a third-generation system developed by TypeZero 
200 
Technologies, Inc. (under license from UVA) - the inControl product family (Figure 2), which includes 
201 
both local (e.g. insulin dosing advice or closed-loop control) and global (e.g. parameter management, 
202 
notifications, alerts, remote monitoring) functions. The inControl local applications are implemented 
203 
on a standard Android smartphone and uses Bluetooth (BT) to communicate with a CGM and Near 
204 
Field Communication (NFC) to communicate with insulin pens. Currently, inControl runs on a 
205 
modified release of the Android operating system (OS).  Modifications of the OS include the removal 
206 
of unnecessary applications and functions, and fixes to the BT stack to permit communication with 
207 
peripheral medical devices. The local inControl module is an Android application with a JS/CSS UI.   
208 
•  
209 
inControl-AP:  When running closed-loop control, inControl-AP communicates with an insulin pump 
210 
and modulates insulin delivery automatically to keep blood glucose in a target range. inControl-AP 
211 
operates on a 5-minute cycle based on the highest frequency of input data.  There are three insulin 
212 
dosing modes (stopped, pump and closed loop) and three operating modes (normal, sleep and 
213 

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exercise). The combination of insulin dosing mode and operating mode determines what actions 
214 
inControl-AP will perform and what options are presented to the user. 
215 
inControl-Cloud is an external server system that communicates with the Network Service within 
216 
inControl-AP over a secure SSL to: 
217 
• Allow the patient to log in with their inControl-Cloud ID;  
218 
• Deliver user biometric data (height, weight, date of birth etc.) and therapy profile information 
219 
(basal rate, carbohydrate to insulin ratio, correction factor). 
220 
inControl Advice: In this protocol, we now intend to use inControl-Advice, which is designed to 
221 
provide advice to users, instead of directly controlling the insulin delivery system. inControl Advice 
222 
shares many of the features of inControl-AP described above, but does not implement automated 
223 
insulin delivery and receives data from an insulin pen. Instead of automated 5-min adjustments to the 
224 
insulin delivery, the system provides a series of real-time alerts and on-demand advice, for both dosing 
225 
of insulin and ingestion of carbohydrates, based on data collected from T1DM patients (i.e. 
226 
carbohydrate consumption, insulin injected, CGM) and inConrol Cloud analytics. inControl Advice 
227 
includes 6 modules: 
228 
1. Retrospective analysis of the past few weeks, based on replay simulation technologies which 
229 
optimizes the patient’s functional insulin therapy parameters (basal doses, insulin sensitivity 
230 
(ISF) factors, and carbohydrate ratios); 
231 
2. A CGM-based bolus calculator that enhances usual computations (bolus=CHO/CR+(SMBG-
232 
target)/ISF –IOB) by replacing the SMBG value with a short term (30 minutes) glucose 
233 
prediction; 
234 
3. A Hypoglycemia alert system capable of predicting hypoglycemic events within the next 3 
235 
hours;  
236 
4. A long-term tracker of average glycemia using CGM to estimate changes in HbA1c; 
237 
5. A nighttime adviser, minimizing the risk of overnight exposure to hypoglycemia by proposing 
238 
adequate bedtime carbohydrate intake which is optimized to minimize the exposure to 
239 
hyperglycemia; 
240 
6. A physical activity adviser, allowing for safe physical activity without hypoglycemia and 
241 
without increasing the risk of rebound hyperglycemia.  
242 

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The feasibility and safety of a prototype DSS is currently being tested in 30 adults with T1DM, both 
243 
insulin pump and MDI users. This single-site clinical trial follows a non-blinded randomized crossover 
244 
design, with two 48-hour 
245 
observation periods where 
246 
patients are exposed to a 
247 
variety of meal and physical 
248 
activities to challenge the 
249 
patients’ own control 
250 
strategies and the advisory 
251 
system. Preliminary analysis 
252 
of the first 11 patients 
253 
showed a clear trend towards 
254 
increased time spent in good 
255 
control (between 70-
256 
180mg/dL, which was 
257 
associated with a reduction in 
258 
both hyperglycemia and 
259 
hypoglycemia exposure (See 
260 
Figure 3). The effect size was 
261 
above 0.5. Use of the 
262 
decision support system also 
263 
reduced glucose variability, 
264 
as shown by the Low BG 
265 
Index [13] and by the 
266 
Average Daily Risk Range 
267 
[14], with effect size of 0.4. 
268 
Our previous decision-
269 
support trial [7] and these preliminary data were used in the power calculations for this study. 
270 
 
271 
1.3 Synopsis of Study Protocol 
272 
1.3.1 Study Objective 
273 
The objective of the study is to assess the efficacy of CGM+DSS versus CGM alone to improve 
274 
glucose control in T1DM patients using multiple daily injections (MDI). The system will be deployed 
275 
on a portable medical application platform (inControl Advice) and will include the following elements: 
276 
1. An MDI treatment parameters optimization routine, using a month of collected Continuous 
277 
Glucose Monitoring (CGM)/insulin/meal data 
278 
2. A smart bolus calculator based on CGM glucose measurements and glycemic prediction. 
279 
3. A hypoglycemia detector with accompanying warning system and recommendation for BG 
280 
monitoring and treatment.  
281 
4. A long-term average glycemia tracker 
282 
5. A bedtime button that is activated by the user before bedtime that assesses risk for overnight 
283 
hypoglycemia and recommends a bedtime snack if hypoglycemia risk is elevated.  
284 
6. An exercise risk warning system, capable of predicting hypoglycemia at the onset of physical 
285 
activity and advising on mitigating treatments such as carbohydrate consumption. 
286 
 
287 
 
Figure 3: Results from pilot-feasibility testing of Decision Support System 

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1.3.2 Study Design 
288 
Prior to outpatient use of substantially changed or updated DSS system components (as deemed by the 
289 
FDA), there will be pilot testing in 2-5 subjects for approximately 48 hours each in a monitored 
290 
transitional setting. Pilot testing may occur at multiple times during the study, dependent on whether 
291 
significant changes are made to the DSS that requires testing prior to home use. Upon successful 
292 
completion of pilot testing (assessed as no device anomalies or malfunctions and no device-related 
293 
adverse events), the tested DSS system may be deployed in the main protocol home setting.  
294 
 
295 
The main protocol is a 12-week parallel group multi-center randomized trial designed to compare 
296 
CGM+DSS with CGM alone. 
297 
 
298 
1.3.3 Major Eligibility Criteria 
299 
• Willingness to provide informed consent. 
300 
• Clinical diagnosis of type 1 diabetes, treated with insulin for at least 1 year 
301 
• Using basal  and meal insulin (NovoLog® [insulin aspart], Humalog® [insulin lispro] or 
302 
Apidra® [insulin glulisine]) for Intensive Insulin Therapy including carbohydrate counting and 
303 
use of pre-defined parameters for glucose goal, carbohydrate ratio, and insulin sensitivity factor 
304 
for at least 1 month.  
305 
  
306 
• Age ≥15 years old 
307 
• Willingness to use the study basal insulin (Tresiba® [insulin degludec]) and meal insulin 
308 
(NovoLog® [insulin aspart]) for the duration of the study.  
309 
• Willingness to use the home or DSS-optimized carbohydrate counting parameters for all meal 
310 
dosing and enter the information into the inControl APP.  
311 
 
312 
1.3.4 Sample Size 
313 
For pilot testing of new DSS system components, up to 30 subjects may be recruited in total across the 
314 
study sites. Pilot subjects may additionally participate in the main study.  
315 
 
316 
We plan on 132 subjects completing the study at three clinical sites. Based on our experience with 
317 
similar studies, we estimate an expected 17.5% screen failures, dropouts or withdrawal due to the data 
318 
collection and eligibility requirements. Therefore, up to 160 subjects may sign consent for the main 
319 
study. Every effort will be made to recruit a broad range of ages into the study. 
320 
 
321 
1.3.5 Main Study Treatment Groups 
322 
Following the initial 2 weeks of baseline blinded CGM data, subjects will be randomized in a 2:1 ratio 
323 
to either CGM+DSS or CGM alone.  
324 
 
325 
1.3.6 Main Study Visit and Phone Contact Schedule 
326 
Subjects will have a Screening Visit with a baseline central HbA1c. They will then complete a 2-week 
327 
period of blinded study CGM and glucometer use to characterize baseline glycemic control. During 
328 
this time, they will use their home insulins dosed according to their pre-defined home parameters for 
329 
carbohydrate counting. 
330 
 
331 
Eligible subjects will complete baseline questionnaires and be randomized to either CGM+DSS or 
332 
CGM alone for the remainder of the study. All subjects will continue to use the study CGM 
333 
(unblinded) and study glucometer and will be transitioned to the study basal insulin pens (Tresiba® 
334 
[insulin degludec] 100 U/mL) per product guidelines. For meal insulin, subjects with average total 
335 

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daily insulin (TDI) <60 U/day will use NovoLog® (insulin aspart) pens capable of 0.5U increment 
336 
dosing and subjects with average TDI ≥60 U/day will use NovoLog® (insulin aspart) pens capable of 
337 
1.0U increment dosing. All subjects will receive insulin pen training including pen differentiation 
338 
training. The differences between the pen for Tresiba® (insulin degludec) and for NovoLog® (insulin 
339 
aspart) will be emphasized to the patient. The training will include the explanation of the user 
340 
interfaces of both the insulin pens and inControl Advice and how the equipment interacts with the 
341 
other. 
342 
• Participants in the CGM+DSS group will be trained on the inControl Advice APP and will use 
343 
it for insulin dose calculations for the remainder of the study.  
344 
• Participants in the CGM alone group will use their pre-defined home carbohydrate counting 
345 
parameters for insulin dose calculations for the remainder of the study. 
346 
 
347 
All participants have the same post-randomization clinic visit and phone contact schedule, with the 
348 
possible exception of additional phone contacts based on DSS-requested optimization of insulin 
349 
parameters for the CGM+DSS group.  
350 
• Phone contacts after: 2 weeks, 4 weeks, 6 weeks, 8 weeks, and 10 weeks for collection of CGM 
351 
downloads 
352 
• Alternately, emails may be used to contact study subjects.  
353 
  
354 
The Study Conclusion will be a clinic visit for central HbA1c and post-intervention questionnaires. 
355 
 
356 
 
 
357 

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Figure 4: Study Flow Diagram 
358 
 
359 
 
360 

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1-14 
Table 1:  Schedule of Study Visits/Phone Contacts and Examination Procedures During 12 week 
361 
RCT Phase  (Randomization at Week 0) 
362 
 
Pre 
0 
2w 
4w 
6w 
8w 
10w 
12w 
Visit or Phone 
V 
V 
P 
P 
P 
P 
P 
V, P 
Comment 
Screen/Enroll, 
Blinded CGM 
run-in 
Rand 
 
 
 
 
 
Conc 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
Blinded CGM (2 weeks) 
X 
 
 
 
 
 
 
 
HbA1c (Central lab) 
X 
 
 
 
 
 
 
X 
Blood draw for screening labs (chemistry panel, 
liver function tests, and TSH) 
X 
 
 
 
 
 
 
 
Urine or serum pregnancy test (premenopausal 
females not surgically sterile) 
X 
X 
 
 
 
 
 
 
CGM Data download 
 
X 
X 
X 
X 
X 
X 
X 
Assessment for BGs <50 or >300 and AEs 
 
X 
X 
X 
X 
X 
X 
X 
Clarke Hypoglycemia Awareness Scale, 
Hyperglycemia Avoidance Scale, Fear of 
Hypoglycemia Survey, Diabetes Distress Scale, 
Diabetes Specific Personality Questionnaire, and 
Technology Expectations Survey (CGM+DSS 
group) 
 
X 
 
 
 
 
 
 
Clarke Hypoglycemia Awareness Scale, 
Hyperglycemia Avoidance Scale, Fear of 
Hypoglycemia Survey, Diabetes Distress Scale, 
and Technology Acceptance Survey (CGM+DSS 
group) 
 
 
 
 
 
 
 
X 
363 

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1-15 
1.3.7 Endpoints 
364 
 
365 
Primary Efficacy Outcome: 
366 
The primary efficacy outcome is increased % time within target range defined as CGM readings of 70-
367 
180 mg/dL during the day and 80-140 mg/dL overnight.  
368 
 
369 
Secondary Efficacy Endpoints: 
370 
Secondary efficacy endpoints include 
371 
1. Optimized metabolic control for the entire study population defined as: 
372 
a. Reduced risk for hypoglycemia, and 
373 
b. Reduced postprandial blood glucose variability defined by the postprandial High Blood 
374 
Glucose Index and by area under the postprandial CGM glucose curve; 
375 
2. Selective improvements for specific sub-populations defined as follows: 
376 
a. Reduced HbA1c without increasing risk for hypoglycemia (measured by the Low Blood 
377 
Glucose Index), particularly for those who were poorly controlled at the baseline 
378 
(baseline A1c > 8%); 
379 
b. Reduced incidence and risk for hypoglycemia without deterioration in HbA1c for those 
380 
with an A1c <8%; 
381 
3. Improved psycho-behavioral markers and acceptance of the system feedback by patients, 
382 
including:  
383 
a. Improved patient/parent diabetes quality of life scores; 
384 
b. Improved hypoglycemia perception/awareness and reduced patient/parent fear of 
385 
hypoglycemia in those with hypoglycemia unawareness and/or history of severe 
386 
hypoglycemia at the baseline. 
387 
 
388 
Main Safety Endpoints: 
389 
• Episodes of severe hypoglycemia 
390 
• Episodes of diabetic ketoacidosis (DKA) 
391 
• Other serious adverse events 
392 
 
393 
Interim Analysis: 
394 
All CGM-related study endpoints and data collected will be analyzed for the first 6 weeks of study 
395 
intervention in the first 40 subjects.  
396 
 
397 
1.4 General Considerations 
398 
The study is being conducted in compliance with the policies described in the study policies document, 
399 
with the ethical principles that have their origin in the Declaration of Helsinki, with the protocol 
400 
described herein, and with the standards of Good Clinical Practice (GCP). (www.wma.net/en/ 
401 
30publications/10policies/b3/.) 
402 
Data will be directly collected in case report forms, which will be considered the source data.   
403 
There is no restriction on the number of subjects to be enrolled by each site towards the overall 
404 
recruitment goal. 
405 

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1-16 
The protocol is considered a significant risk device study, due to the fact that the inControl Advice 
406 
system is experimental.  Therefore, an investigational device exemption (IDE) from the U.S. Food and 
407 
Drug Administration (FDA) is required to conduct the study. 
408 
 
409 
This study is supported by third party collaborators for the provision of study drugs, devices, and 
410 
software. Current study collaborators are: 
411 
• Novo Nordisk (Bagsværd, Denmark) 
412 
• TypeZero Technologies Inc., (Charlottesville, VA) 
413 

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2-17 
2 
SUBJECT SCREENING AND ENROLLMENT  
414 
 
415 
2.1 Study Population 
416 
Up to 30 pilot subjects may be enrolled for pilot DSS system testing. These subjects will sign a 
417 
separate Pilot Subject consent form. Pilot subjects may also participate in the main study.  
418 
 
419 
Enrollment for the main study will proceed with the goal of at least 132 subjects ≥15 years old 
420 
completing the trial. A maximum of 160 subjects may be enrolled in the study in order to achieve 
421 
that goal. 
422 
 
423 
2.2 Eligibility and Exclusion Criteria 
424 
2.2.1 Eligibility 
425 
To be eligible for the pilot and main study, a subject must meet the following criteria: 
426 
1. Willingness to provide informed consent 
427 
2. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one 
428 
year and using insulin for at least 1 year  
429 
3. Using basal  and meal insulin (NovoLog® [insulin aspart], Humalog® [insulin lispro] or 
430 
Apidra® [insulin glulisine]) for Intensive Insulin Therapy including carbohydrate 
431 
counting and use of pre-defined parameters for glucose goal, carbohydrate ratio, and 
432 
insulin sensitivity factor for at least 1 months.  
433 
4. Age ≥15.0 years old 
434 
5. Willingness to use the study basal insulin (Tresiba® [insulin degludec]) and meal insulin 
435 
(NovoLog® [insulin aspart]) for the duration of the study.   
436 
6. Willingness to use the home or DSS-optimized carbohydrate counting parameters for all 
437 
meal dosing and enter the information into the inControl APP (for CGM+DSS group).  
438 
7. For females, not currently known to be pregnant 
439 
8. If female and sexually active, must agree to use a highly effective form of contraception 
440 
to prevent pregnancy while a participant in the study.  A negative serum or urine 
441 
pregnancy test will be required for all premenopausal women who are not surgically 
442 
sterile.  Subjects who become pregnant will be discontinued from the study. Also, 
443 
subjects who during the study develop and express the intention to become pregnant 
444 
within the timespan of the study will be discontinued. 
445 
9. Ability to access the Internet to provide data to the clinical team or to travel to the 
446 
research center so that the study equipment can be downloaded.  
447 
10. Ability to have 3G or Wi-Fi to be able to use the DSS smart bolus calculator and advice 
448 
given (i.e. sleep, exercise). 
449 
11. Demonstration of proper mental status and cognition for the study 
450 
12. Investigator has confidence that the subject can successfully operate all study devices and 
451 
is capable of adhering to the protocol 
452 
13. If on a non-insulin hyperglycemic therapy, stability on that therapy for the prior 3 months 
453 
and willingness not to alter the therapy for the study duration. 
454 
 
455 
2.2.2 Exclusion 
456 
The presence of any of the following is an exclusion for the study: 
457 
1. Medical need for chronic acetaminophen 
458 

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2. Use of any medication that at the discretion of the clinical protocol chair is deemed to 
459 
interfere with the trial.  
460 
3. Current treatment of a seizure disorder. 
461 
4. Coronary artery disease or heart failure, unless written clearance is received from a 
462 
cardiologist. 
463 
5. Hemophilia or any other bleeding disorder 
464 
6. A known medical condition, which in the opinion of the investigator or designee, would 
465 
put the participant or study at risk such as the following examples: 
466 
a. Inpatient psychiatric treatment in the past 6 months  
467 
b. Presence of a known adrenal disorder 
468 
c. Abnormal liver function test results (Transaminase >3 times the upper limit of 
469 
normal) 
470 
d. Abnormal renal function test results (calculated GFR <60 mL/min/1.73m2).  
471 
e. Active gastroparesis requiring medical therapy 
472 
f. Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L). 
473 
g. Abuse of alcohol or recreational drugs 
474 
h. Infectious process not anticipated to be resolved prior to study procedures (e.g. 
475 
meningitis, pneumonia, osteomyelitis, deep tissue infection).  
476 
i. Uncontrolled arterial hypertension (Resting diastolic blood pressure >100 mmHg 
477 
and/or systolic blood pressure >180 mmHg). 
478 
j. Uncontrolled microvascular complications such as current active proliferative 
479 
diabetic retinopathy defined as proliferative retinopathy requiring treatment (e.g. 
480 
laser therapy or VEGF inhibitor injections) in the past 12 months. 
481 
7. A recent injury to body or limb, muscular disorder, use of any medication, any 
482 
carcinogenic disease, or other significant medical disorder if that injury, medication or 
483 
disease in the judgment of the investigator will affect the completion of the protocol. 
484 
8. Current use of the following drugs and supplements:   
485 
k. Regular acetaminophen user, or not willing to suspend acetaminophen 24 hours 
486 
before and during the entire length of the trial  
487 
l. Oral steroids 
488 
m. Any other medication that the investigator believes is a contraindication to the 
489 
subject’s participation 
490 
9. Participation in another pharmaceutical or device trial at the time of enrollment or during 
491 
the study 
492 
 
493 
2.3 Authorization Procedures 
494 
Written informed consent must be obtained prior to performing any study specific procedures 
495 
with the subject that are not part of the subject’s routine care. 
496 
 
497 
For eligible subjects 18 years of age or older, the study will be discussed with the subject and the 
498 
subject will be provided with an Informed Consent Form to read and will be given the 
499 
opportunity to ask questions.  If the subject agrees to participate, the Informed Consent Form 
500 
will be signed. A copy of the consent form will be provided to the subject and another copy will 
501 
be added to the subject’s clinic chart. 
502 
 
503 

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2-19 
For eligible subjects under 18 years of age, a parent/legal guardian (referred to subsequently as 
504 
“parent”) will be provided with an Informed Consent Form to read and will be given the 
505 
opportunity to ask questions. Each subject will be given a Child Assent Form to read and discuss 
506 
with parents and study personnel. If the parent and child agree to participate, the Informed 
507 
Consent Form and Child Assent Form will be signed. A copy of the consent forms will be 
508 
provided to the subject and his/her parent and another copy will be added to the subject’s clinic 
509 
chart. 
510 
 
511 
Separate Informed Consent Forms will be used for the pilot study and the main study.  
512 
 
513 
2.4 Screening and Enrollment Visit Logistics 
514 
Potential subjects will be evaluated for study eligibility through the elicitation of a medical 
515 
history, performance of a physical examination by study personnel and local laboratory testing to 
516 
screen for exclusionary medical conditions.  Subject exclusion will be at the discretion of the 
517 
investigator based on study inclusion/exclusion criteria.    
518 
 
519 
Subjects travelling from a distance or subjects wishing to be pre-screened for eligibility 
520 
may elect to have the consent +/- assent read and explained by study staff by phone. Once 
521 
all questions have been answered, the signed consent +/- assent will be faxed or mailed to 
522 
study personnel and the subject may then have pre-screening with labs performed locally 
523 
(e.g. LabCorp) prior to Visit 1. The consent +/- assent form will be reviewed again with 
524 
the subject +/- parents at Visit 1. 
525 
 
526 
• Once all results of the screening evaluations are available, a decision will be 
527 
made to determine the subject eligibility for the study.  The study physician will 
528 
have the discretion to repeat screening tests. The repeat screening tests may be 
529 
conducted locally (e.g. LabCorp). The subject may request a copy of any of the 
530 
results from the screening evaluation to review with their primary care provider. 
531 
Screening procedures do not need to be repeated for a subject participating in 
532 
both the pilot and main study if the subject proceeds to the main study within 8 
533 
weeks of the original screening visit. After 8 weeks, the medical history will be 
534 
updated, labs repeated, and eligibility criteria reevaluated. If an exclusionary 
535 
condition is identified, the study subject will be excluded from participation with 
536 
follow up and referral to their primary care physician as needed.  
537 
• If the study subject is pregnant, the study physician will discuss the results of the 
538 
blood test with the subject and the subject will be asked to seek confirmation of 
539 
the test and the appropriate medical care.  
540 
• Subjects may be re-screened at a later date if their clinical situation changes as 
541 
determined by the study physician. Subjects that stopped study participation due 
542 
to need for oral glucocorticoids (e.g. bout of poison ivy) may be re-screened and 
543 
re-enrolled after there is no further anticipated need for oral glucocorticoids. 
544 
 
545 
Subjects may begin the Blinded CGM phase of the study before laboratory results return if the 
546 
study physician believes that the laboratory results are unlikely to reveal an exclusionary 
547 
condition. 
548 
 
549 

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2-20 
2.4.1 Data Collection and Testing 
550 
A standard physical exam (including vital signs and height and weight measurements) will be 
551 
performed by the study investigator or designee (a physician, fellow, nurse practitioner or a 
552 
physician assistant).   
553 
 
554 
The following procedures will be performed/data collected/eligibility criteria checked and 
555 
documented:  
556 
• Subject, and where indicated parent/guardian fully informed about the study and informed 
557 
consent form/assent form signed according to IRB requirements  
558 
• Inclusion and exclusion criteria assessed 
559 
• Demographics (date of birth, gender, race and ethnicity) 
560 
• Diabetic history  
561 
• Medical history  
562 
• Substance use history (drinking, smoking, and drug habits) 
563 
• Concomitant medications 
564 
• Physical examination to include: 
565 
o Weight, height 
566 
o Vital signs including measurement of blood pressure and pulse 
567 
• A blood sample will be drawn to send to the central laboratory for baseline HbA1c 
568 
determination to be used in endpoint analyses and for local assessment of a chemistry panel, 
569 
liver function tests and TSH. 
570 
• Urine or serum pregnancy test for all premenopausal women who are not surgically sterile 
571 
 
572 
Screening procedures will last approximately 1-2 hours. 
573 
574 

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4-21 
3 
PILOT TESTING OF DSS 
575 
 
576 
3.1 Pilot Testing Overview 
577 
Prior to outpatient use of substantially changed or updated DSS system components (as deemed 
578 
by the FDA), we will conduct a pilot study of 2-5 subjects using CGM+DSS under supervision. 
579 
These subjects will have an approximately 48-hour visit to an outpatient transitional setting such 
580 
as a hotel. The subjects will be monitored continuously with remote monitoring and will be 
581 
supervised by study staff with medical personnel (e.g. nurse, EMT, physician) available during 
582 
the entire visit. Subjects will eat at restaurants or take-out meals and participate in at least 45 
583 
minutes of activities such as walking or shopping each day. If there are no device anomalies or 
584 
malfunctions and no device-related adverse events during the pilot testing, the DSS may be 
585 
deployed for home use. Pilot testing may be repeated as needed after addressing software or 
586 
device anomalies until successful pilot testing occurs.  
587 
 
588 
 
589 
4 
 2-WEEK BLINDED CGM 
590 
 
591 
4.1 2-Week Blinded CGM Overview 
592 
Prior to randomization, the subject will initiate 2 weeks of home use of blinded CGM for 
593 
characterization of baseline glycemic control and collection of baseline CGM data.  
594 
The subject will use carbohydrate counting per their usual routine with their usual home insulins 
595 
during this time.   
596 
 
597 
The subject will receive supplies for blood glucose and ketone testing during this period: 
598 
• Blood glucose testing 
599 
o Subjects will be provided with a study blood glucose meter, test strips, and 
600 
standard control solution to perform quality control (QC) testing at home per 
601 
manufacturer guidelines.   
602 
o All study blood glucose meters will be QC tested during all office visits.  A tested 
603 
meter will not be used in a study if it does not read within the target range at each 
604 
concentration per manufacturer labeling.  The subject will be instructed to contact 
605 
study staff for a replacement of the meter, test strips, and control solution if a 
606 
meter fails QC testing at home. 
607 
o The blood glucose meter training will include instructions to follow labeling 
608 
instructions with regards to the glucose meter and test strips. 
609 
o Subjects will be reminded to use the study blood glucose meter for all fingerstick 
610 
blood glucose measurements during the trial.   
611 
o Subjects will be given guidelines for treatment of low or high blood glucose 
612 
o Subjects will be asked to perform fingerstick BG testing according to the CGM 
613 
manufacturer guidelines and as needed to follow study guidelines for the 
614 
treatment of low or high blood glucose.  
615 
• Blood ketone testing 
616 
o Subjects will be provided with a study blood ketone meter and test strips. All 
617 
study blood ketone meters will be QC tested at the start of the study with at least 
618 
two different concentrations of control solution if available.  A tested meter will 
619 

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4-22 
not be used in a study if it does not read within the target range at each 
620 
concentration per manufacturer labeling.   
621 
o All study blood ketone meters will be QC tested during all office visits.  A tested 
622 
meter will not be used in a study if it does not read within the target range at each 
623 
concentration per manufacturer labeling.  The subject will be instructed to contact 
624 
study staff for a replacement of the meter, test strips, and control solution if a 
625 
meter fails QC testing at home.   
626 
o Subjects will be instructed to perform blood ketone testing as described in Section  
627 
7.1.2.2. 
628 
o Subjects will be given guidelines for treatment of elevated blood ketones 
629 
• Subjects will be required to have a home glucagon emergency kit. Subjects who currently 
630 
do not have one will be given a prescription for the glucagon emergency kit.  
631 
 
632 
Blinded CGM Use 
633 
At the screening visit, a CGM sensor will be placed.  For subjects not currently using a CGM, the 
634 
study CGM receiver will be blinded so that the participant is not able to see the CGM glucose 
635 
values.  The participant will be instructed on sensor use including insertion of a new sensor as 
636 
recommended by the manufacturer (or sooner if the sensor comes out). Additional sensors will be 
637 
provided.  Subjects that currently use a CGM may use the study CGM in the unblinded mode to 
638 
maintain usual care.  
639 
 
640 
Participants will be informed that in order to be eligible for the randomized trial, the study CGM 
641 
must be used on a minimum of 10 out of 14 days.   
642 
 
643 
4.1.1 Blinded CGM Use Assessment 
644 
Enrolled participants will return approximately 19 ± 5 days after screening to assess the blinded 
645 
CGM wear.  The purpose of the visit will include the following: 
646 
• Assessment of compliance with the use of the CGM 
647 
• Assessment of skin reaction in areas where a CGM sensor was worn 
648 
•  
649 
• CGM download. 
650 
• Collection and assessment of adverse events, adverse device effects, and device issues 
651 
• Assessment of occurrence of BG <50 or >300 mg/dL. (If BG <50 or >300 mg/dL 
652 
occurred during the blinded CGM use, the Dexcom data will be reviewed by the study 
653 
physician to evaluate whether an insulin parameter adjustment is needed. Adjustments 
654 
will be made prior to randomization to the CGM+DSS or CGM alone group.  
655 
 
656 
The CGM data will be downloaded and reviewed to assess whether the participant has used the 
657 
CGM on at least 10 out of 14 days.   
658 
 
659 
Participants who are unable to meet the CGM compliance requirement will be withdrawn from 
660 
the study, unless the investigator believes that there were extenuating circumstances that 
661 
prevented successful completion. In such cases, the subject may be asked to repeat this portion of 
662 
the study. 
 
663 

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5-23 
5 
Randomized Trial 
664 
 
665 
5.1 Randomization Visit 
666 
The Randomization Visit will occur concurrently with the Blinded CGM Use Assessment.  
667 
 
668 
A urine pregnancy test will be repeated for all premenopausal women who are not surgically 
669 
sterile.  The test must be negative to be eligible for continuation in the study. 
670 
 
671 
Subjects will complete the following baseline questionnaires: 
672 
• Fear of Hypoglycemia Survey (HFS-II) 
673 
• Hyperglycemia Avoidance Scale 
674 
• Diabetes Distress Scale 
675 
• Clarke’s Hypoglycemia Awareness scale  
676 
• Diabetes Specific Personality Questionnaire 
677 
 
678 
The home insulin regimen will be reviewed and the subject will be transitioned to the study 
679 
insulins consisting of Tresiba® (insulin degludec) (100 U/mL) for basal insulin dosing and 
680 
NovoLog® (insulin aspart) (100 U/mL) for meal and correction insulin dosing. The investigators 
681 
making the basal insulin recommendations will be physicians knowledgeable in insulin titration. 
682 
The starting dose of Tresiba will be the same unit dose as the total daily long acting unit dose, as 
683 
per the product manufacturer guidelines for adults already on insulin therapy.  
684 
  
685 
To mitigate the risk of hypoglycemia when transitioning from the home basal insulin to Tresiba, 
686 
subjects will be asked to perform fingerstick blood glucose measurements a minimum of four 
687 
times daily for the first 2 weeks of Tresiba use (premeal and bedtime, for CGM calibrations, to 
688 
confirm low or high CGM alarms, and for symptoms of low or high blood sugar). The subjects 
689 
will have the additional protection of wearing a CGM system, approved for non-adjunct use 
690 
(Dexcom G5), with the low alarm set to 70 mg/dL and the high alarm set to 300 mg/dL. These 
691 
alerts will allow the subject to time the required fingersticks to when the risk to the subject is 
692 
highest. During the first 2 weeks of Tresiba use, subjects will be instructed to verify that their 
693 
CGM functions before bedtime, and strongly advised to measure their blood glucose around 3am 
694 
using the study provided blood glucose meter. 
695 
 
696 
The study insulin degludec (Tresiba®) will be available in a PenFill® cartridge which is inserted 
697 
into a NovoPen® 5 Plus pen. The study insulin aspart (NovoLog®) will be available in a 
698 
PenFill® cartridge which is inserted into a NovoPen Echo® Plus or NovoPen® 5 Plus pen. The 
699 
individual PenFill® is labelled with the drug type. The differences between the pen for Tresiba® 
700 
(insulin degludec) and for NovoLog® (insulin aspart) will be emphasized to the patient. The 
701 
insulin delivery device containing NovoLog® (insulin aspart) PenFill® will deliver in 0.5 U 
702 
increments for subjects with average total daily insulin <60 U/day and in 1 U increments for 
703 
subjects with average total daily insulin ≥60 U/day. Pen needles will also be provided. The 
704 
Instruction for Use for the pens will be reviewed with the subject and the subject will 
705 
demonstrate proper insulin pen priming, injection technique and the ability to change the insulin 
706 
cartridge to the training staff. If the subject receives a prandial insulin recommendation that is 
707 
not capable of being delivered by the pen, the subject will be asked to round to the next closest 
708 
number per the clinical scenario (e.g. if CGM arrow flat or downward, round down; if CGM 
709 

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5-24 
arrow upward, round up). Storage and in use conditions for the insulins will be per the trial 
710 
product label. Initial once daily doses of Tresiba® (insulin degludec) will be determined per the 
711 
product guidelines.  
712 
 
713 
Subjects will be advised that they may experience more high or low blood sugars when 
714 
switching from the home insulins to the study insulins. Subjects will be provided with study staff 
715 
contact information and will be instructed to contact study staff for any concerns regarding an 
716 
increase in high or low blood sugars. 
717 
 
718 
Subjects will be provided with study supplies and will be asked to perform fingerstick blood 
719 
glucose measurements a minimum of four times daily for the first 2 weeks of using the study 
720 
insulins (premeal and bedtime, for CGM calibrations, to confirm low or high CGM alarms, and 
721 
for symptoms of low or high blood sugar). Thereafter, subjects will be asked to perform 
722 
fingersticks in accordance with the labeling of the study CGM device and as needed to follow 
723 
study guidelines for the treatment of low or high blood glucose. Subjects will continue to use the 
724 
study basal and meal insulin pens for the remainder of the study. 
725 
 
726 
5.1.1  CGM Training 
727 
The participant will be provided with sensors and instructed to use the CGM daily for the 
728 
remainder of the trial. Depending on the subject’s prior CGM experience, the subject will have 
729 
approximately 1 hour of training on how to use CGM for daily diabetes management using the 
730 
manufacturer’s training materials. Product labeling for the Dexcom G5 mobile system states that 
731 
it is indicated for the management of diabetes in persons age 2 years and older. It is designed to 
732 
replace fingerstick blood glucose testing for diabetes treatment decisions. Per the product 
733 
guidelines, fingersticks are required for calibration, or if symptoms or expectations do not match 
734 
readings, or when taking medications containing acetaminophen.  
735 
 
736 
During the CGM training session, subjects will view the interactive Dexcom G5 mobile training 
737 
tutorial that is available on the Dexcom website:  
738 
(https://s3-us-west-2.amazonaws.com/dexcommisc/tutorial/story_html5.html). Of relevance, 
739 
proper calibration timing and technique is described in the training tutorial. This training session 
740 
also covers but is not limited to the following topics: 
741 
• Dexcom G5 mobile components 
742 
• Display device options 
743 
• Setting high/low alerts 
744 
• Inserting sensor 
745 
• Starting sensor session 
746 
• Entering BG meter value 
747 
• Ending sensor session 
748 
 
749 
5.1.2  Randomization 
750 
Eligible subjects will be randomly assigned to one of two treatment groups: 
751 
1. CGM+DSS Group 
752 
2. CGM alone Group  
753 
 
754 
Subjects randomized to CGM+DSS will complete an additional baseline questionnaire: 
755 

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5-25 
• Technology Expectations Survey 
756 
 
757 
5.1.3  CGM Data Downloads 
758 
Subjects in both groups will be provided with the software needed to download the study CGM 
759 
and transmit the data to study personnel and will be asked to do so prior to scheduled phone 
760 
contacts for the remainder of the study. 
761 
 
762 
5.2 Procedures for the CGM+DSS Group 
763 
 
764 
5.2.1  DSS Training 
765 
Subjects randomized to the CGM+DSS group will receive DSS training.  
766 
 
767 
The subject will be trained by qualified study staff to use the DSS (inControl Advice) APP to 
768 
calculate insulin doses for meals and corrections. Prior to initial use, the inControl system will be 
769 
initialized by a study team member with each subject’s individual insulin dosing parameters, 
770 
including carbohydrate ratio, insulin sensitivity factor and basal insulin dose.   
771 
 
772 
Study team members will train the subject in performing specific tasks including the following: 
773 
• The study team will confirm the carbohydrate counting parameters entered in the system 
774 
with the study physician. 
775 
• How to activate the “meal” screen of the inControl system any time insulin will be given 
776 
with a meal and the “add correction” screen any time additional correction insulin is 
777 
desired 
778 
• How to use the NFC communication on the insulin pens to inform and confirm on the 
779 
inControl system that an insulin dose was injected.  
780 
• How to inform the system of hypoglycemia treatment via a “hypoglycemia treatment” 
781 
button on the inControl user interface after glucose is consumed that is not accompanied 
782 
by an insulin bolus 
783 
• What to do when exercising while using the system and how to react to the exercise 
784 
advice given 
785 
• How to react to the hypoglycemia risk alarm. 
786 
• How to access the bedtime button and react to the possible advice for a bedtime snack. 
787 
 
788 
The subject will also be instructed to contact study staff during periods of illness with an 
789 
elevated temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant 
790 
illness, or during periods of use of medications such as epinephrine (e.g. for the emergency 
791 
treatment of a severe allergic reaction or asthma attack) or oral or injectable glucocorticoids to 
792 
determine if study procedures should be temporarily discontinued.  
793 
 
794 
Subjects will be given the inControl Advice device and will be provided with sufficient supplies 
795 
to last until the final clinic visit. 
796 
 
797 
5.3 Procedures for the CGM Group 
798 
Subjects in the CGM Group will continue to use the study CGM and will be provided with 
799 
sufficient supplies to last until the final clinic visit.   
800 
 
801 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
5-26 
The subject will also be instructed to contact study staff during periods of illness with an 
802 
elevated temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant 
803 
illness, or during periods of use of medications such as epinephrine (e.g. for the emergency 
804 
treatment of a severe allergic reaction or asthma attack) or oral or injectable glucocorticoids to 
805 
determine if study procedures should be temporarily discontinued.  
806 
 
807 
5.4 Follow-up Phone Contacts for Both Groups 
808 
The schedule for remaining follow-up visits and phone contacts is the same for both treatment 
809 
groups. A primary purpose of the contacts will be to collect the CGM downloads and to assess for 
810 
BGs <50 or >300 and any AEs.   
811 
 
812 
5.4.1 Phone Contacts 
813 
A phone call will be made at the following times: 
814 
• 2 weeks (+3 days) 
815 
• 4 weeks (+1 week) 
816 
• 6 weeks (+1 week) 
817 
• 8 weeks (+1 week) 
818 
• 10 weeks (+1 week) 
819 
 
820 
The following procedures will be performed in both groups during each phone contact, unless 
821 
otherwise specified: 
822 
• Assessment of compliance with study device use 
823 
• Assessment of occurrence of BG <50 or >300 mg/dL.  
824 
• CGM download. 
825 
• Collection and assessment of adverse events, adverse device effects, and device issues 
826 
 
827 
5.4.2 Study Conclusion Visit 
828 
The following procedures will be performed in both groups at the study conclusion visit: 
829 
• All study devices will be returned and downloaded 
830 
• Blood will be drawn for central HbA1c assessment. 
831 
 
832 
Subjects will complete the following post-intervention questionnaires: 
833 
• Fear of Hypoglycemia Survey (HFS-II) 
834 
• Hyperglycemia Avoidance Scale 
835 
• Diabetes Distress Scale 
836 
• Clarke’s Hypoglycemia Awareness scale  
837 
• Technology Acceptance Survey (CGM+DSS group) 
838 
 
839 
Study participants will meet with the study physician and the Dexcom data will be reviewed. The 
840 
subject will be instructed on how to transition back to the home insulins and the doses to be used. 
841 
Subjects will be informed that there may be a risk of severe hypoglycemia and/or severe 
842 
hyperglycemia during the transition back to the subject’s usual home basal insulin from the study 
843 
basal insulin (Tresiba). They will be asked to perform fingerstick BGs before meals, at bedtime, 
844 
and at 3AM for the first 3 days on the home insulin.  
845 
 
846 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
5-27 
5.5  Follow-up Phone Contacts for Both Groups: Post-study 
847 
A follow-up safety call will be made with the subject within 3-7 days to assess for any problems 
848 
transitioning to the home insulin, including any episodes of BG 300 mg/dL.
849 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
6-28 
6 
QUESTIONNAIRES 
850 
 
851 
6.1 Introduction 
852 
The following questionnaires will be completed at the randomization visit: 
853 
• Diabetes Specific Personality Questionnaire  
854 
• Clarke Hypoglycemia Awareness Scale 
855 
• Fear of Hypoglycemia Survey (HFS-II) 
856 
• Hyperglycemia Avoidance Scale 
857 
• Diabetes Distress Scale 
858 
• Technology Expectations Survey (CGM+DSS group only) 
859 
 
860 
The following questionnaires will be completed at the final visit at week 12: 
861 
• Clarke’s Hypoglycemia Awareness Scale  
862 
• Fear of Hypoglycemia Survey (HFS-II) 
863 
• Hyperglycemia Avoidance Scale 
864 
• Diabetes Distress Scale 
865 
• Technology Acceptance Survey (CGM+DSS group only) 
866 
 
867 
Each questionnaire is described briefly below.  The procedures for administration are described in the 
868 
study procedures manual. 
869 
 
870 
6.2 Diabetes Specific Personality Questionnaire 
871 
The Diabetes Specific Personality Questionnaire (24) is based on the original Six Factor Personality 
872 
Questionnaire (25), a well-validated measure that was adapted for the diabetes-specific version of the 
873 
questionnaire. The SFPQ is a measure of six personality dimensions each consisting of three facet 
874 
scales, measured by 108 Likert items. The SFPQ facet scales are organized in terms of six factor 
875 
scales.  
876 
 
877 
Administration time is approximately 15 minutes.  
878 
 
879 
6.3 Clarke’s Hypoglycemia Awareness Scale 
880 
The scale (26) comprises eight questions characterizing the participant's exposure to episodes of 
881 
moderate and severe hypoglycemia. It also examines the glycemic threshold for, and symptomatic 
882 
responses to, hypoglycemia. A score of four or more on a scale of 0 to 8 implies impaired awareness of 
883 
hypoglycemia.    
884 
 
885 
Administration time is approximately 5 minutes.   
886 
 
887 
6.4 Hypoglycemia Fear Survey (HFS-II) / Low Blood Sugar Survey 
888 
The Hypoglycemia Fear Survey-II (27) was developed to measure behaviors and worries related to fear 
889 
of hypoglycemia in adults with type 1 diabetes. It is composed of 2 subscales, the Behavior (HFS-B) 
890 
and Worry (HFS-W). HFS-B items describe behaviors in which patients may engage to avoid 
891 
hypoglycemic episodes and/or their negative consequences (e.g., keeping blood glucose levels above 
892 
150 mg/dL, making sure other people are around, and limiting exercise or physical activity). HFS-W 
893 
items describe specific concerns that patients may have about their hypoglycemic episodes (e.g., being 
894 
alone, episodes occurring during sleep, or having an accident).  
895 
 
896 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
6-29 
Administration time is approximately 10 minutes. 
897 
  
898 
6.5 Hyperglycemia Avoidance Survey (HAS) / High Blood Sugar Survey 
899 
The HAS (28) reliably quantifies affective and behavioral aspects of hyperglycemia avoidance and is 
900 
used to assess the extent of potentially problematic avoidant attitudes and behaviors regarding 
901 
hyperglycemia in people with Type 1 diabetes mellitus (T1DM).  
902 
Administration time is approximately 10 minutes. 
903 
 
904 
6.6 Diabetes Distress Scale 
905 
The Diabetes Distress Scale (29) is a measure of diabetes-related emotional distress and consists of a 
906 
scale of 28 items. These include 7 items from each of four domains central to diabetes-related 
907 
emotional distress.  Patients rate the degree to which each item is currently problematic for them on a 
908 
6-point Likert scale, from 1 (no problem) to 6 (serious problem). 
909 
 
910 
Administration time is approximately 10 minutes. 
911 
 
912 
6.7 Technology Expectation and Technology Acceptance Surveys 
913 
The Technology Expectation and Technology Acceptance Surveys were developed for a Bionic 
914 
Pancreas camp study (30). The 38 items in the Questionnaire were based on interviews conducted with 
915 
individuals who had participated in previous Bionic Pancreas trials about their experience regarding 
916 
the Bionic Pancreas. It was subsequently adapted to assess these same measures for the inControl 
917 
Advice system. It assesses both positive and negative experiences with inControl, including blood 
918 
glucose management, device burden, and overall satisfaction. Items are rated on a 5-point scale. 
919 
 
920 
Administration time is approximately 10 minutes. 
 
921 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
7-30 
7 
SAFETY MEASURES 
922 
 
923 
7.1 Safety Measures 
924 
 
925 
7.1.1 CGM Calibration 
926 
Throughout the study, subjects will be instructed to calibrate the study CGM in accordance with 
927 
manufacturer labelling. 
928 
 
929 
7.1.2 Safety Measures 
930 
 
931 
7.1.2.1 Hypoglycemia Safety Protocol 
932 
All subjects will be required to set the CGM hypoglycemia threshold alarm to a value no less than 70 
933 
mg/dL. 
934 
 
935 
If a subject receives a CGM hypoglycemia threshold alarm or notes that the CGM glucose is <70 
936 
mg/dL, confirmatory fingerstick testing will be recommended and the subject will be instructed to treat 
937 
hypoglycemia with ~16 grams of fast-acting oral glucose.  
938 
 
939 
7.1.2.2 Hyperglycemia Safety Protocol 
940 
Subjects will be required to set the CGM hyperglycemia threshold alarm to a value no greater than 300 
941 
mg/dL. 
942 
 
943 
If a subject receives a CGM hyperglycemia threshold alarm or notes that the CGM glucose is >300 
944 
mg/dL, confirmatory fingerstick testing will be recommended.   
945 
 
946 
If a subject’s CGM reading is ≥300 mg/dL for over 1 hour, or ≥400 mg/dL at any point, the subject 
947 
will be instructed to take the following steps: 
948 
• Perform a blood ketone measurement with the study ketone meter. Subjects will also be 
949 
encouraged to check ketones if they are clinically concerned. 
950 
• Correction insulin may be taken per the subject’s usual routine (CGM group) or per the 
951 
inControl Advice recommendation (CGM+DSS group).  
952 
• Subjects will be instructed to administer correction insulin per the subject’s usual routine 
953 
(CGM group) or per the inControl Advice recommendation (CGM+DSS group) for ketones 
954 
≥0.6 mmol/L and to additionally notify study staff for ketones ≥3.0 mmol/L. 
955 
 
956 
7.1.2.3 Study System Failure 
957 
If the inControl Advice APP stops working, subjects will be instructed to resume their regular home 
958 
insulin therapy until he/she can contact study staff for confirmation of the current carbohydrate 
959 
counting parameters or until the study system can be repaired or replaced. 
960 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
8-31 
8 
ADVERSE EVENTS, DEVICE ISSUES, POTENTIAL RISKS, AND STOPPING RULES  
961 
 
962 
8.1 Adverse Event Definition 
963 
A reportable adverse event for this protocol includes any untoward medical occurrence that meets 
964 
criteria for a serious adverse event or any unanticipated medical occurrence in a study subject that is 
965 
study- or device-related, including severe hypoglycemia as defined below and severe 
966 
hyperglycemia/diabetic ketoacidosis (DKA) as defined below.  Skin reactions from sensor placement 
967 
are only reportable if severe and/or required treatment. 
968 
 
969 
Hypoglycemic events are recorded as Adverse Events (severe hypoglycemic event) if the event 
970 
required assistance of another person due to altered consciousness, and required another person to 
971 
actively administer carbohydrate, glucagon, or other resuscitative actions. This means that the 
972 
participant was impaired cognitively to the point that he/she was unable to treat himself/herself, was 
973 
unable to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced 
974 
seizure or coma. These episodes may be associated with sufficient neuroglycopenia to induce seizure 
975 
or coma.  If plasma glucose measurements are not available during such an event, neurological 
976 
recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence 
977 
that the event was induced by a low plasma glucose concentration. 
978 
 
979 
Hyperglycemic events are recorded as Adverse Events (severe hyperglycemic event) if the event 
980 
involved DKA, as defined by the Diabetes Control and Complications Trial (DCCT) and described 
981 
below, or in the absence of DKA if evaluation or treatment was obtained at a health care provider 
982 
facility for an acute event involving hyperglycemia with ketosis.  
983 
 
984 
Hyperglycemic events are classified as DKA if the following are present:  
985 
• 
Symptoms such as polyuria, polydipsia, nausea, or vomiting;  
986 
• 
Serum ketones >1.5 mmol/L or large/moderate urine ketones;  
987 
• 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
988 
• 
Treatment provided in a health care facility     
989 
 
990 
8.2 Recording of Adverse Events 
991 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse events 
992 
or untoward findings.  The first concern will be the safety of the study participant, and appropriate 
993 
medical intervention will be made. 
994 
 
995 
All reportable adverse events whether volunteered by the subject, discovered by study personnel 
996 
during questioning, or detected through physical examination, laboratory test, or other means will be 
997 
reported on an adverse event form online.  Each adverse event form is reviewed by the Medical 
998 
Monitor at the Coordinating Center to verify the coding and the reporting that is required.  
999 
 
1000 
The study investigator will assess the relationship of any adverse event to be related or unrelated by 
1001 
determining if there is a reasonable possibility that the adverse event may have been caused by the 
1002 
study intervention. 
1003 
 
1004 
To ensure consistency of adverse event causality assessments, investigators should apply the following 
1005 
general guideline when determining whether an adverse event is related: 
1006 
 
1007 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
8-32 
Yes 
1008 
There is a plausible temporal relationship between the onset of the adverse event and the study 
1009 
intervention, and the adverse event cannot be readily explained by the subject’s clinical state, 
1010 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of 
1011 
response to the study intervention; and/or the adverse event abates or resolves upon discontinuation of 
1012 
the study intervention or dose reduction and, if applicable, reappears upon re-challenge. 
1013 
 
1014 
No 
1015 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
1016 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); 
1017 
and/or the adverse event has no plausible temporal relationship to study intervention.    
1018 
 
1019 
The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 
1020 
severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse event is 
1021 
not necessarily serious. For example, itching for several days may be rated as severe, but may not be 
1022 
clinically serious. 
1023 
 
1024 
Adverse events will be coded using the MedDRA dictionary.  
1025 
 
1026 
All adverse events including adverse events that continue after the study participant’s discontinuation 
1027 
or completion of the study will be followed until their medical outcome is determined or until no 
1028 
further change in the condition is expected.   
1029 
 
1030 
8.3 Reporting Serious Adverse Events, Unexpected Adverse Device Effects, Serious Adverse 
1031 
Reactions (SAR) and Serious Adverse Drug Reaction (SARD) 
1032 
Any untoward occurrence that: 
1033 
• Results in death. 
1034 
• Results in transmission of a bloodborne pathogen. 
1035 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
1036 
become life-threatening, is not necessarily considered a serious adverse event). 
1037 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
1038 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
1039 
conduct normal life functions. 
1040 
• Is a congenital anomaly or birth defect 
1041 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
1042 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
1043 
the endpoints listed above). 
1044 
 
1045 
An Unanticipated Adverse Device Effect is defined as any serious adverse effect on health or safety or 
1046 
any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
1047 
death was not previously identified in nature, severity, or degree of incidence in the investigational 
1048 
plan or application (including a supplementary plan or application), or any other unanticipated serious 
1049 
problem associated with a device that relates to the rights, safety, or welfare of subjects (21 CFR 
1050 
812.3(s)). Reporting timelines are noted in Table 2.  
1051 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
8-33 
Subjects will be instructed to notify the study team immediately if they become pregnant during the 
1052 
trial. Pregnancies will be reported to third party collaborators within 15 calendar days of the study 
1053 
team being notified of the event. However, pregnancy will not be considered an adverse event in this 
1054 
trial. Pregnancy complications will be recorded as adverse event(s).  
1055 
 
1056 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1057 
abiding by any other reporting requirements specific to his/her Institutional Review Board and third 
1058 
party collaborators. 
1059 
 
1060 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Any event resulting in 
death that is deemed 
DEFINITELY related to 
(caused by) study 
participation 
 
IRB 
Third party 
collaborators 
Within 24 hours 
IRB Online and phone call 
 
 
Serious Adverse Event, 
Unexpected Adverse 
Event,  
Serious Adverse 
Reactions (SAR),  
Serious Adverse Drug 
Reaction (SARD) 
 
IRB 
Third party 
collaborators 
Within 7 calendar 
days from the time, 
the study team 
received knowledge 
of the event. 
 
Timeline includes 
submission of signed 
hardcopy of AE 
form. 
IRB Online 
 
 
 
Unanticipated Problems 
that are not adverse 
events or protocol 
violations. This would 
include a Data Breach.   
 
IRB 
Third party 
collaborators 
Within 10 day 
calendar days of the 
study team receiving 
knowledge of the 
event 
IRB Online 
 
 
 
Protocol Violations/ 
Noncompliance  
The IRB only requires 
that MAJOR violation be 
reported, unless otherwise 
required by the sponsor 
OR 
Enrollment Exceptions 
IRB 
 
 
Within 7 calendar 
days from the time, 
the study team 
received knowledge 
of the event.  
Unanticipated Problem report 
form.  
 
 
Data Breach  
IRB 
 
 
Within 7 calendar 
days from the time, 
the study team 
received knowledge 
of the event.  
 
Protocol Violation, 
Noncompliance and 
Enrollment Exception 
Reporting Form 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
8-34 
OUTSIDE SPONSOR 
The UVa 
Corporate 
Compliance and 
Privacy Office, a 
 
ITC:  if breach 
involves  
electronic data-  
 
 
Police if breach 
includes items 
that are stolen: 
 
Stolen on UVA 
Grounds 
 
OR  
 
Stolen off UVa 
Grounds- contact 
police department 
of jurisdiction of 
last known 
location of PHI 
As soon as possible 
and no later than 24 
hours from the time, 
the incident is 
identified. 
 
As soon as possible 
and no later than 24 
hours from the time, 
the incident is 
identified. 
 
IMMEDIATELY.  
 
 
UVa Corporate Compliance 
and Privacy Office- Phone 
924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting 
procedure,  http://www.itc.vir
ginia.edu/security/reporting.ht
ml 
 
 
 
 
 
 
UVa Police- Phone-  
(434) 924-7166 
UVA PI IDE 
Life-threatening and/or 
fatal unexpected events 
related or possibly 
related to the use of the 
investigational device. 
FDA 
Third party 
collaborators 
Within 7 calendar 
days of the study 
team learning of the 
event 
Form FDA 3500A 
(MedWatch) or narrative 
Serious, unexpected and 
related or possibly 
related adverse events 
FDA 
Third party 
collaborators 
Within 15 calendar 
days after the study 
team receives 
knowledge of the 
event 
Form FDA 3500A 
(MedWatch) or narrative 
For Device Studies:  
Unanticipated adverse 
device effects (internal 
or external) 
FDA 
Third party 
collaborators 
Within 10 working 
days of the study 
team receiving 
knowledge of the 
event 
Form FDA 3500A 
(MedWatch) or narrative 
All adverse events 
FDA 
Annually 
IDE annual report 
Table 2:  Adverse Event Reporting Table 
1061 
 
1062 
8.4 Device Issues 
1063 
Device malfunctions (failure of device to perform as intended) will be reported, irrespective of whether 
1064 
associated with an adverse event.  However, CGM sensors lasting less than 7 days will not be reported 
1065 
unless associated with an adverse event. Additionally, inControl CGM disconnections will not be 
1066 
reported unless associated with an adverse event. 
1067 
 
1068 
8.5 Potential Risks and Side Effects 
1069 
Loss of confidentiality is a potential risk; however, data are handled to minimize this risk.  
1070 
Hyperglycemia and ketone formation and hypoglycemia are always a risk in subjects with type 1 
1071 
diabetes and subjects will be closely monitored for this.  When wearing sensors and insulin infusion 
1072 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
8-35 
sets there is always a risk of skin rashes, allergic reactions to the tape, or infections at the insertion site.  
1073 
There is always a risk for a small piece of a sensor remaining under the skin or a sensor or infusion set 
1074 
breaking off under the skin.  
1075 
 
1076 
8.5.1 Venipuncture Risks 
1077 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws can 
1078 
cause some common reactions like pain, bruising, or redness at the sampling site.  Less common 
1079 
reactions include bleeding from the sampling site, formation of a small blood clot or swelling of the 
1080 
vein and surrounding tissues, and fainting. 
1081 
 
1082 
8.5.2 Fingerstick Risks 
1083 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
1084 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital laboratory 
1085 
tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount of bleeding under 
1086 
the skin will produce a bruise.  A small scar may persist for several weeks.  The risk of local infection 
1087 
is less than 1 in 1000.  This should not be a significant contributor to risks in this study as fingersticks 
1088 
are part of the usual care for people with diabetes. 
1089 
 
1090 
8.5.3 Subcutaneous Catheter Risks (CGM) 
1091 
Subjects using the CGM will be at low risk for developing a local skin infection at the site of the 
1092 
sensor needle placement.  If a catheter is left under the skin for more than 24 hours it is possible to get 
1093 
an infection where it goes into the skin, with swelling, redness and pain.  There may be bleeding where 
1094 
the catheter is put in and bleeding under the skin causes a bruise (1 in 10 risk).   
1095 
 
1096 
Study staff should verbally alert the subject that on rare occasions, the CGM may break and leave a small 
1097 
portion of the sensor under the skin that may cause redness, swelling or pain at the insertion site.  The 
1098 
subject should be further instructed to notify the study coordinator immediately if this occurs. 
1099 
 
1100 
8.5.4 Risk of Hypoglycemia 
1101 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a low 
1102 
blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and possibly less 
1103 
than it would be as part of daily living.  Symptoms of hypoglycemia can include sweating, jitteriness, 
1104 
and not feeling well.  Just as at home, there is the possibility of fainting or seizures (convulsions) and 
1105 
that for a few days the subject may not be as aware of symptoms of hypoglycemia.  A CGM 
1106 
functioning poorly and significantly over-reading glucose values could lead to inappropriate insulin 
1107 
delivery. Inadvertent mix-ups of short-acting and long-acting insulins could contribute to the risk of 
1108 
hypoglycemia.     
1109 
 
1110 
8.5.5 Risk of Hyperglycemia 
1111 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
1112 
extended period.  A CGM functioning poorly and significantly under-reading glucose values could 
1113 
lead to an inappropriate insulin recommendation. Inadvertent mix-ups of short-acting and long-acting 
1114 
insulins could contribute to the risk of hyperglycemia.         
1115 
 
1116 
8.5.6 Risk of Device Reuse 
1117 
The study CGM system is labeled for single-patient use only. The sensor (the component of the system 
1118 
that enters the skin) will be single-patient use only. The transmitter and receiver may be reused during 
1119 
the study after cleaning the device using a hospital-approved cleaning procedure. The transmitter is 
1120 

U1191-3911 DSS_Protocol_v 1.3_083117_CLEAN.docx  
 
8-36 
attached to the sensor but does not enter the skin and the receiver is a hand held device. Subjects will 
1121 
be informed that FDA or relevant national authorities have approved these devices for single use and 
1122 
that by using them among multiple patients, bloodborne pathogens (i.e. Hepatitis B) may be spread by 
1123 
multiple users.  
1124 
 
1125 
8.5.7 Psychosocial Questionnaires 
1126 
As part of the study, participants will complete psychosocial questionnaires which include questions 
1127 
about their private attitudes, feelings and behavior related to diabetes.  It is possible that some people 
1128 
may find these questionnaires to be mildly upsetting. Similar questionnaires have been used in 
1129 
previous research and these types of reactions have been uncommon. 
1130 
 
1131 
8.5.8 Other Risks 
1132 
Some subjects may develop skin irritation or allergic reactions to the adhesives used to secure the 
1133 
CGM.  If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, 
1134 
Tegaderm, etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
1135 
medication may be required. 
1136 
 
1137 
Whenever the skin is broken there is the possibility of an infection.  The CGM sensors are inserted 
1138 
under the skin.  It is possible that any part that is inserted under the skin may cause an infection.  These 
1139 
occur very infrequently, but, if an infection was to occur, oral and/or topical antibiotics can be used.  
1140 
The risk of skin problems could be greater if you use a sensor for longer than it is supposed to be used.  
1141 
Therefore, participants will be carefully instructed about proper use of the sensor. 
1142 
 
1143 
Data downloaded from the CGM and blood glucose and ketone meters will be collected for the study 
1144 
as measures of diabetes self-management behaviors.  Some people may be uncomfortable with the 
1145 
researchers' having such detailed information about their daily diabetes habits. 
1146 
 
1147 
8.6 Study Stopping Criteria 
1148 
 
1149 
8.6.1 Subject Discontinuation of Study Treatment 
1150 
Rules for discontinuing inControl Advice (if randomized to CGM+DSS group) or study CGM use (if 
1151 
randomized to the CGM group) are as follows: 
1152 
1. One episode of severe hypoglycemia, or of hyperglycemia/DKA as defined in Section 8.1 
1153 
2. One serious adverse event related to device malfunction. 
1154 
3. The subject requests that the treatment be stopped 
1155 
4. Subject pregnancy 
1156 
 
1157 
8.6.2 Criteria for Suspending/Stopping Overall Study 
1158 
In the case of inControl Advice resulting in a severe hypoglycemia or severe hyperglycemia event (as 
1159 
defined in Section 8.1) that is thought to be advice-related (due to excess insulin administration) and 
1160 
occurs more than three times, the overall study will be suspended while the problem is diagnosed.  The 
1161 
study may resume if the underlying problem can be corrected by a protocol or system modification that 
1162 
will not invalidate the results obtained prior to suspension. The overall study will be stopped in the 
1163 
event of three serious adverse events related to device malfunction. 
1164 

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9-37 
9 
MISCELLANEOUS CONSIDERATIONS 
1165 
 
1166 
9.1 Benefits 
1167 
One purpose of this research is to reduce the frequency of hypoglycemia and severe hypoglycemic 
1168 
events. Hypoglycemia is the number one fear of many individuals and families with someone who has 
1169 
type 1 diabetes and this fear often prevents optimal glycemic control.  
1170 
 
1171 
It is expected that this protocol will yield increased knowledge about using a decision support system 
1172 
to help control the glucose level.  In addition, it is the belief of the investigators that this study also presents 
1173 
prospect of direct benefit to the subjects and general benefit to others with diabetes. 
1174 
 
1175 
9.2 Subject Compensation 
1176 
Pilot subjects completing the 48-hour transitional setting admission will be compensated $200.  
1177 
  
1178 
Subjects will be compensated $50 for each clinic visit during the study. 
1179 
 
1180 
9.3 Subject Withdrawal 
1181 
Participation in the study is voluntary, and a subject may withdraw at any time.  For subjects who 
1182 
withdraw, their data will be used up until the time of withdrawal. 
1183 
 
1184 
9.4 Confidentiality 
1185 
For security and confidentiality purposes, subjects will be assigned an identifier that will be used 
1186 
instead of their name.  Protected health information gathered for this study will be shared with the third 
1187 
party collaborators.  De-identified subject information may also be provided to research sites involved 
1188 
in the study. 
1189 
 
1190 
9.5 Drug Accountability and Storage 
1191 
Insulin will be provided by a third party collaborator and delivered to the Investigational Pharmacy. 
1192 
The clinical investigator will be responsible for maintaining adequate records of the disposition of the 
1193 
drug. The clinical investigator will also ensure proper security and storage of the investigational drug.  
1194 
 
1195 
Documentation: The site will document drug receipt, subject dispensing and return, returns of used and 
1196 
unused supplies to a third party collaborator (or on-site destruction), and will maintain a current 
1197 
accounting of all supplies in inventory—that is, a balance-on-hand log. The balance-on-hand, or 
1198 
dispensing, log will contain the protocol number, the investigative site(s), the drug name, and the 
1199 
medication units—such as cartridge). The site will document receipt of each drug shipment in the 
1200 
balance-on-hand log, noting the date, amount, and lot, batch, or ID numbers. When dispensing drug to 
1201 
a subject, site personnel will record the date, subject number, and amount dispensed. When a subject 
1202 
returns a drug, the amount used and unused will be documented, and an explanation for any 
1203 
inadvertent loss or destruction of supplies will also be recorded.  
1204 
 
1205 
Ensuring compliance and reconciliation: Site personnel will assess dosing regimen compliance and 
1206 
drug reconciliation in an ongoing manner. At each subject visit, subject compliance will be evaluated 
1207 
and documented, including calculating the expected amount of consumed drug given the regimen and 
1208 
amount of time between visits. This figure will be compared with the amount dispensed minus the 
1209 
amount the subject returned. Site personnel will question the subject regarding any discrepancies in 
1210 
these amounts and document the explanation. 
1211 
 
1212 

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9-38 
Insulin Storage: Insulin will be stored per product labeling as follows: 
1213 
Insulin 
Temperature 
Use up to 
In use (opened) 
Room temperature: up to 86°F 
28 days 
Not in use (unopened) 
Room temperature: up to 86°F 
28 days 
Not in use (unopened) 
Refrigerated: 36°F to 46°F 
Expiration date 
 
1214 
 
1215 
1216 
1217 

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10-39 
 
10 STATISTICAL CONSIDERATIONS 
1218 
 
1219 
The approaches to sample size and statistical analyses are summarized below. A detailed statistical 
1220 
analysis plan will be written and finalized prior to the completion of the study.  
1221 
 
1222 
 
1223 
10.1 Sample Size 
1224 
We plan on 132 subjects finishing the study, leading to a potential enrollment of 160, with up to 17.5% 
1225 
attrition. We base our analysis on our previous decision-support trial [7] which recruited N=120 
1226 
subjects and concluded with N=96 yielding effect size of 0.2 on key parameters, and on the feasibility 
1227 
and safety study described in the background. In this study, 11 T1DM pump users tested a prototype of 
1228 
the DSS leading to an estimated moderate effect size of 0.5 (Cohen D method). Assuming a substantial 
1229 
reduction of effect size due to (i) the focus on MDI patients, (ii) the presence of CGM in both the 
1230 
experimental and the control groups, and (iii) the translation of the effect to an uncontrolled 
1231 
environment similar to the environment of our previous trial [7], we assume a small to medium effect 
1232 
size. Using the statistical analysis presented below, a 0.15 effect size, with 2 groups randomized in a 
1233 
ratio of 2:1 (experimental-control), and 3 repeated measures (inter measure correlation of 0.5) leads to 
1234 
a required sample size of N=132 (expected power of 95.6%) [15]. 
1235 
 
1236 
10.2 Primary Endpoints Analyses 
1237 
The primary analysis will follow the intention-to-treat principle [16]. It will include all subjects and the 
1238 
data will be analyzed in the group to which the subjects were assigned through randomization. Percent 
1239 
in range (70-180 during the day and 80-140 at night) will be computed over each month of data and 
1240 
entered in a Repeated Measure ANOVA, where the within-between interaction (group x period) will 
1241 
be studied.  
1242 
 
1243 
10.3 Secondary Efficacy Analyses 
1244 
In addition to the primary endpoint we will study: 
1245 
• HbA1c: estimated effect size of 0.15; repeated measures ANOVA, 2 groups, 2 measures, 
1246 
results in power of 90% with current enrollment; 
1247 
• Exposure to hypoglycemia, as measured by the percent of time spent below 70mg/dL and by 
1248 
the Low BG Index [13]; estimated effect size 0.25; power for repeated measures ANOVA 2x3 
1249 
>99%; 
1250 
• Exposure to hyperglycemia, as measured by the percent of time spent above 300mg/dL; 
1251 
estimated effect size 0.2; power for repeated measure ANOVA 2x3 = 99%; 
1252 
• Glucose variability as measured by the Average Daily Risk Range [14] (over 2-week period); 
1253 
estimated effect size 0.15; power for repeated measure ANOVA 2x6 = 95%.  
1254 
 
1255 
10.4 Questionnaires 
1256 
The following questionnaires will be completed at the randomization visit: 
1257 
• Diabetes Specific Personality Questionnaire  
1258 
• Clarke Hypoglycemia Awareness Scale [17] 
1259 
• Fear of Hypoglycemia Survey (HFS-II) [18] 
1260 
• Low Blood Sugar Survey 
1261 
• High Blood Sugar Survey 
1262 
• Diabetes Distress Scale 
1263 
• Technology Expectations Survey (CGM+DSS group) 
1264 

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10-40 
 
 
1265 
The following questionnaires will be completed at the final visit at week 12: 
1266 
• Clarke’s Hypoglycemia Awareness Scale  
1267 
• Fear of Hypoglycemia Survey (HFS-II) 
1268 
• Low Blood Sugar Survey 
1269 
• High Blood Sugar Survey 
1270 
• Diabetes Distress Scale 
1271 
• Technology Acceptance Survey (CGM+DSS group) 
1272 
 
1273 
For each questionnaire, mean ± SD values or percentiles appropriate to the distribution will be given 
1274 
by randomization group for the total score and each subscale. For questionnaires administered to both 
1275 
randomization groups comparisons will be made using similar ANCOVA models as described above 
1276 
for the primary endpoints.  No formal adjustment will be made for multiple comparisons. 
1277 
 
1278 
10.5 Primary Safety Analyses 
1279 
All subjects will be included in these analyses.   
1280 
 
1281 
The circumstances of all reportable cases of the following will be summarized and tabulated by 
1282 
treatment group: 
1283 
• Severe hypoglycemia (as defined in Section 8.1) 
1284 
• Diabetic ketoacidosis (as defined in Section 8.1) 
1285 
• Other serious adverse events (SAE) and serious adverse device events (SADE) 
1286 
• 
Unanticipated adverse device effects (UADE) 
1287 
  
1288 
The total number of SH or DKA events per subject will be compared using robust Poisson regression 
1289 
and the percentage of subjects with at least one event will be compared using Fisher’s exact test. 
1290 
 
1291 
10.6 Additional Tabulations 
1292 
The following tabulations will be performed without statistical testing:  
1293 
- 
baseline demographics and clinical characteristics  
1294 
- 
flow chart accounting for all subjects for all visits  
1295 
- 
visit completion rates for each follow-up visit  
1296 
- 
hours of sensor use 
1297 
- 
days of sensor use per week 
1298 
- 
phone contact completion rates for each follow-up visit  
1299 
- 
protocol deviations  
1300 
- 
number and reasons for unscheduled visits and phone calls  
1301 
- 
device malfunctions requiring study team contact and other reported device issues 
1302 
- 
In addition, performance metrics will be tabulated, describing the inControl Advice system and 
1303 
its components. 
1304 
 
1305 
10.7 Interim Analysis 
1306 
All CGM-related study endpoints will be analyzed for the first 6 weeks of study intervention in the 
1307 
first 40 subjects. The purpose of the interim analysis is to support regulatory submissions for the 
1308 
CGM+DSS system.  
1309 
1310 

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11-41 
 
11  DATA COLLECTION AND MONITORING 
1311 
 
1312 
11.1 Case Report Forms and Device Data 
1313 
The main study data are collected through a combination of case report forms (CRFs) and electronic 
1314 
device data files obtained from the study software and individual hardware components.  These 
1315 
electronic device files and electronic CRFs from the study website are considered the primary source 
1316 
documentation. 
1317 
 
1318 
11.2 Document Storage and Retention 
1319 
The Investigator of each clinical site will retain all records and documents pertaining to this study. 
1320 
They will be available for inspection by the appropriate regulatory agencies. In addition, the 
1321 
Investigator will retain the source documents from which the information entered on the CRFs was 
1322 
derived. These records are to be retained in a secure storage facility maintained by the investigational 
1323 
center until 3 years (or longer/shorter if local laws require) after approval of the above-listed study 
1324 
devices or termination of the study, whichever is longer. The investigator should take measures to 
1325 
prevent accidental or early destruction of the clinical study related materials. 
1326 
 
 
1327 

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12-42 
 
12 Publication Policy  
1328 
The contents of this protocol, the manuals pertaining to this study and the results of the investigation 
1329 
are confidential and may not be published or disclosed without the written consent of University of 
1330 
Virginia. The identity of the subjects may not be disclosed, unless required by law, to any persons not 
1331 
immediately involved in the study or the study procedures. The results of the clinical study will be 
1332 
submitted for publication in a peer-reviewed scientific journal upon study completion.   
1333 

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13 REFERENCES 
1334 
1. Clarke WL, Cox DJ, Gonder-Frederick LA, Julian DM, Kovatchev BP, Young-Hyman D. The bio-psycho-
1335 
behavioral model of severe hypoglycemia II: Self-management behaviors. Diabetes Care 22: 580-584, 1999. 
1336 
2. Gonder-Frederick L, Cox D, Kovatchev B, Schlundt D, Clarke W. A biopsychobehavioral model of risk of 
1337 
severe hypoglycemia. Diabetes Care, 20:661-669, 1997. 
1338 
3. Kovatchev BP, Cox DJ, Gonder-Frederick LA, Schlundt D and WL Clarke. Stochastic model of self-
1339 
regulation decision making exemplified by decisions concerning hypoglycemia. Health Psychology, 17:277-
1340 
284, 1998. 
1341 
4. Cox DJ, Gonder-Frederick LA, Kovatchev BP, Young-Hyman D, Schlundt D, Julian DM, Clarke WL. Bio-
1342 
psycho-behavioral model of severe hypoglycemia II: Understanding causes of severe hypoglycemia. 
1343 
Diabetes Care 22: 2018-2025, 1999. 
1344 
5. Cox DJ, Gonder-Frederick LA, Polonsky W, Schlundt D, Julian D, Clarke WL: A multicenter evaluation of 
1345 
blood glucose awareness training-II. Diabetes Care, 18: 523-528, 1995. 
1346 
6. Cox DJ, Gonder-Frederick LA, Polonsky W, Schlundt D, Julian D, Kovatchev BP, Clarke WL. Blood 
1347 
Glucose Awareness Training (BGAT-II): Long term benefits.  Diabetes Care, 24: 637-642, 2001. 
1348 
7. Kovatchev BP, Mendosa P, Anderson SM, Hawley JS, Ritterband LM, & Gonder-Frederick L. Effect of 
1349 
automated bio-behavioral feedback on the control of type 1 diabetes. Diabetes Care, 34:302-307, 2011. 
1350 
8. Kovatchev, B.P., Breton, M.D., Keith-Hynes, P.T., Patek, S.D. The Diabetes Assistant (DiAs) – Unified 
1351 
platform for monitoring and control of blood glucose levels in diabetic patients; PCT/US12/43910, 2012. 
1352 
9. MAF 2109: Artificial pancreas mobile medical platform. Received by FDA 11/08/2012.  
1353 
10. Keith-Hynes, P., Guerlain, S., Mize, L.B., Hughes-Karvetski, C., Khan, M., McElwee-Malloy, M. & 
1354 
Kovatchev, B.P. DiAs user interface: A patient-centric interface for mobile artificial pancreas systems. J 
1355 
Diabetes Sci Technol, 7, 1416–1426 (2013). PMID: 24351168 
1356 
11. Place, J., Robert, A., Ben Brahim, N., Keith-Hynes, P., Farret, A., Pelletier, M.J., Buckingham, B., Breton, 
1357 
M., Kovatchev, B.P. & Renard, E. DiAs web monitoring: A real-time remote monitoring system designed 
1358 
for artificial pancreas outpatient trials. J Diabetes Sci Technol, 7, 1427–1435. (2013). PMID: 24351169 
1359 
12. Keith-Hynes, P., Mize, B., Robert, A., Place, J. The Diabetes Assistant: A smartphone-based system for 
1360 
real-time control of blood glucose. Electronics 2014, 3, 609-623; doi:10.3390/electronics3040609 
1361 
13. Kovatchev BP, Cox DJ, Gonder-Frederick LA Young-Hyman D, Schlundt D, Clarke WL. Assessment of 
1362 
risk for severe hypoglycemia among adults with IDDM: Validation of the Low Blood Glucose Index, 
1363 
Diabetes Care 21: 1870-1875, 1998. 
1364 
14. Kovatchev BP, Otto E, Cox DJ, Gonder-Frederick LA, Clarke WL. Evaluation of a New Measure of Blood 
1365 
Glucose Variability in Diabetes. Diabetes Care, 29: 2433-2438, 2006. 
1366 
15. Faul F, Erdfelder E, Lang A-G, & Buchner A. G*Power 3: A flexible statistical power analysis program for 
1367 
the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 175-191, 2007. 
1368 
16. Lachin JM. Statistical considerations in the intent-to-treat principle, Control Clin Trials. 21:167-89, 2000. 
1369 
17. Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of 
1370 
hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated 
1371 
symptoms. Diabetes Care 18:517-22, 1995 
1372 
18. Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J. Fear of hypoglycemia: quantification, 
1373 
validation, and utilization. Diabetes Care 10:617-21, 1987 
1374 
 
1375