Clinical Acceptance of the Artificial Pancreas: the International Diabetes Closed Loop (iDCL) Trial: A Randomized Clinical Trial to Assess the Efficacy of Adjunctive Closed Loop Control Versus Sensor-Augmented Pump Therapy in the Management of Type 1 Diabetes
Phase: NA
Conditions: Type1 Diabetes Mellitus
Sponsor: University of Virginia

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Clinical Acceptance of the Artificial Pancreas:  
the International Diabetes Closed Loop (iDCL) Trial  
 
 
 
 
 
 
A Randomized Clinical Trial to Assess the Efficacy of Adjunctive Closed Loop Control Versus 
Sensor-Augmented Pump Therapy in the Management of Type 1 Diabetes 
 
 
 
 
 
 
 
 
Version 10.0 
February 9, 2017 
 
 
 
 
 
 
ALL INFORMATION & ANY ATTACHMENTS CONTAINED IN THIS PROTOCOL 
ARE CONFIDENTIAL INFORMATION, in accordance with the Non-Disclosure 
Agreement covering information related to the “Advanced Clinical Trials to test Artificial 
Pancreas Device Systems in Type 1 Diabetes (UC4)” study. 
 
 
 
 
 
 
 
 

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1 
 
2 
Protocol Chair 
3 
Stacey Anderson, M.D., University of Virginia  
4 
 
5 
Participating Institutions 
6 
University of Virginia, Charlottesville, Virginia 
7 
Harvard University and the Joslin Diabetes Center, Massachusetts 
8 
Sansum Diabetes Research Institute, Santa Barbara, California 
9 
Mount Sinai School of Medicine, New York City 
10 
Mayo Clinic, Rochester, Minnesota 
11 
Barbara Davis Center, University of Colorado, Colorado 
12 
Stanford University, California 
13 
 
14 
Coordinating Center 
15 
Jaeb Center for Health Research, Tampa, FL  
16 
 
 
17 

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TABLE OF CONTENTS 
18 
 
19 
 INTRODUCTION .................................................................................................. 8 
20 
 Background and Rationale ................................................................................................. 8 
21 
 Preliminary Studies ............................................................................................................ 8 
22 
 Closed-Loop Control System ........................................................................................... 12 
23 
 Synopsis of Study Protocol .............................................................................................. 13 
24 
 Study Objective ............................................................................................................. 13 
25 
 Study Design ................................................................................................................. 13 
26 
 Major Eligibility Criteria ............................................................................................... 13 
27 
 Sample Size .................................................................................................................. 13 
28 
 Treatment Groups.......................................................................................................... 14 
29 
 Visit and Phone Contact Schedule ................................................................................. 14 
30 
 Outcomes ...................................................................................................................... 18 
31 
 General Considerations .................................................................................................... 18 
32 
 SUBJECT SCREENING AND ENROLLMENT .............................................. 19 
33 
 Study Population .............................................................................................................. 19 
34 
 Eligibility and Exclusion Criteria ..................................................................................... 19 
35 
 Eligibility ...................................................................................................................... 19 
36 
 Exclusion ...................................................................................................................... 19 
37 
 Authorization Procedures ................................................................................................. 20 
38 
 Screening and Enrollment Visit Logistics ......................................................................... 20 
39 
 Data Collection and Testing .......................................................................................... 21 
40 
 CGM RUN-IN PHASE ......................................................................................... 22 
41 
 CGM Run-in Phase Overview .......................................................................................... 22 
42 
 Optimization of Insulin Pump Settings ............................................................................. 23 
43 
 Blinded CGM Use ............................................................................................................ 23 
44 
 Blinded CGM Assessment/Unblinded CGM Initiation Visit .......................................... 23 
45 
 Assessment of Blinded CGM ........................................................................................ 24 
46 
 Unblinded CGM Use ........................................................................................................ 24 
47 
 Initiation of Unblinded CGM ........................................................................................ 24 
48 
 Assessment of Successful Completion of the Unblinded CGM Run-in Phase ................ 24 
49 
 RANDOMIZED TRIAL....................................................................................... 25 
50 
 Randomization Visit......................................................................................................... 25 
51 
 Timing of Visit .............................................................................................................. 25 
52 
 HbA1c .......................................................................................................................... 25 
53 
 Baseline C-Peptide Assessment ..................................................................................... 25 
54 
 Randomization .............................................................................................................. 25 
55 
 Questionnaires............................................................................................................... 25 
56 
 Procedures for the CTR Group ......................................................................................... 25 
57 
 Study Pump Training and inControl Training ................................................................ 25 
58 
 Blinded CGM Insertion ................................................................................................. 27 
59 
 Home Use of inControl System ..................................................................................... 27 
60 
 Study Device Data Transmission ................................................................................... 28 
61 
 1-Week Phone Contact .................................................................................................. 28 
62 
 2-Week Visit (Training Review and Insulin Pump Optimization) .................................. 28 
63 
 Procedures for the SAP Group ......................................................................................... 28 
64 
 Study Device Data Transmission ................................................................................... 28 
65 

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 1-Week Phone Contact .................................................................................................. 28 
66 
 2-Week Visit (Training Review and Insulin Pump Optimization) .................................. 29 
67 
 Follow-up Visits and Phone Contacts for Both Groups ..................................................... 29 
68 
 Follow-up Visits ............................................................................................................ 29 
69 
4.4.1.1. Procedures at Follow-up Visits ................................................................................... 29 
70 
 Phone Contacts .............................................................................................................. 30 
71 
 QUESTIONNAIRES ............................................................................................ 31 
72 
 Introduction ..................................................................................................................... 31 
73 
 Diabetes Specific Personality Questionnaire ..................................................................... 31 
74 
 Clarke’s Hypoglycemia Awareness Scale ......................................................................... 31 
75 
 Hypoglycemia Fear Survey (HFS-II) / Low Blood Sugar Survey ...................................... 31 
76 
 Hyperglycemia Avoidance Survey (HAS) / High Blood Sugar Survey ............................. 32 
77 
 Hypoglycemia Confidence Scale ...................................................................................... 32 
78 
 Diabetes Distress Scale .................................................................................................... 32 
79 
 Technology Expectation and Technology Acceptance Surveys ......................................... 32 
80 
 INSPIRE Survey .............................................................................................................. 32 
81 
 SAFETY MEASURES ......................................................................................... 33 
82 
 Safety Measures ............................................................................................................... 33 
83 
 CGM Calibration ........................................................................................................... 33 
84 
 Safety Measures for Open-Loop CGM Use ................................................................... 33 
85 
6.1.2.1. Hypoglycemia Threshold Alarm and Safety Protocol ................................................. 33 
86 
6.1.2.2. Hyperglycemia Threshold Alarm and Safety Protocol ................................................ 33 
87 
 Safety Measures Specific to Control-to-Range (CTR) Closed-Loop Group .................... 33 
88 
6.1.3.1. Insulin Dosing ............................................................................................................ 33 
89 
6.1.3.2. Hypoglycemia Safety Protocol ................................................................................... 34 
90 
6.1.3.3. Hyperglycemia Safety Protocol .................................................................................. 34 
91 
6.1.3.4. Remote Monitoring .................................................................................................... 34 
92 
6.1.3.5. CGM Sensor Connection Failure ................................................................................ 35 
93 
6.1.3.6. Pump Connection Failure ........................................................................................... 35 
94 
6.1.3.7. Study System Failure .................................................................................................. 35 
95 
 ADVERSE EVENTS, DEVICE MALFUNCTIONS, POTENTIAL RISKS, AND 
96 
STOPPING RULES....................................................................................................................... 36 
97 
 Definitions ....................................................................................................................... 36 
98 
 Hypoglycemic Events.................................................................................................... 37 
99 
 Hyperglycemic Events/Diabetic Ketoacidosis ............................................................... 37 
100 
 Relationship of Adverse Event to Study Device............................................................. 37 
101 
 Intensity of Adverse Event ............................................................................................ 38 
102 
 Coding of Adverse Events ............................................................................................. 38 
103 
 Outcome of Adverse Event ............................................................................................ 38 
104 
 Data and Safety Monitoring Board ................................................................................... 40 
105 
 Potential Risks and Side Effects ....................................................................................... 40 
106 
 Venipuncture Risks ....................................................................................................... 40 
107 
 Fingerstick Risks ........................................................................................................... 41 
108 
 Subcutaneous Catheter Risks (CGM) ............................................................................ 41 
109 
 Risk of Hypoglycemia ................................................................................................... 41 
110 
 Risk of Hyperglycemia .................................................................................................. 41 
111 
 Risk of Device Reuse .................................................................................................... 41 
112 
 Psychosocial Questionnaires ......................................................................................... 42 
113 

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 Other Risks ................................................................................................................... 42 
114 
 Risk Assessment .............................................................................................................. 42 
115 
 Study Stopping Criteria .................................................................................................... 42 
116 
 Subject Discontinuation of Study Treatment .................................................................. 42 
117 
 Criteria for Suspending/Stopping Overall Study ............................................................ 43 
118 
 MISCELLANEOUS CONSIDERATIONS ........................................................ 44 
119 
 Benefits ............................................................................................................................ 44 
120 
 Subject Compensation ...................................................................................................... 44 
121 
 Subject Withdrawal .......................................................................................................... 44 
122 
 Confidentiality ................................................................................................................. 44 
123 
 STATISTICAL CONSIDERATIONS ................................................................ 45 
124 
 Sample Size ..................................................................................................................... 45 
125 
 Calculation of Outcome Metrics and Handling of Missing Data ....................................... 45 
126 
 Primary Analyses ............................................................................................................. 46 
127 
 Changes in CGM-Measured % below 70 mg/dL from Run-in to 3-Months Post-
128 
Randomization Period between the Two Treatment Arms ....................................................... 46 
129 
 Changes in CGM-Measured % above 180 mg/dL from Run-in to 3-Months Post-
130 
Randomization Period between the Two Treatment Arms ....................................................... 46 
131 
 Secondary Efficacy Analyses ........................................................................................... 47 
132 
 Additional Treatment Group Comparisons ....................................................................... 48 
133 
 Quality of Life Questionnaires ......................................................................................... 48 
134 
 Subgroup Analyses .......................................................................................................... 48 
135 
 Safety Analyses ................................................................................................................ 49 
136 
 Additional Tabulations and Plots ...................................................................................... 50 
137 
 Tabulations in CTR Arm Only ....................................................................................... 50 
138 
 Sensitivity Analyses ....................................................................................................... 50 
139 
 Other Analyses ............................................................................................................... 50 
140 
 DATA COLLECTION AND MONITORING ................................................. 51 
141 
 Case Report Forms and Device Data .............................................................................. 51 
142 
 Quality Assurance and Monitoring ................................................................................. 51 
143 
APPENDIX: SAMPLE SIZE ESTIMATION FOR THE IDCL TRIAL ................................. 52 
144 
REFERENCES .............................................................................................................................. 54 
145 
 
146 
 
 
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TABLE OF ACRONYMS 
148 
Acronym 
Abbreviation For 
ADA 
American Diabetes Association 
AP 
Artificial Pancreas 
ATTD 
Advanced Technologies & Treatments for Diabetes 
AUC 
Area Under the Curve 
BAM 
Basal Attenuation Module 
BG 
Blood Glucose 
BIM 
Basal Increase Modulator 
BT/BTLE 
Bluetooth, Bluetooth low energy 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
CLC 
Closed-Loop Control 
CSII 
Continuous Subcutaneous Insulin Infusion 
CTR 
Control-to-Range 
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 
HCM 
Hyperglycemia Correction Module 
ID 
Identification 
iDCL 
International Diabetes Closed Loop 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
IQR 
Interquartile Range 
JDRF 
Juvenile Diabetes Research Foundation 
NIH 
National Institutes of Health 
POC 
Point-of-Care 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled/Clinical Trial 
RMB 
Risk-Based Monitoring 
SADE 
Serious Adverse Device Event 
SAE 
Serious Adverse Event 
SAP 
Sensor-Augmented Pump 

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Acronym 
Abbreviation For 
SD 
Standard Deviation 
SFPQ 
Six Factor Personality Questionnaire 
SH 
Severe Hypoglycemia 
SMBG 
Self-Monitoring of Blood Glucose 
SSL 
Secure Sockets Layer 
TDI 
Total Daily Insulin 
UADE 
Unanticipated Adverse Device Effect 
UI 
User Interface 
UVA 
University of Virginia 
 
149 
 
 
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 INTRODUCTION 
151 
 
152 
 Background and Rationale 
153 
The transition of closed-loop control (CLC, known as the “artificial pancreas”) to everyday diabetes 
154 
therapy is contingent upon the acceptance by patients and physicians of an advanced CLC system 
155 
ensuring concerted work of continuous glucose monitors (CGMs), insulin pumps, and control 
156 
algorithms. In 2011, a new pathway towards the development of such a system was charted by the 
157 
Diabetes Assistant (DiAs) – a smart-phone multi-use platform designed at the University of Virginia 
158 
(UVA)to operate in several treatment modes ranging from CGM or insulin pump support to overnight 
159 
and 24/7 CLC. Since its introduction in 2011, DiAs has earned regulatory approvals in the U.S., 
160 
France, Italy, Netherlands, and Israel; 3 different control algorithms have been implemented on the 
161 
DiAs platform and used in 18 clinical trials, including long-term studies at home. To date, over 300 
162 
patients with type 1 diabetes have tested DiAs for over 220,000 hours of outpatient use. We can 
163 
therefore affirm that reliable technology has been developed and sufficient data have been accumulated 
164 
to warrant a large-scale clinical trial aiming to establish the artificial pancreas as a clinically accepted 
165 
treatment for type 1 diabetes that is superior to the current sensor-augmented pump (SAP) therapies. A 
166 
key distinction of our approach is that the artificial pancreas is not considered a single-function 
167 
device–it is a platform for technology deployment that can run open- or closed-loop control modalities 
168 
depending on physician recommendation, patient preference, or signal availability.  Recently, we have 
169 
built and tested a third-generation version of our DiAs system named inControl, as described below, to 
170 
support larger-scale clinical trials. 
171 
 
172 
 Preliminary Studies 
173 
Figure 1 below presents the extensive sequence of innovative outpatient clinical trials done in the past 5 
174 
years since the introduction of our DiAs system: 
175 
Figure 1: Past, current, and upcoming outpatient studies identified by their source of funding: JDRF, NIH, 
176 
the Helmsley Charitable Trust (HCT), and the European Commission (EC) 
177 
 
 
178 

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179 
These studies included multi-site and international trials done at several prominent clinical centers in the 
180 
U.S. and overseas, ranging from early-feasibility 2-day studies in supervised outpatient environment to 
181 
6-months trials at home. Our overall strategy has been to test, re-test, and test again, in various 
182 
conditions, clinical centers, and age groups. As noted above, these studies accumulated a wealth of data 
183 
(21 patient years of closed-loop control) and AP know-how, which now allow us to transition to the 
184 
large-scale International Diabetes Closed-Loop pivotal trial. The upper panel of Figure 1 includes 
185 
pediatric studies, while the lower panel presents studies in adults. 
186 
 
187 
Briefly, in 2012/2013 we completed two international multi-site trials, which confirmed the feasibility 
188 
of DiAs and its efficacy to reduce hypoglycemia in the outpatient setting; both were selected for the 
189 
Diabetes Care symposiums at the 2013 and 2014 American Diabetes Association (ADA) Scientific 
190 
Sessions (1, 2). Three summer camp trials of remote monitoring (3), overnight CLC (4), and 24/7 CLC 
191 
(5) confirmed the efficacy of DiAs in children with T1D. In Europe, AP@home ran two pilot trials to 
192 
pave the way for the large-scale AP@Home-3 which included 2-month overnight and 2-month 24/7 CLC 
193 
at home (6), which was the first study to report statistically significant reduction in HbA1c with CLC 
194 
(7). The longest to-date (6-month) multi-center trial of 24/7 CLC at home was reported in February 2016 
195 
at the ATTD conference in Milan, Italy and showed very significant several-fold reduction in 
196 
hypoglycemia without deterioration in HbA1c (8, 9). Adult studies now continue with Project Nightlight 
197 
– an 11-month trial which compares dinner/overnight vs. 24/7 CLC in terms of glycemic outcomes and 
198 
patient acceptance (10), and with the International Diabetes Closed-Loop Trial. Three new exciting 
199 
pediatric studies complete the lineage presented in Figure 1: (i) the multi-center Italian PedArPan trial 
200 
recruited 5–9-year-old children and their parents from 5 sites for a summer camp (11); (ii) the French 
201 
Stop Hypo at Night trial compares the prevention of hypoglycemia in 7-12 year old children achieved 
202 
by the Safety System described in the previous section vs. threshold low glucose suspend, and (iii) an 
203 
AP study on skis recruited 16 children at Wintergreen, Virginia in January 2016 to test the ability of the 
204 
system to cope with extreme winter conditions and prolonged vigorous physical activity (5 hours of 
205 
skiing daily for 5 days) (12). 
206 
While our overall progress with the development and the clinical testing of a wearable artificial pancreas 
207 
(AP) is depicted in Figure 1, the results below are of particular relevance to the proposed Study: 
208 
(1) CLC Algorithm Performance: We illustrate our expectations for this project with data from two 
209 
studies that have tested the same CTR system we are planning to use now with adolescents missing or 
210 
Blood Glucose Level (mg/dl)
250
01:00
03:00
05:00
100
150
200
07:00
23:00
09:00
10:00
11:00
12:00
13:00
100
150
200
250
300
A
B
Time of Day (h)
Time of Day (h)
Sensor-Augmented Pump (SAP), mean; quartiles
Control-to-Range (CTR), mean; quartiles
Figure 2: CLC in Adolescents Missing/Underestimating Pre-meal Bolus (A) and in Adults Overnight (B) 

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underestimating their pre-meal boluses (13) and with adults during overnight control (14), presented in 
211 
Figure 2, panels A and B: 
212 
In the first of these studies CLC reduced the extent and duration of postprandial BG excursions: mean 
213 
BG of 197 vs. 235 mg/dL (p<0.05) on CLC vs. SAP (13). In the second study, CLC compared to SAP 
214 
reduced mean BG level at 07:00h (119.3 vs. 152.9 mg/dL; p<0.001) and overnight (139.0 vs. 170.3 
215 
mg/dL; p<0.001) (14). 
216 
(2) JDRF Multi-Center 6-Month Trial of 24/7 Closed-Loop Control: In the summer of 2014, we initiated 
217 
a two-phase long-term (6 months) trial evaluating DiAs in the natural environment. Phase 1 (1 month) 
218 
recruited 30 patients with T1DM at 6 clinical centers: UVA, Stanford University, the William Sansum 
219 
Diabetes Center, Santa Barbara, CA, the Universities of Padua (Italy) and Montpellier (France), and the 
220 
Schneider Children’s Medical Center of Israel (1). During Phase 1, subjects participated in 2 weeks of 
221 
overnight-only and 2 weeks of 24/7 CLC. Phase 2 continued with N=14 patients at 4 of these sites (UVA, 
222 
Stanford, Sansum, Padua), for 5 additional months of 24/7 CLC (9). The study was coordinated by the 
223 
Jaeb Center for Health Research.  
224 
Median subject characteristics: age=45 years; duration of diabetes=27 years; total daily insulin=0.54 
225 
(U/kg/day); basal daily insulin=0.22 (U/kg/day); 10/4 male/female. 
226 
Results:  
227 
Figure 3 below presents the time within target range achieved during CLC in Phase 1 of this study during 
228 
overnight CLC and during 24/7 CLC, compared to sensor-augmented pump. As seen in Figure 3, CLC 
229 
achieved over 70% time in the target range overall, accompanied by significant reduction in 
230 
hypoglycemia.  
231 
 
232 
 
233 
Figure 3: Summary of the results from Phase 1 which included 2 weeks of overnight CLC and 2 
weeks of 24/7 CLC 

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During the 5-month Phase 2, CLC achieved over 75% time in the target range overall and separately 
234 
during the day and during the night. The rest of the data were primarily distributed between 180 and 250 
235 
mg/dL. Extreme BG excursions were rare (Figure 4): 
236 
 
237 
Overall, HbA1c was reduced from 7.2% at the baseline to 7.0% (p=0.16) at the end of the 
238 
study. This was accompanied by a significant 3-fold reduction in the frequency of 
239 
hypoglycemia from baseline to the last three months of CGM monitoring 4.1% vs. 1.3% 
240 
(p<0.001). Improvement in HbA1c was highly correlated with the percent time of system use, 
241 
r=0.59; in particular those with above-median system use (>70% of the time) achieved HbA1c 
242 
reduction of 0.44%, from 7.19% at the baseline to 6.74% at the end of study (9).  
243 
Table 1 below presents a summary of the results: 
244 
 
245 
Table 1: 6-month CLC Trial Key Results 
246 
 
247 
Meta-Analysis of All DiAs Studies to Date: 
248 
Table 2 presents meta-analysis of 184,000 hours (21 patient years) of data from several previous 
249 
studies that used the DiAs artificial pancreas platform over the past 5 years. These studies were 
250 
conducted at several research centers in the U.S. and overseas and enrolled a total of 420 patients with 
251 
type 1 diabetes.  Despite the geographical and patient diversity, the across-site results were consistent:  
252 
 
253 
 
 
254 
 
Baseline 
End of Study 
P-value 
%CGM < 70 mg/dL (median (IQR)) 
4.1 (2.9-7.5) 
1.3 (0.6-1.7) 
<0.001 
%CGM < 60 mg/dL (median (IQR)) 
2.2 (1.5-3.4) 
0.3 (0.2-0.6) 
<0.001 
%CGM < 50 mg/dL (median (IQR)) 
1.0 (0.8-1.3) 
0.1 (0.0-0.2) 
<0.001 
A1c (mean ± SD) 
7.2 ± 0.6 
7.0 ± 0.6 
0.16 
A1c for those with A1c >7.0 at baseline 
7.5 ± 0.4 
7.1 ± 0.7 
0.12 
Figure 4: Summary of the results from Phase 2 – additional 5 months of 24/7 CLC 

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Table 2: CLC Meta-Analysis 
255 
 
% time within 70-180 mg/dL 
Average BG (mg/dL) 
% time < 70 mg/dL 
CLC 
SAP 
CLC 
SAP 
CLC 
SAP 
Overall 
71.7% 
63.8% 
152.4 
158.3 
2.0% 
3.9% 
Overnight 
76.5% 
60.7% 
148.6 
161.4 
1.1% 
3.1% 
 
256 
 Closed-Loop Control System 
257 
inControl-AP is an “artificial pancreas” (AP) application that uses advanced 
258 
closed loop control algorithms to automatically manage blood glucose levels for 
259 
people with Type 1 Diabetes. The current mobile implementation of inControl-
260 
AP runs on a standard Android smartphone and uses Bluetooth (BT) and 
261 
Bluetooth Low Energy (BLE) connectivity to communicate with a Continuous 
262 
Glucose Monitor (CGM) and insulin pump.  The system modulates insulin to 
263 
keep blood glucose in a targeted range.  inControl-AP runs on a modified release 
264 
of the Android operating system.  Modifications include the removal of 
265 
unnecessary applications and functions, and fixes to the BT stack to permit 
266 
communication with the insulin pump. While inControl-AP is an Android 
267 
application with a JS/CSS UI, system upgrades during the study will be 
268 
considered when new technology becomes available and is sufficiently tested. 
269 
For example, new generations of CGM sensors or insulin pumps with embedded 
270 
inControl-AP could become available for inclusion in this trial and could be used, 
271 
provided that these new development do not change the core functionality of the 
272 
system described below and in Figure 5.    
273 
 
274 
The system services include the following processing elements: 
275 
• Core:  handles timing and main loop calls, intercepts system messages and 
276 
handles data changes 
277 
• Metabolic state estimation:  calculates the patient’s current metabolic 
278 
state, including current and predicted blood glucose and IOB, and stores 
279 
values in a database 
280 
• Controller:  calls the modules that calculate algorithmic and manually 
281 
requested insulin delivery quantities in sequence  
282 
• UIM – User Input Module handles the delivery of insulin requested 
283 
manually by the user which includes meal and correction boluses 
284 
• BIM – Basal Increase Module increases basal delivery in response 
285 
to estimated blood glucose levels based on a circadian target profile 
286 
• HCM – Hyperglycemic Correction Module calculates a correction 
287 
bolus in response to estimated blood glucose above its target 
288 
• BAM – Basal Attenuation Module may reduce basal insulin 
289 
delivery if the system determines a risk of hypoglycemia 
290 
• Supervisor:  determines which dosing algorithm outputs are valid and 
291 
active based on the current operating state of the system 
292 
 
293 
The inControl system operates on a 5-minute cycle based on the highest frequency of input data.  There 
294 
are two insulin dosing modes (pump and closed loop) and three operating modes (normal, sleep and 
295 
exercise). The combination of insulin dosing mode and operating mode determines what actions 
296 
inControl will perform and what options are presented to the user. 
297 
 
298 
Figure 5: inControl-AP 
Schematic 

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299 
Figure 6: Schematic of inControl-AP system hardware components 
300 
 
301 
 Synopsis of Study Protocol 
302 
 Study Objective 
303 
The objective of the study is to assess the efficacy and safety of home use of a Control-to-Range 
304 
(CTR) closed-loop (CL) system.   
305 
 
306 
 Study Design 
307 
The protocol is a 3-month parallel group multi-center randomized trial designed to compare Control-
308 
to-Range (CTR) closed-loop (CL) with sensor augmented pump therapy (SAP). 
309 
 
310 
 Major Eligibility Criteria 
311 
• Clinical diagnosis of type 1 diabetes, treated with insulin for at least 1 year 
312 
• Use of an insulin infusion pump for at least 6 months 
313 
• Age ≥14 years old 
314 
• HbA1c level <10.5% at screening 
315 
o A study goal will be to have a minimum of 50 subjects with HbA1c ≥7.5% and 50 with 
316 
HbA1c <7.5%. 
317 
• No use of glucose-lowering agents other than insulin in the 3 months prior to enrollment 
318 
• Willingness to establish network connectivity on at least a weekly basis either via local Wi-Fi 
319 
network or via a study-provided cellular service 
320 
 
321 
 Sample Size 
322 
Approximately 126 subjects will enter into the randomized trial conducted at approximately 7 clinical 
323 
sites in the United States.  
324 

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325 
 Treatment Groups 
326 
Subjects in the trial will be randomly assigned in a 1:1 ratio to the Control-to-Range (CTR) Closed-
327 
Loop or sensor augmented pump therapy (SAP) groups, respectively.   
328 
 
329 
 Visit and Phone Contact Schedule 
330 
Subjects who used a personal CGM that is the same brand as the study CGM prior to the study for at 
331 
least 21 of the prior 28 days will proceed directly to randomization.  These subjects will have the 
332 
personal CGM downloaded for capture of the two-week baseline data. 
333 
 
334 
All other subjects will participate in the following CGM run-in phases requiring additional clinic visits 
335 
as shown in Figure 7: 
336 
• Two-week period of blinded study CGM use to characterize baseline glycemic control; subjects 
337 
using a personal CGM prior to the study will continue to use it during this period. 
338 
• Two-week period of unblinded study CGM use, with training in using CGM if necessary; 
339 
subjects using a personal CGM prior to the study will discontinue the personal CGM beginning 
340 
in this period. 
341 
 
342 
After randomization, all subjects will have an initial two-week training period as shown in Figure 8: 
343 
• Participants in the SAP Group will use the study CGM and will continue to use their personal 
344 
insulin pump, with a phone contact after one week to assess usage and reinforce CGM training 
345 
if needed.  
346 
• Participants in the CTR Group will cease use of their personal insulin pump and will receive 
347 
study pump training followed by inControl training and then use the inControl system at home 
348 
(study pump, study CGM and inControl device). There will be a phone contact after one week 
349 
to assess usage and reinforce pump, CGM and/or inControl training if needed. 
350 
 
351 
As shown in Table 3, all subjects have the same post-randomization clinic visit and phone contact 
352 
schedule, with the possible exception of an additional training session on a different day for CTR 
353 
Group subjects if there is insufficient time at the randomization visit to train fully on the closed-loop 
354 
system components.  This training session will occur within one week of the Randomization Visit, and 
355 
the remaining schedule is as follows: 
356 
• Visits after: 2 weeks, 5 weeks, 9 weeks, 13 weeks 
357 
• Phone contacts after: 1 week, 3 weeks 
358 
 
359 

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15 
 
 
 
 
Figure 7: Enrollment and Pre-Randomization Flow Diagram 
360 
 
361 
 
Randomization Visit 
•
Reassess eligibility & participant’s willingness to follow protocol 
•
HbA1c from local lab/POC device for completion of Randomization Visit CRF 
•
Blood draw for central lab HbA1c and C-peptide 
•
Random assignment to Control SAP or CTR Group 
•
Study insulin pump and inControl training for CTR Group participants 
•
Questionnaires 
Screening/Enrollment Visit 
•
Eligibility assessment and informed consent 
•
HbA1c from local lab or POC device (to determine eligibility) 
•
Device download and adherence assessment for current CGM users 
  
Two weeks blinded study CGM use at home 
Blinded Run-in Review Visit 
•
Reassess eligibility 
•
Study CGM training, if needed 
Two weeks unblinded study CGM use at home 
Yes 
Use of  
same brand CGM 
≥ 21 of past 28 
days? 
No 
Unblinded Run-in Review Visit 
•
Reassess eligibility 

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16 
 
 
 
 
Figure 8: Post-Randomization Flow Diagram 
362 
 
363 
 
 
364 
Randomization Visit 
 
Week 2 Visit 
•
Refresher training on devices 
Phone Contacts: Week 3 
 
Clinic Visits: Weeks 5, 9, 13 
 
 
Study pump and inControl system training 
and home use of inControl system: 
 
Training begins immediately after 
randomization and continues if necessary on 
up to one additional session within 1-7 days 
of randomization 
 
Up to one week of inControl closed-loop 
system use at home 
Primary Outcome 
(13 weeks) 
CTR Group 
SAP Group 
One week of inControl closed-loop 
system use at home 
One week of SAP at home with study 
CGM and personal pump 
Week 1 Phone Contact 
•
SAP data assessment 
One week of SAP at home with study 
CGM and personal pump 
Week 1 Phone Contact 
•
inControl data assessment 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
17 
 
 
 
 
Table 3:  Schedule of Study Visits, Phone Contacts, and Key Procedures (Randomization at Week 0) 
365 
Purpose 
Screen/
Enroll 
CGM 
run-in, if 
needed 
Rand 
Follow-Up 
Timing from Randomization 
0-6w 
prior 
~2-3w 
prior 
0 
1w 
+3d  
2w 
+3d 
3w
+3d 
5w 
+1w 
9w 
+1w 
13w 
+1w 
Visit or Phone 
V 
V1 
V 
P 
V 
P 
V 
V2 
V 
Eligibility Assessment 
X 
X 
X 
 
 
 
 
 
 
Blinded CGM (2 weeks) 
 
X 
X3 
 
 
 
 
X 
 
HbA1c (DCA Vantage or similar 
point of care device, or local lab) 
X 
 
X 
 
 
 
 
 
X 
HbA1c (Central lab) 
 
 
X 
 
 
 
 
 
X 
C-peptide (Central lab) 
 
 
X 
 
 
 
 
 
 
Pregnancy test (female 
participants of child-bearing 
potential) 
X 
 
X 
 
 
 
 
 
 
Device data downloads 
X 
X 
X 
 
X 
 
X 
X 
X 
Review diabetes management and 
AEs 
 
X 
X 
X 
X 
X 
X 
 
X 
Optimization of insulin pump 
settings 
X 
X 
X 
 
X 
 
 
 
 
Clarke Hypoglycemia Awareness 
Scale, Hyperglycemia Avoidance 
Scale, Fear of Hypoglycemia 
Survey, Hypoglycemia 
Confidence Scale, INSPIRE 
Survey, and Diabetes Distress 
Scale  
 
 
X 
 
 
 
 
 
X 
Diabetes Specific Personality 
Questionnaire 
 
 
X 
 
 
 
 
 
 
Technology Expectations Survey 
(CTR group) 
 
 
X 
 
 
 
 
 
 
Technology Acceptance Survey 
(CTR group) 
 
 
 
 
 
 
 
 
X 
 
366 
1 Visit not required for all subjects—refer to Figure 7 and Figure 8 above 
367 
2 Non-medical visit; insertion of blinded CGM sensor and download of study device data only 
368 
3 For CTR subjects only who are not using a CGM receiver whose data can be downloaded  
 
369 

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18 
 
 
 
 
 Outcomes 
370 
Primary Efficacy Outcomes: 
371 
The co-primary outcomes are differences in CGM-measured metrics between baseline and 3-month post-
372 
randomization period: 
373 
• superiority in CGM-measured time below 70 mg/dL, and  
374 
• non-inferiority in CGM-measured time above 180 mg/dL 
375 
 
376 
The study will be declared a success if a statistically significant superiority in CGM-measured time below 
377 
70 mg/dL along with a non-inferiority in CGM-measured time above 180 mg/dL is observed. 
378 
 
379 
Main Safety Outcomes: 
380 
• Episodes of severe hypoglycemia 
381 
• Episodes of diabetic ketoacidosis (DKA) 
382 
• Other serious adverse events 
383 
 
384 
 General Considerations 
385 
The study is being conducted in compliance with the policies described in the study policies document, 
386 
with the ethical principles that have their origin in the Declaration of Helsinki, with the protocol 
387 
described herein, and with the standards of Good Clinical Practice (GCP). 
388 
 
389 
Data will be directly collected in electronic case report forms, which will be considered the source 
390 
data.   
391 
 
392 
There is no restriction on the number of subjects to be enrolled by each site towards the overall 
393 
recruitment goal. 
394 
 
395 
The protocol is considered a significant risk device study, due to the fact that the closed-loop system is 
396 
experimental.  Therefore, an investigational device exemption (IDE) from the U.S. Food and Drug 
397 
Administration (FDA) is required to conduct the study. 
398 
 
399 
Investigational device components may be used by study staff for the purpose of system training and 
400 
troubleshooting as long as there is no insulin infusion.
401 

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19 
 
 
 
 
 SUBJECT SCREENING AND ENROLLMENT 
402 
 
403 
 Study Population 
404 
Enrollment will proceed with the goal of randomizing 126 subjects and having at least 110 
405 
subjects with sufficient data to include in the primary analysis. A maximum of 200 subjects may 
406 
be enrolled in the study in order to achieve the goal of randomizing 126 subjects. 
407 
 
408 
In order to have a broad range of glycemic control among the subjects, a study goal will be to 
409 
have a minimum of 50 subjects with HbA1c ≥7.5% and 50 with HbA1c <7.5%. 
410 
 
411 
 Eligibility and Exclusion Criteria 
412 
 
413 
 Eligibility 
414 
To be eligible for the study, a subject must meet the following criteria: 
415 
1) Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year 
416 
and using insulin for at least 1 year  
417 
2) Use of an insulin pump for at least 6 months 
418 
3) Age ≥14 years old 
419 
4) HbA1c level <10.5% at screening 
420 
5) For females, not currently known to be pregnant 
421 
• If female and sexually active, must agree to use a form of contraception to prevent 
422 
pregnancy while a participant in the study.  A negative serum or urine pregnancy test 
423 
will be required for all females of child-bearing potential.  Subjects who become 
424 
pregnant will be discontinued from the study. Also, subjects who during the study 
425 
develop and express the intention to become pregnant within the timespan of the 
426 
study will be discontinued. 
427 
6) Willingness not to add non-insulin glucose-lowering agents (such as Pramlintide, Metformin, 
428 
GLP-1 analogs, SGLT2 inhibitors) during the study 
429 
7) Willingness, if not assigned to the closed-loop group, to avoid use of any closed-loop control 
430 
system for the duration of the clinical trial  
431 
8) Willingness to suspend use of any personal CGM for the duration of the clinical trial 
432 
beginning with the unblinded study CGM run-in period 
433 
9) Willingness to establish network connectivity on at least a weekly basis either via local Wi-Fi 
434 
network or via a study-provided cellular service 
435 
10) Currently using no insulins other than one of the following rapid-acting insulins at the time 
436 
of enrollment: insulin lispro (Humalog), insulin aspart (Novolog), or insulin glulisine 
437 
(Apidra) 
438 
11) Investigator has confidence that the subject can successfully operate all study devices and is 
439 
capable of adhering to the protocol 
440 
12) For subjects <18 years old, living with one or more parent/legal guardian (referred to 
441 
subsequently as diabetes care partner) committed to participating in study training for 
442 
emergency procedures for severe hypoglycemia and able to contact the subject in case of an 
443 
emergency. 
444 
 
445 
 Exclusion 
446 
The presence of any of the following is an exclusion for the study: 
447 

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20 
 
 
 
 
1) Medical need for chronic acetaminophen 
448 
2) Use of any glucose-lowering agent (such as Pramlintide, Metformin, GLP-1 analogs, SGLT2 
449 
inhibitors) in the 3 months prior to enrollment 
450 
3) Hemophilia or any other bleeding disorder 
451 
4) A condition, which in the opinion of the investigator or designee, would put the participant or 
452 
study at risk including any contraindication to the use of any of the study devices per FDA 
453 
labelling  
454 
• Individuals should not be enrolled with uncontrolled thyroid disease, renal failure 
455 
(e.g., dialysis or eGFR <30), or unstable cardiovascular disease.  Laboratory testing 
456 
and other work up needed to determine that an individual is a suitable candidate for 
457 
the study should be performed as part of usual care. 
458 
5) Participation in another pharmaceutical or device trial at the time of enrollment or during the 
459 
study 
460 
6) Use of a closed-loop system within the last month prior to enrollment 
461 
7) Employed by, or having immediate family members employed by TypeZero Technologies, 
462 
LLC; or having a direct supervisor at place of employment who is also directly involved in 
463 
conducting the clinical trial (as a study investigator, coordinator, etc.); or having a first-
464 
degree relative who is directly involved in conducting the clinical trial 
465 
 
466 
 Authorization Procedures 
467 
Written informed consent must be obtained prior to performing any study specific procedures 
468 
with the subject that are not part of the subject’s routine care. 
469 
 
470 
For eligible subjects 18 years of age or older, the study will be discussed with the subject and the 
471 
subject will be provided with an Informed Consent Form to read and will be given the 
472 
opportunity to ask questions.  If the subject agrees to participate, the Informed Consent Form 
473 
will be signed. A copy of the consent form will be provided to the subject and another copy will 
474 
be added to the subject’s clinic chart. 
475 
 
476 
For eligible subjects under 18 years of age, the care partner will be provided with an Informed 
477 
Consent Form to read and will be given the opportunity to ask questions. Each subject will be 
478 
given a Child Assent Form to read and discuss with parents and study personnel. If the care 
479 
partner and child agree to participate, the Informed Consent Form and Child Assent Form will be 
480 
signed. A copy of the consent forms will be provided to the subject and his/her care partner and 
481 
another copy will be added to the subject’s clinic chart. 
482 
 
483 
 Screening and Enrollment Visit Logistics 
484 
Potential subjects will be evaluated for study eligibility through the elicitation of a medical 
485 
history, performance of a physical examination by study personnel and local laboratory testing if 
486 
needed to screen for exclusionary medical conditions.  Subject exclusion will be at the discretion 
487 
of the investigator based on study inclusion/exclusion criteria.    
488 
 
489 
Subjects who do not initially meet study eligibility requirements may be rescreened once at a 
490 
later date per investigator discretion. 
491 
 
492 

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21 
 
 
 
 
 Data Collection and Testing 
493 
A standard physical exam (including vital signs and height and weight measurements) will be 
494 
performed by the study investigator or designee (a physician, fellow, nurse practitioner or a 
495 
physician assistant).   
496 
 
497 
The following procedures will be performed/data collected/eligibility criteria checked and 
498 
documented:  
499 
• Subject, and where indicated parent/guardian fully informed about the study and informed 
500 
consent form/assent form signed according to IRB requirements  
501 
• Inclusion and exclusion criteria assessed 
502 
• Demographics (date of birth, gender, race and ethnicity, and socioeconomic indicators) 
503 
• Contact information 
504 
• Diabetic history  
505 
• Medical history  
506 
• Substance use history (drinking, smoking, and drug habits) 
507 
• Concomitant medications 
508 
• Physical examination to include: 
509 
o Weight, height 
510 
• Weight measurement will be repeated during the final study visit, in addition 
511 
to height for subjects <21 years old  
512 
o Vital signs including measurement of blood pressure and pulse 
513 
• HbA1c level measured using the DCA Vantage or similar point of care device or local lab 
514 
(used to assess eligibility)  
515 
o Measurement performed as part of usual clinical care up to two weeks prior to 
516 
obtaining informed consent for participation in the trial may be used 
517 
• Urine or serum pregnancy test for all females of child-bearing potential 
518 
 
519 
Blood draws for any other laboratory testing needed to determine that an individual is a suitable 
520 
candidate for the study should be performed as part of usual care. 
521 
 
522 
Subjects who are female and menstruating will be asked to keep a log to track menstrual cycles 
523 
and will be given a paper log to record this information.   
524 
 
525 
Screening procedures will last approximately 1-2 hours.
526 
527 

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22 
 
 
 
 
 CGM RUN-IN PHASE 
528 
 
529 
 CGM Run-in Phase Overview 
530 
Concurrent with the screening and enrollment visit, the subject will be assessed for the need for 
531 
CGM run-in activities prior to randomization.    
532 
 
533 
Subjects who used a personal CGM that is the same brand as the study CGM prior to the study 
534 
for at least 21 of the prior 28 days will proceed directly to randomization. These subjects will 
535 
have the personal CGM downloaded for capture of two-week baseline data.   
536 
 
537 
All other subjects will participate in the following CGM run-in phases requiring additional clinic 
538 
visits as shown in Figure 7: 
539 
• Two-week period of blinded study CGM use to characterize baseline glycemic control; 
540 
subjects using a personal CGM prior to the study will continue to use it during this 
541 
period. 
542 
• Two-week period of unblinded study CGM use, with training in using CGM if necessary; 
543 
subjects using a personal CGM prior to the study will discontinue the personal CGM 
544 
beginning in this period. 
545 
 
546 
Subjects participating in the CGM run-in phase will receive appropriate training on incorporating 
547 
CGM into their diabetes management.  Training will include the hypoglycemia and 
548 
hyperglycemia safety protocols in section 6.1 as well as instruction that study CGM readings are 
549 
affected by acetaminophen use and may be inaccurate for at least 4 hours if a medication 
550 
containing acetaminophen is taken. 
551 
 
552 
Subjects will receive supplies for blood glucose and ketone testing during this period: 
553 
• Blood glucose testing 
554 
o Subjects will be provided with a study blood glucose meter, test strips, and 
555 
standard control solution to perform quality control (QC) testing at home per 
556 
manufacturer guidelines.   
557 
o All study blood glucose meters will be QC tested with at least two different 
558 
concentrations of control solution if available during all office visits.  A tested 
559 
meter will not be used in a study if it does not read within the target range at each 
560 
concentration per manufacturer labeling.  The subject will be instructed to contact 
561 
study staff for a replacement of the meter, test strips, and control solution if a 
562 
meter fails QC testing at home. 
563 
o Subjects will be reminded to use the study blood glucose meter for all fingerstick 
564 
blood glucose measurements during the run-in period.   
565 
o Subjects will be given guidelines for treatment of low or high blood glucose. 
566 
• Blood ketone testing 
567 
o Subjects will be provided with a study blood ketone meter, test strips, and 
568 
standard control solution to perform QC testing at home per manufacturer 
569 
guidelines. 
570 
o All study blood ketone meters will be QC tested with at least two different 
571 
concentrations of control solution if available during all office visits.  A tested 
572 
meter will not be used in a study if it does not read within the target range at each 
573 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
23 
 
 
 
 
concentration per manufacturer labeling.  The subject will be instructed to contact 
574 
study staff for a replacement of the meter, test strips, and control solution if a 
575 
meter fails QC testing at home.   
576 
o Subjects will be instructed to perform blood ketone testing as described in Section 
577 
6.1.2.2. 
578 
o Subjects will be given guidelines for treatment of elevated blood ketones 
579 
• Subjects will be required to have a home glucagon emergency kit. Subjects who currently 
580 
do not have one will be given a prescription for the glucagon emergency kit.  
581 
 
582 
 Optimization of Insulin Pump Settings 
583 
Data-driven optimization of pump settings will occur at the following times: 
584 
• Prior to Randomization: 
585 
o At the Enrollment Visit for study subjects that do not need to complete a CGM run-
586 
in 
587 
o At the Blinded CGM Run-in Review and Unblinded CGM Run-in Review Visits 
588 
for study subjects participating in the CGM Run-in 
589 
• Following Randomization: 
590 
o At the Week 2 visit for all study subjects (both the CTR and SAP Group). 
591 
o If the study subject contacts the study physician due to concerns about their pump 
592 
settings due to recurring hypo- or hyperglycemia.  
593 
 
594 
Adjustments to pump settings (basal rates, correction factor, insulin-to-carbohydrate ratio, etc.) 
595 
will be made in response to major trends observed in the CGM data, with flexibility for clinicians 
596 
to adhere to guidelines and practices established at each individual practice rather than a fixed set 
597 
of heuristics for all sites. 
598 
 
599 
 Blinded CGM Use 
600 
At the screening visit, a CGM sensor will be placed for subjects who will complete the blinded 
601 
CGM phase.  The CGM receiver will be blinded so that the subject is not able to see the CGM 
602 
glucose values.  The subject will be instructed on sensor use including insertion of a new sensor 
603 
after 7 days (or sooner if the sensor comes out) and will be asked to wear the sensor for 14 days. 
604 
Additional sensors will be provided.  Subjects that currently use a CGM may continue to use the 
605 
personal CGM in addition to the blinded study CGM. 
606 
 
607 
Subjects will be informed that in order to be eligible for the randomized trial, the blinded CGM 
608 
must be used on a minimum of 11 out of 14 days.   
609 
 
610 
 Blinded CGM Assessment/Unblinded CGM Initiation Visit 
611 
Enrolled subjects will return 14 to 21 days after screening to assess the blinded CGM wear.  The 
612 
purpose of the visit will include the following: 
613 
• Assessment of compliance with the use of the CGM 
614 
• Assessment of skin reaction in areas where a CGM sensor was worn  
615 
• Initiation of unblinded CGM use and instructions on its use 
616 
 
617 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
24 
 
 
 
 
 Assessment of Blinded CGM 
618 
The CGM data will be downloaded and reviewed to assess whether the subject has used the 
619 
CGM on at least 11 out of 14 days.  If the subject is eligible to continue in the study, study staff 
620 
will follow the procedure for insulin pump optimization described above in section 3.2. 
621 
 
622 
Subjects who are unable to meet the CGM compliance requirement will be withdrawn from the 
623 
study, unless the investigator believes that there were extenuating circumstances that prevented 
624 
successful completion. In such cases, the investigator will contact the protocol chair to request 
625 
approval to repeat this part of the run-in phase. 
626 
 
627 
 Unblinded CGM Use 
628 
 Initiation of Unblinded CGM 
629 
The subject will be provided with sensors and instructed to use the CGM on a daily basis for 2 
630 
weeks. Training will be provided to subjects not experienced with CGM use as to how to use the 
631 
CGM in real-time to make management decisions and how to review the data after an upload for 
632 
retrospective review. Subjects using a personal CGM prior to the study will discontinue the 
633 
personal CGM beginning in this period. 
634 
 
635 
The subject will be observed placing the sensor. The study CGM user’s guide will be provided for 
636 
the subject to take home.                                             
637 
 
638 
 Assessment of Successful Completion of the Unblinded CGM Run-in Phase 
639 
Enrolled subjects will return 14 to 21 days after the initiation of the unblinded CGM visit to 
640 
assess the unblinded CGM wear.  The purpose of the visit will include the following: 
641 
• Assessment of compliance with the use of the CGM 
642 
• Assessment of skin reaction in areas where a CGM sensor was worn  
643 
• Assessment of eligibility to continue to the RCT phase of the study 
644 
 
645 
The CGM data will be downloaded and reviewed.  To enter the randomized trial, subjects must 
646 
have obtained CGM readings on at least 11 out of 14 days.  If the subject is eligible to continue 
647 
in the study, study staff will follow the procedure for insulin pump optimization described above 
648 
in section 3.2 
649 
 
650 
The exclusion criteria from screening will be reviewed again and if the subject is no longer 
651 
eligible based on these criteria, he or she will be dropped from the study.   
652 
 
653 
An assessment of CGM knowledge will be made and the subject must demonstrate sufficient 
654 
competency to proceed to the RCT. 
655 
 
656 
Subjects who are unable to meet the CGM compliance requirements will be withdrawn from the 
657 
study, unless the investigator believes that there were extenuating circumstances that prevented 
658 
successful completion.  In such cases, the investigator will contact the protocol chair to request 
659 
approval to repeat this part of the run-in phase. 
660 
 
 
661 

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25 
 
 
 
 
 Randomized Trial 
662 
 Randomization Visit 
663 
 
664 
 Timing of Visit 
665 
The randomization visit may occur concurrently with the Enrollment Visit for subjects who meet CGM 
666 
use requirements described above.  Otherwise, the visit will be concurrent with the Unblinded CGM 
667 
Run-in Review Visit.   
668 
 
669 
Subjects will receive supplies for blood glucose and ketone testing and associated use guidelines and a 
670 
prescription for a glucagon emergency kit if needed, as described above.  Subjects will be advised to 
671 
contact the manufacturer’s technical support center for technical issues with the study CGM and to call 
672 
the study physician for any health related issues.  
673 
 
674 
A urine pregnancy test will be repeated for all females of child-bearing potential who participated in 
675 
the CGM run-in phase.   
676 
 
677 
  HbA1c 
678 
HbA1c will be measured using DCA Vantage or similar POC device or local lab.  A blood sample will 
679 
also be drawn to send to the central laboratory for baseline HbA1c determination to be used in outcome 
680 
analyses. 
681 
 
682 
 Baseline C-Peptide Assessment 
683 
A blood sample will be drawn to send to the central laboratory for a random, non-fasting C-peptide 
684 
determination to characterize baseline residual insulin production.  
685 
 
686 
  Randomization 
687 
Eligible subjects will be randomly assigned to one of two treatment groups in a 1:1 ratio: 
688 
1. Control-to-Range (CTR) Closed-Loop Group 
689 
2. SAP Group 
690 
 
691 
The subject’s randomization group assignment is determined by completing a Randomization Visit case 
692 
report form on the study website. The randomization list will use a permuted block design, stratified by 
693 
clinical center. 
694 
 
695 
The subject will be included in the data analysis regardless of whether or not the protocol for the 
696 
assigned randomization group is followed.  Thus, the investigator must not randomize a subject until 
697 
he/she is convinced that the subject/parent will accept assignment to either of the two groups. 
698 
 
699 
  Questionnaires 
700 
Subjects will complete a set of baseline questionnaires, described in section 5.1, prior to 
701 
randomization.  Subjects randomized into the CTR group will also complete an additional Technology 
702 
Expectation Survey after randomization.  
703 
 
704 
 Procedures for the CTR Group 
705 
 
706 
 Study Pump Training and inControl Training 
707 
Subjects randomized to the CTR group will receive study pump training and inControl training. These 
708 
training sessions can occur on the same day or extend to up to one additional day if needed within 1-7 
709 

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26 
 
 
 
 
days from randomization; subjects will not take the inControl system component home until training 
710 
has been completed.   
711 
 
712 
For subjects <18 years old, the diabetes care partner will be trained on severe hypoglycemia 
713 
emergency procedures including removal of the study pump and administration of glucagon. The 
714 
diabetes care partner may also attend any/all of the other training procedures as desired.  
715 
  
716 
Pump training will include: 
717 
• The subject [and care partner] will be fully instructed on the study insulin pump. A qualified 
718 
staff member will conduct the training and in particular discuss differences from their home 
719 
pump in important aspects such as calculation of insulin on board and correction boluses. 
720 
Additional topics not limited to but may include: infusion site initiation, cartridge/priming 
721 
procedures, setting up the pump, changing batteries, navigation through menus, bolus 
722 
procedures including stopping a bolus, etc. 
723 
• The study team will assist the subject in study pump infusion site initiation and will start the 
724 
subject on the study pump. The study pump will be programmed with the subject’s usual 
725 
basal rates and pump parameters. The subject’s personal pump will be removed. 
726 
• The subject will be supervised with the study pump during at least one meal or snack bolus to 
727 
ensure subject understanding of the pump features. 
728 
• The subject [and care partner] will be encouraged to review the literature provided with the 
729 
pump, infusion sets, and meter remote after the training is completed. 
730 
• Subjects will be asked to perform fingerstick blood glucose measurements in accordance 
731 
with the labelling of the study CGM device.  
732 
 
733 
The subject [and care partner] will be trained by qualified study staff to use inControl to control the 
734 
study pump, including meal announcement, meal bolusing, exercise, and switching back and forth 
735 
between all operational modes (i.e. normal, sleep, and exercise)  and insulin modes (closed-loop and 
736 
pump). 
737 
 
738 
Training will include a series of practice challenges using the different modes of the study system.  
739 
Prior to initial use, the inControl system will be initialized by a study team member with each subject’s 
740 
individual parameters, including carbohydrate ratio, correction factor, and basal rate pattern.   
741 
 
742 
Subjects will be provided Hypoglycemia, Hyperglycemia and Ketone Guidelines (section 6.1.2.2) for 
743 
when their glucose levels are >300 mg/dL for more than one hour or >400 mg/dL at any time or <80 
744 
mg/dL or ketones ≥0.6 mmol/L.  
745 
 
746 
Study team members will train the subject [and care partner] in performing specific tasks including the 
747 
following: 
748 
• The study team will confirm the pump parameters entered in the system with the study 
749 
physician. 
750 
• How to switch between Closed-Loop mode and Pump mode depending on circumstances, 
751 
including the need to stop closed-loop for at least 4 hours if a medication containing 
752 
acetaminophen is taken. 
753 
• How to calibrate the CGM unit during the study 
754 
• How to access the CGM trace from the sensor via the inControl user interface 
755 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
27 
 
 
 
 
• How to activate the “meal” screen of the inControl system any time insulin will be given with a 
756 
meal and the “add correction” screen any time additional correction insulin is desired 
757 
• How to inform the system of hypoglycemia treatment via a “hypoglycemia treatment” button 
758 
on the inControl user interface after glucose is consumed that is not accompanied by an insulin 
759 
bolus 
760 
• What to do when exercising while using the system 
761 
• How to enable the sleep function when sleep schedule will differ from normal parameters 
762 
• How to perform blood ketone testing and perform rescue therapy actions with the glucagon kit 
763 
• The subject [and care partner] will be assessed for understanding of the system interface and 
764 
how to react to safety/alert notification. 
765 
• Subjects will be reminded to perform fingerstick blood glucose measurements in accordance 
766 
with the labelling of the study CGM device.   
767 
• The subject [and care partner] will be given a printed User Guide as a reference. 
768 
 
769 
The subject will be instructed to use the system in closed-loop mode except when no calibrated CGM 
770 
sensor is available.   
771 
 
772 
The subject will also be instructed to contact study staff during periods of illness with an elevated 
773 
temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant illness, or during 
774 
periods of use of medications such as epinephrine (e.g. for the emergency treatment of a severe allergic 
775 
reaction or asthma attack) or oral or injectable glucocorticoids to determine if closed-loop use should 
776 
be temporarily discontinued.  
777 
 
778 
Subjects will be given the inControl device and will be provided with sufficient supplies to last until 
779 
the subsequent clinic visit. 
780 
 
781 
Subjects will be provided with technical support or manufacturer contact information for technical 
782 
issues with inControl, study insulin pump or study CGM and will be asked to call the study physician 
783 
for any health related issues. Subjects may use the study pump and study CGM during periods of 
784 
inControl disconnections or technical difficulties.  Subjects will also receive study staff contact 
785 
information to ask any questions they may have during the study.  
786 
 
787 
 Blinded CGM Insertion 
788 
Subjects in the CTR group who are not using a CGM receiver whose data can be downloaded will have 
789 
an additional CGM sensor and transmitter placed and will be given a blinded CGM receiver to collect 
790 
data from this sensor during the first two weeks following randomization.  This will allow the clinician 
791 
to retrospectively assess CGM data from this period at the 2-Week visit using the exact same tool that 
792 
will be used for subjects in the SAP group. 
793 
 
794 
  Home Use of inControl System 
795 
After training on the study pump and inControl system has been completed, subjects will proceed with 
796 
home use (meaning free-living use at work, home, etc.) of the inControl system.  
797 
 
798 
Subjects will be instructed not to use any non-study software applications that are designed to receive 
799 
real-time CGM values from the study CGM transmitter. 
800 
 
801 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
28 
 
 
 
 
  Study Device Data Transmission 
802 
Subjects will be instructed to establish network connectivity for the inControl system on at least a 
803 
weekly basis throughout the remainder of the study either via local Wi-Fi network or via a study-
804 
provided cellular service to allow data synchronization with study servers. 
805 
 
806 
   1-Week Phone Contact 
807 
Study staff will perform a phone call with the subject within 7 (+3) days following randomization.   
808 
 
809 
The following will occur:  
810 
• Assessment of compliance with study device use by review of any available device data 
811 
• Assessment of adverse events, adverse device effects, and device issues 
812 
• Study staff will answer any questions related to device use 
813 
 
814 
Subjects will then complete an additional week of home use with the inControl system.  Subjects will 
815 
return to clinic 14 (+3) days from the date of randomization. 
816 
 
817 
   2-Week Visit (Training Review and Insulin Pump Optimization) 
818 
The subject will be offered review training to address any questions on the use of inControl and the 
819 
study pump, including meal announcement, meal bolusing, exercise, and switching back and forth 
820 
between all operational modes.  
821 
 
822 
The following will occur:  
823 
• Assessment of compliance with study device use by review of any available device data 
824 
• Assessment of adverse events, adverse device effects, and device issues 
825 
• Study staff will answer any questions related to device use and follow the procedure for insulin 
826 
pump optimization described above in section 3.2 using the available downloaded CGM data 
827 
from the previous two weeks. 
828 
• The study blood glucose meter and study ketone meter will be downloaded and QC tested with 
829 
at least two different concentrations of control solution if available. 
830 
 
831 
 Procedures for the SAP Group 
832 
Subjects in the SAP Group will continue to use their personal insulin pumps in conjunction with the 
833 
study CGM, blood glucose meter, and ketone meter.  Subjects may use commercially available 
834 
features of the study CGM system related to mobile data access or remote monitoring, but will be 
835 
instructed not to use any third-party components for this purpose. 
836 
 
837 
  Study Device Data Transmission 
838 
Subjects will be instructed to upload data from the CGM receiver prior to the 1-week phone contact 
839 
and prior to the 2-week clinic visit for clinician review.  Subjects will be provided with any software 
840 
and hardware needed to perform these data uploads. 
841 
 
842 
   1-Week Phone Contact  
843 
Study staff will perform a phone call with the subject within 7 (+3) days following randomization.  
844 
 
845 
The following will occur:  
846 
• Assessment of compliance with study device use by review of any available device data 
847 
• Assessment of adverse events, adverse device effects, and device issues 
848 
• Study staff will answer any questions related to device use 
849 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
29 
 
 
 
 
 
850 
The subject will continue on SAP for a second week, then return to the clinic 14 (+3) days from the 
851 
date of randomization. 
852 
 
853 
   2-Week Visit (Training Review and Insulin Pump Optimization) 
854 
The subject will be offered review training on the use of SAP during the remainder of the study, 
855 
including meal bolus strategies and strategies related to pump use and exercise.   
856 
 
857 
The following will occur:  
858 
• Assessment of compliance with study device use by review of any available device data 
859 
• Assessment of adverse events, adverse device effects, and device issues 
860 
• Study staff will review uploaded CGM data, answer any questions related to device use, and 
861 
follow the procedure for insulin pump optimization described above in section 3.2. 
862 
• The study blood glucose meter and study ketone meter will be downloaded and QC tested with 
863 
at least two different concentrations of control solution if available. 
864 
 
865 
The subject will be instructed to upload data from the CGM receiver at least once every two weeks for 
866 
the remainder of the study.  
867 
 
868 
 Follow-up Visits and Phone Contacts for Both Groups 
869 
The schedule for remaining follow-up visits and phone contacts is the same for both treatment groups.  
870 
Study staff will discuss with the subject that periodic contact is required and will make arrangements 
871 
with the subject for the contacts.  If the subject (or care partner, for subjects less than 18 years old) 
872 
cannot be reached, the subject’s other contact methods will be utilized, including the emergency 
873 
contact.  
874 
 
875 
 Follow-up Visits  
876 
Follow-up visits will occur at:  
877 
• 5 weeks (+1 week) 
878 
• 9 weeks (+1 week) 
879 
• 13 weeks (+1 week) 
880 
 
881 
4.4.1.1. Procedures at Follow-up Visits 
882 
Procedures performed in both groups at each visit, unless otherwise specified below: 
883 
• Assessment of compliance with study device use by review of any available device data 
884 
• Assessment of adverse events, adverse device effects, and device issues 
885 
• Download of device data (study CGM, study BG meter, study ketone meter, inControl cloud 
886 
data, pump if supported) 
887 
 
888 
Procedures Specific to the 9-Week Visit 
889 
A blinded CGM device will be inserted in subjects in both the CTR and SAP groups, to be worn for 
890 
the subsequent two weeks for the purpose of: 
891 
• Obtaining CGM data for outcome assessment of subjects who have become non-adherent to 
892 
use of the study CGM 
893 
• Obtaining CGM data from a sensor independent from closed-loop system operation to support 
894 
assessment of bias in CGM-measured outcomes 
895 
 
896 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
30 
 
 
 
 
Blinded CGM devices will be physically returned to the clinic or mailed to the clinic for assessment.  
897 
If it is found that fewer than 14 days of data were captured, the subject may be asked to capture 
898 
additional blinded data prior to the 13-week visit.    
899 
 
900 
Procedures Specific to the 13-Week Visit 
901 
• HbA1c determination using the DCA Vantage or similar point of care device 
902 
• Collection of a blood sample to send to the central laboratory for HbA1c determination 
903 
• Completion of end-of-study questionnaires 
904 
• Weight measurement will be repeated, in addition to height for subjects <21 years old  
905 
 
906 
 Phone Contacts 
907 
In addition to the 1-week phone contact described above for the respective treatment groups, the 
908 
following phone call will be made: 
909 
 
910 
3-Week Phone Contact 
911 
A phone call will be made to the subject or care partner at 3 weeks (+3 days) and the following 
912 
procedures performed in both treatment groups: 
913 
• Review of available CGM and/or inControl data to identify any safety issues associated with 
914 
insulin pump settings and current diabetes management approach 
915 
• Assessment of adverse events, adverse device effects, and device issues 
 
916 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
31 
 
 
 
 
 QUESTIONNAIRES 
917 
 
918 
 Introduction 
919 
The following questionnaires will be completed at the randomization visit: 
920 
• Diabetes Specific Personality Questionnaire 
921 
• Clarke’s Hypoglycemia Awareness Scale 
922 
• Fear of Hypoglycemia Survey (HFS-II) 
923 
• Hyperglycemia Avoidance Scale 
924 
• Hypoglycemia Confidence Scale 
925 
• Diabetes Distress Scale 
926 
• INSPIRE Survey 
927 
• Technology Expectations Survey (CTR group only) 
928 
 
929 
The following questionnaires will be completed at the final visit at week 13: 
930 
• Clarke’s Hypoglycemia Awareness Scale  
931 
• Fear of Hypoglycemia Survey (HFS-II) 
932 
• Hyperglycemia Avoidance Scale 
933 
• Hypoglycemia Confidence Scale 
934 
• Diabetes Distress Scale 
935 
• INSPIRE Survey 
936 
• Technology Acceptance Survey (CTR group only) 
937 
 
938 
Each questionnaire is described briefly below.  The procedures for administration are described in the 
939 
study procedures manual. 
940 
 
941 
 Diabetes Specific Personality Questionnaire 
942 
The Diabetes Specific Personality Questionnaire (15) is based on the original Six Factor Personality 
943 
Questionnaire (16), a well-validated measure that was adapted for the diabetes-specific version of the 
944 
questionnaire. The SFPQ is a measure of six personality dimensions each consisting of three facet 
945 
scales, measured by 108 Likert items. The SFPQ facet scales are organized in terms of six factor 
946 
scales.  
947 
 
948 
Administration time is approximately 15 minutes.  
949 
 
950 
 Clarke’s Hypoglycemia Awareness Scale 
951 
The scale (17) comprises eight questions characterizing the subject's exposure to episodes of moderate 
952 
and severe hypoglycemia. It also examines the glycemic threshold for, and symptomatic responses to, 
953 
hypoglycemia. A score of four or more on a scale of 0 to 7 implies impaired awareness of hypoglycemia.    
954 
 
955 
Administration time is approximately 5 minutes.   
956 
 
957 
 Hypoglycemia Fear Survey (HFS-II) / Low Blood Sugar Survey 
958 
The Hypoglycemia Fear Survey-II (18) was developed to measure behaviors and worries related to fear 
959 
of hypoglycemia in adults with type 1 diabetes. It is composed of 2 subscales, the Behavior (HFS-B) 
960 
and Worry (HFS-W). HFS-B items describe behaviors in which patients may engage to avoid 
961 
hypoglycemic episodes and/or their negative consequences (e.g., keeping blood glucose levels above 
962 
150 mg/dL, making sure other people are around, and limiting exercise or physical activity). HFS-W 
963 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
32 
 
 
 
 
items describe specific concerns that patients may have about their hypoglycemic episodes (e.g., being 
964 
alone, episodes occurring during sleep, or having an accident).  
965 
 
966 
Administration time is approximately 10 minutes. 
967 
  
968 
 Hyperglycemia Avoidance Survey (HAS) / High Blood Sugar Survey 
969 
The HAS (19) reliably quantifies affective and behavioral aspects of hyperglycemia avoidance and is 
970 
used to assess the extent of potentially problematic avoidant attitudes and behaviors regarding 
971 
hyperglycemia in people with Type 1 diabetes (T1D).  
972 
 
973 
Administration time is approximately 10 minutes. 
974 
 
975 
 Hypoglycemia Confidence Scale 
976 
The HCS (20) is a 9-item self-report scale that examines the degree to which people with diabetes feel 
977 
able, secure, and comfortable regarding their ability to stay safe from hypoglycemic-related problems. 
978 
It has been validated for use in adults with type 1 diabetes and insulin-using type 2 diabetes. 
979 
 
980 
Administration time is approximately 5 minutes. 
981 
 
982 
 Diabetes Distress Scale 
983 
The Diabetes Distress Scale (21) is a measure of diabetes-related emotional distress and consists of a 
984 
scale of 28 items. These include 7 items from each of four domains central to diabetes-related 
985 
emotional distress.  Patients rate the degree to which each item is currently problematic for them on a 
986 
6-point Likert scale, from 1 (no problem) to 6 (serious problem). 
987 
 
988 
Administration time is approximately 10 minutes. 
989 
 
990 
 Technology Expectation and Technology Acceptance Surveys 
991 
The Technology Expectation and Technology Acceptance Surveys were developed for a Bionic 
992 
Pancreas camp study (22). The 38 items in the Questionnaire were based on interviews conducted with 
993 
individuals who had participated in previous Bionic Pancreas trials about their experience regarding 
994 
the Bionic Pancreas. It was subsequently adapted to assess these same measures for the inControl 
995 
closed-loop system. It assesses both positive and negative experiences with inControl, including blood 
996 
glucose management, device burden, and overall satisfaction. Items were rated on a 5-point scale. 
997 
 
998 
Administration time is approximately 10 minutes. 
999 
 
1000 
 INSPIRE Survey 
1001 
The INSPIRE (Insulin Delivery Systems: Perceptions, Ideas, Reflections and Expectations) survey was 
1002 
developed to assess various aspects of a user’s experience regarding automated insulin delivery for 
1003 
both patients and family members. The surveys include various topics important to patients with type 1 
1004 
diabetes and their family members based upon >200 hours of qualitative interviews and focus groups. 
1005 
The adult survey includes 31 items; the adolescent survey includes 28 items; and the parent survey 
1006 
includes 30 items. Response options for all surveys include a 5-point Likert scale from strongly agree 
1007 
to strongly disagree, along with an N/A option.  
1008 
 
1009 
Administration time is approximately 5 minutes. 
 
1010 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
33 
 
 
 
 
 SAFETY MEASURES 
1011 
 
1012 
 Safety Measures 
1013 
 
1014 
 CGM Calibration 
1015 
Throughout the study, subjects will be instructed to calibrate the study CGM in accordance with 
1016 
manufacturer labelling. 
1017 
 
1018 
 Safety Measures for Open-Loop CGM Use 
1019 
These measures apply to subjects in the SAP group throughout the course of the study and also to 
1020 
subjects in the CTR group during periods when the closed-loop system is not being used or is not 
1021 
communicating with the CGM device. 
1022 
 
1023 
6.1.2.1. Hypoglycemia Threshold Alarm and Safety Protocol 
1024 
All subjects will initially be required to set the CGM hypoglycemia threshold alarm to a value no less 
1025 
than 60 mg/dL.  During the course of the study, subjects will be permitted to change this setting, but 
1026 
will be instructed to choose a value no less than 60 mg/dL. 
1027 
 
1028 
If a subject receives a CGM hypoglycemia threshold alarm or notes that the CGM glucose is below the 
1029 
hypoglycemia threshold alarm value, confirmatory fingerstick testing will be performed if required by 
1030 
CGM labelling and the subject will be instructed to treat hypoglycemia with ~16 grams of fast-acting 
1031 
oral glucose.  
1032 
 
1033 
6.1.2.2. Hyperglycemia Threshold Alarm and Safety Protocol 
1034 
All subjects will initially be required to set the CGM hyperglycemia threshold alarm to a value no 
1035 
greater than 300 mg/dL.  During the course of the study, subjects will be permitted to change this 
1036 
setting, but will be instructed to choose a value no greater than 300 mg/dL. 
1037 
 
1038 
If a subject receives a CGM hyperglycemia threshold alarm or notes that the CGM glucose is above 
1039 
the hyperglycemia threshold alarm value, confirmatory fingerstick testing will be performed if required 
1040 
by CGM labelling.   
1041 
 
1042 
If a subject’s CGM reading is ≥300 mg/dL for over 1 hour, or ≥400 mg/dL at any point, the subject 
1043 
user manual instructs the subject to take the following steps: 
1044 
• Perform a blood ketone measurement with the study ketone meter. Subjects will also be 
1045 
encouraged to check ketones if they are clinically concerned. 
1046 
• Correction insulin may be taken per the subject’s usual routine.  
1047 
• Subjects will be instructed to change their pump site and administer correction insulin via 
1048 
insulin syringe or pen for ketones ≥0.6 mmol/L and to additionally notify study staff for 
1049 
ketones ≥3.0 mmol/L. 
1050 
 
1051 
 Safety Measures Specific to Control-to-Range (CTR) Closed-Loop Group 
1052 
 
1053 
6.1.3.1. Insulin Dosing 
1054 
In Closed-Loop mode, all dosing is supervised by a dedicated basal attenuation module.  Insulin 
1055 
injection for meal boluses must be manually confirmed, and insulin on board (IOB) constraints avoid 
1056 
inappropriate insulin stacking.  In the case of a system crash or any interruption of communication 
1057 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
34 
 
 
 
 
between inControl and the insulin pump, the pump will revert to the preprogrammed basal delivery 
1058 
within a short period of time (maximum 30 minutes).  Each bolus is checked by the algorithm to 
1059 
ensure that it does not exceed a maximum threshold depending on whether the bolus is for a meal, for a 
1060 
correction, or for usual basal delivery. 
1061 
 
1062 
6.1.3.2. Hypoglycemia Safety Protocol 
1063 
The inControl system will issue a hypoglycemia alarm if the CGM is <70 mg/dL or when the system 
1064 
predicts BG <70 mg/dL within the next 15 to 30 minutes.  The system also includes an additional 
1065 
threshold alarm that may be configured by study staff per subject preference. 
1066 
 
1067 
If the subject receives a hypoglycemia alarm from inControl, a message appears on the UI that is 
1068 
accompanied by vibration and sound.  This alert recurs if not acknowledged by the user. The user 
1069 
is prompted with a checklist to do the following: 
 
1070 
• Check blood glucose 
1071 
• Treat with fast acting carbohydrates 
1072 
 
1073 
6.1.3.3. Hyperglycemia Safety Protocol 
1074 
The inControl system will issue a predictive hyperglycemia alarm if the system detects prolonged 
1075 
resistance to insulin treatment and the BG is estimated to be above 200 mg/dL. 
1076 
 
1077 
If the subject receives a hyperglycemia alarm from inControl, a message appears on the UI that is 
1078 
accompanied by vibration and sound. This alert recurs if not acknowledged by the user. The user 
1079 
is prompted with a checklist to do the following: 
1080 
• Confirm hyperglycemia with a fingerstick 
1081 
• Consider possible reasons including missed boluses for carbs, infusion site problems, 
1082 
pump occlusions, insulin degradation, sickness, and menstruation 
1083 
 
1084 
If a subject’s CGM reading is ≥300 mg/dL for over 1 hour, or ≥400 mg/dL at any point, the subject 
1085 
user manual instructs the subject to take the following steps: 
1086 
• Perform a blood ketone measurement with the study ketone meter. Subjects will also be 
1087 
encouraged to check ketones if they are clinically concerned. 
1088 
• Correction insulin may be taken per the subject’s usual routine.  
1089 
• Subjects will be instructed to change their pump site and administer correction insulin via 
1090 
insulin syringe or pen for ketones ≥0.6 mmol/L and to additionally notify study staff for 
1091 
ketones ≥3.0 mmol/L. 
1092 
 
1093 
6.1.3.4. Remote Monitoring 
1094 
The inControl remote monitoring portal (inControl Cloud) automatically logs system data such as 
1095 
CGM values, insulin delivery details, and system alarms and allows data from any inControl device to 
1096 
be monitored remotely in real-time, provided the device has Wi-Fi or cellular data connectivity. 
1097 
 
1098 
Clinical site personnel may perform ad hoc real-time monitoring during the study in response to 
1099 
subject questions or to troubleshoot system problems.  However, the system will not be configured to 
1100 
send automated notification messages regarding subject glycemic control or potential system 
1101 
malfunctions to these personnel. 
1102 
 
1103 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
35 
 
 
 
 
Technical personnel may also perform ad hoc real-time monitoring during the study to support clinical 
1104 
personnel with subject questions and troubleshooting.  In addition, the system will log information 
1105 
regarding potential system malfunctions to a central location for periodic technical monitoring. 
1106 
 
1107 
6.1.3.5. CGM Sensor Connection Failure 
1108 
If the CGM signal becomes unavailable for >20 minutes, Closed-Loop mode will not operate. If the 
1109 
pump is connected, the system will revert to Pump mode and deliver insulin with the most recent 
1110 
insulin dosing parameters programmed in the system for that individual. Resumption of Closed-Loop 
1111 
will occur automatically by the system once CGM signal is available again. 
1112 
 
1113 
6.1.3.6. Pump Connection Failure 
1114 
If inControl is unable to establish required pump connectivity for >20 minutes, the system will revert 
1115 
to Stopped mode and display a message accompanied by vibration or sound.   The insulin pump will 
1116 
automatically revert to preprogrammed basal insulin delivery without any need for instruction from the 
1117 
controller once the 0% temporary basal rate last directed by inControl times out. Alternatively, the 
1118 
subject can cancel the temp basal on the insulin pump and immediately resume basal insulin 
1119 
administration.  
1120 
 
1121 
6.1.3.7. Study System Failure 
1122 
If the study system stops working for more than 30 minutes, the pump will automatically revert to 
1123 
preprogrammed basal insulin delivery without any need for instruction from the controller.  
1124 
 
1125 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
36 
 
 
 
 
 ADVERSE EVENTS, DEVICE MALFUNCTIONS, POTENTIAL RISKS, AND 
1126 
STOPPING RULES  
1127 
 
1128 
 Definitions 
1129 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
1130 
relationship between the adverse event and the device(s) under investigation. 
1131 
 
1132 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
1133 
• Results in death. 
1134 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
1135 
become life-threatening, is not necessarily considered a serious adverse event). 
1136 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
1137 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
1138 
conduct normal life functions (sight threatening). 
1139 
• Is a congenital anomaly or birth defect. 
1140 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
1141 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
1142 
the outcomes listed above). 
1143 
 
1144 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any 
1145 
life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
1146 
death was not previously identified in nature, severity, or degree of incidence in the investigational 
1147 
plan or application (including a supplementary plan or application), or any other unanticipated serious 
1148 
problem associated with a device that relates to the rights, safety, or welfare of participants (21 CFR 
1149 
812.3(s)). 
1150 
 
1151 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which the 
1152 
device may have caused or to which the device may have contributed. (Note that an Adverse Event 
1153 
Form is to be completed in addition to a Device Deficiency or Issue Form). 
1154 
 
1155 
Device Complaints: A device complication or complaint is something that happens to a device or is 
1156 
related to device performance, whereas an adverse event happens to a participant. A device complaint 
1157 
may occur independently from an AE, or along with an AE. An AE may occur without a device 
1158 
complaint or there may be an AE related to a device complaint. 
1159 
 
1160 
Device Malfunction: Any failure of a device to meet its performance specifications or otherwise 
1161 
perform as intended. Performance specifications include all claims made in the labeling for the device. 
1162 
The intended performance of a device refers to the intended use for which the device is labeled or 
1163 
marketed. (21 CFR 803.3)     
1164 
 
1165 
 Reportable Adverse Events 
1166 
For this protocol, a reportable adverse event includes any untoward medical occurrence that meets one 
1167 
of the following criteria:   
1168 
1) A serious adverse event 
1169 
2) An Adverse Device Effect as defined in section 7.1, unless excluded from reporting in 
1170 
section 7.3 
1171 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
37 
 
 
 
 
3) An Adverse Event occurring in association with a study procedure  
1172 
4) Hypoglycemia meeting the definition of severe hypoglycemia as defined below  
1173 
5) Diabetic ketoacidosis (DKA) as defined below 
1174 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
1175 
events unless associated with an Adverse Device Effect.  Skin reactions from sensor placement are 
1176 
only reportable if severe and/or required treatment.   
1177 
 
1178 
Pregnancy occurring during the study will be recorded. 
1179 
 
1180 
 Hypoglycemic Events 
1181 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
1182 
when the following definition for severe hypoglycemia is met:  the event required assistance of another 
1183 
person due to altered consciousness, and required another person to actively administer carbohydrate, 
1184 
glucagon, or other resuscitative actions. This means that the participant was impaired cognitively to the 
1185 
point that he/she was unable to treat himself/herself, was unable to verbalize his/ her needs, was 
1186 
incoherent, disoriented, and/or combative, or experienced seizure or coma. These episodes may be 
1187 
associated with sufficient neuroglycopenia to induce seizure or loss of consciousness.  If plasma 
1188 
glucose measurements are not available during such an event, neurological recovery attributable to the 
1189 
restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by 
1190 
a low plasma glucose concentration. 
1191 
 
1192 
 Hyperglycemic Events/Diabetic Ketoacidosis 
1193 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
1194 
when one of the following criteria is met:  (1) the event involved DKA, as defined by the Diabetes 
1195 
Control and Complications Trial (DCCT) and described below, or (2) in the absence of DKA if 
1196 
evaluation or treatment was obtained at a health care provider facility for an acute event involving 
1197 
hyperglycemia or ketosis.  
1198 
 
1199 
Hyperglycemic events are classified as DKA if the following are present:  
1200 
• 
Symptoms such as polyuria, polydipsia, nausea, or vomiting;  
1201 
• 
Serum ketones >1.5 mmol/L or large/moderate urine ketones;  
1202 
• 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
1203 
• 
Treatment provided in a health care facility     
1204 
 
1205 
All reportable Adverse Events whether volunteered by the participant, discovered by study personnel 
1206 
during questioning, or detected through physical examination, laboratory test, or other means will be 
1207 
reported on an adverse event form online. Each adverse event form is reviewed by the Medical 
1208 
Monitor to verify the coding and the reporting that is required.  
1209 
 
1210 
 Relationship of Adverse Event to Study Device 
1211 
The study investigator will assess the relationship of any adverse event to be related or unrelated by 
1212 
determining if there is a reasonable possibility that the adverse event may have been caused by the 
1213 
study device. 
1214 
 
1215 
To ensure consistency of adverse event causality assessments, investigators should apply the following 
1216 
general guideline when determining whether an adverse event is related: 
1217 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
38 
 
 
 
 
 
1218 
Yes 
1219 
There is a plausible temporal relationship between the onset of the adverse event and the study 
1220 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
1221 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of 
1222 
response to the study intervention; and/or the adverse event abates or resolves upon discontinuation of 
1223 
the study intervention or dose reduction and, if applicable, reappears upon re-challenge. 
1224 
 
1225 
No 
1226 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
1227 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); 
1228 
and/or the adverse event has no plausible temporal relationship to study intervention.    
1229 
 
1230 
 Intensity of Adverse Event 
1231 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or (3) 
1232 
severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse event is 
1233 
not necessarily serious. For example, itching for several days may be rated as severe, but may not be 
1234 
clinically serious. 
1235 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
1236 
participant’s daily activities. 
1237 
• MODERATE: Usually causes a low level of inconvenience or concern to the participant and 
1238 
may interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
1239 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug 
1240 
therapy or other treatment. 
1241 
 
1242 
 Coding of Adverse Events 
1243 
Adverse events will be coded using the MedDRA dictionary. The Medical Monitor will review the 
1244 
investigator’s assessment of causality and may agree or disagree. Both the investigator’s and Medical 
1245 
Monitor’s assessments will be recorded. The Medical Monitor will have the final say in determining 
1246 
the causality. 
1247 
 
1248 
Adverse events that continue after the participant’s discontinuation or completion of the study will be 
1249 
followed until their medical outcome is determined or until no further change in the condition is 
1250 
expected. 
1251 
 
1252 
 Outcome of Adverse Event 
1253 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1254 
• RESOLVED – The participant recovered from the AE/SAE without sequelae. Record the 
1255 
AE/SAE stop date. 
1256 
• RESOLVED WITH SEQUELAE – The event persisted and had stabilized without change in 
1257 
the event anticipated. Record the AE/SAE stop date. 
1258 
• FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that was 
1259 
the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time of 
1260 
death; however, were not the cause of death, will be recorded as “resolved” at the time of death. 
1261 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant or the 
1262 
participant’s records to determine the outcome (for example, a participant that was lost to 
1263 
follow-up).  
1264 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
39 
 
 
 
 
• ONGOING – An ongoing AE/SAE is defined as the event was ongoing with an undetermined 
1265 
outcome.  
1266 
o An ongoing outcome will require follow-up by the site in order to determine the final 
1267 
outcome of the AE/SAE. 
1268 
o The outcome of an ongoing event at the time of death that was not the cause of death, 
1269 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
1270 
date.  
1271 
 
1272 
All clinically significant abnormalities of clinical laboratory measurements or adverse events occurring 
1273 
during the study and continuing at study termination should be followed by the participant’s physician 
1274 
and evaluated with additional tests (if necessary) until diagnosis of the underlying cause, or resolution. 
1275 
Follow-up information should be recorded on source documents.  
1276 
 
1277 
If any reported adverse events are present when a participant completes the study, or if a participant is 
1278 
withdrawn from the study due to an adverse event, the participant will be contacted for re-evaluation 
1279 
within 2 weeks. If the adverse event has not resolved, additional follow-up will be performed as 
1280 
appropriate. Every effort should be made by the Investigator or delegate to contact the participant until 
1281 
the adverse event has resolved or stabilized. 
1282 
 
1283 
 Reportable Device Issues 
1284 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
1285 
whether an adverse event occurred, except in the following circumstances.  
1286 
 
1287 
The following device issues are anticipated and will not be reported on a Device Issue Form but will 
1288 
reported as an Adverse Event if the criteria for AE reporting described above are met:  
1289 
• Component disconnections 
1290 
• CGM sensors lasting fewer than 7 days  
1291 
• CGM tape adherence issues 
1292 
• Pump infusion set occlusion not leading to ketosis 
1293 
• Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
1294 
• Intermittent device component disconnections/communication failures not leading to system 
1295 
replacement 
1296 
• Device issues clearly addressed in the user guide manual that do not require additional 
1297 
troubleshooting 
1298 
• Skin reactions from CGM sensor placement or pump infusion set placement that don’t meet 
1299 
criteria for AE reporting 
1300 
 
1301 
 Pregnancy Reporting 
1302 
If pregnancy occurs, the participant will be discontinued from the study. The occurrence of pregnancy 
1303 
will be reported on an AE Form. 
1304 
 
1305 
 Timing of Event Reporting 
1306 
Serious or unexpected device-related adverse events must be reported to the Coordinating Center 
1307 
within 24 hours via completion of the online serious adverse event form.  
1308 
 
1309 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
40 
 
 
 
 
Other reportable adverse events and device malfunctions (with or without an adverse event) will be 
1310 
reported within 3 days of the investigator becoming aware of the event by completion of an electronic 
1311 
case report form. 
1312 
 
1313 
Device complaints not associated with device malfunction or an adverse event must be reported within 
1314 
7 days of the investigator becoming aware of the event. 
1315 
 
1316 
The Coordinating Center will notify all participating investigators of any adverse event that is serious, 
1317 
related, and unexpected. Notification will be made within 10 days after the Coordinating Center 
1318 
becomes aware of the event.  
1319 
 
 
1320 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1321 
abiding by any other reporting requirements specific to his/her Institutional Review Board or Ethics 
1322 
Committee. 
1323 
 
1324 
Upon receipt of a UADE report, the Sponsor will investigate the UADE and if indicated, report the 
1325 
results of the investigation to the sites’ IRBs, and the FDA within ten working days of the Sponsor 
1326 
becoming aware of the UADE per 21CFR 812.46(b) (2). The Medical Monitor must determine if the 
1327 
UADE presents an unreasonable risk to participants. If so, the Medical Monitor must ensure that all 
1328 
investigations, or parts of investigations presenting that risk, are terminated as soon as possible but no 
1329 
later than 5 working days after the Medical Monitor makes this determination and no later than 15 
1330 
working days after first receipt notice of the UADE.  
1331 
 
1332 
Device malfunctions will be handled by the Sponsor or designee as described below. In the case of a 
1333 
CGM transmitter or sensor device malfunction, the Coordinating Center will be contacted and the 
1334 
Sponsor will be notified accordingly. 
1335 
 
1336 
 Data and Safety Monitoring Board 
1337 
The DSMB will be informed of all serious adverse events and any unanticipated adverse device events 
1338 
that occur during the study and will review compiled safety data at periodic intervals.  Details regarding 
1339 
review will be documented in standalone DSMB procedural documentation.   
1340 
 
1341 
 Potential Risks and Side Effects 
1342 
Loss of confidentiality is a potential risk; however, data are handled to minimize this risk.  
1343 
Hypoglycemia, hyperglycemia, and ketone formation are always a risk in subjects with type 1 diabetes 
1344 
and subjects will be closely monitored for this.  When wearing sensors and insulin infusion sets there is 
1345 
always a risk of skin rashes, allergic reactions to the tape, or infections at the insertion site.  There is 
1346 
always a risk for a small piece of a sensor remaining under the skin or a sensor or infusion set breaking 
1347 
off under the skin.  
1348 
 
1349 
 Venipuncture Risks 
1350 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws can 
1351 
cause some common reactions like pain, bruising, or redness at the sampling site.  Less common 
1352 
reactions include bleeding from the sampling site, formation of a small blood clot or swelling of the 
1353 
vein and surrounding tissues, and fainting. 
1354 
 
1355 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
41 
 
 
 
 
 Fingerstick Risks 
1356 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
1357 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital laboratory 
1358 
tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount of bleeding under 
1359 
the skin will produce a bruise.  A small scar may persist for several weeks.  The risk of local infection 
1360 
is less than 1 in 1000.  This should not be a significant contributor to risks in this study as fingersticks 
1361 
are part of the usual care for people with diabetes. 
1362 
 
1363 
 Subcutaneous Catheter Risks (CGM) 
1364 
Subjects using the CGM will be at low risk for developing a local skin infection at the site of the 
1365 
sensor needle placement.  If a catheter is left under the skin for more than 24 hours it is possible to get 
1366 
an infection where it goes into the skin, with swelling, redness and pain.  There may be bleeding where 
1367 
the catheter is put in and bleeding under the skin causes a bruise (1 in 10 risk).   
1368 
 
1369 
Study staff should verbally alert the subject that on rare occasions, the CGM may break and leave a small 
1370 
portion of the sensor under the skin that may cause redness, swelling or pain at the insertion site.  The 
1371 
subject should be further instructed to notify the study coordinator immediately if this occurs. 
1372 
 
1373 
 Risk of Hypoglycemia 
1374 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a low 
1375 
blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and possibly less 
1376 
than it would be as part of daily living.  Symptoms of hypoglycemia can include sweating, jitteriness, 
1377 
and not feeling well.  Just as at home, there is the possibility of fainting or seizures (convulsions) and 
1378 
that for a few days the subject may not be as aware of symptoms of hypoglycemia.  A CGM 
1379 
functioning poorly and significantly over-reading glucose values could lead to inappropriate insulin 
1380 
delivery.     
1381 
 
1382 
 Risk of Hyperglycemia 
1383 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
1384 
extended period or if the pump or infusion set is not working properly.  A CGM functioning poorly 
1385 
and significantly under-reading glucose values could lead to inappropriate suspension of insulin 
1386 
delivery.     
1387 
 
1388 
 Risk of Device Reuse 
1389 
The study CGM system is labeled for single-patient use only. The sensor (the component of the system 
1390 
that enters the skin) will be single-patient use only. The transmitter and receiver may be reused during 
1391 
the study after cleaning the device using a hospital-approved cleaning procedure. The transmitter is 
1392 
attached to the sensor but does not enter the skin and the receiver is a handheld device. Subjects will be 
1393 
informed that FDA or relevant national authorities have approved these devices for single use and that 
1394 
by using them among multiple patients, bloodborne pathogens (i.e. Hepatitis B) may be spread through 
1395 
the use of multiple users.  
1396 
 
1397 
The study insulin pump is labeled for single-patient use. During the study, this device may be reused 
1398 
after cleaning adhering to a hospital-approved cleaning procedure. All infusion set equipment will be 
1399 
single patient use only (infusion set insertion kits, tubing, cartridges etc.)  Subjects will be informed 
1400 
that FDA or relevant national authorities have approved the insulin pump device for single use and that 
1401 
by using them among multiple patients, bloodborne pathogens (i.e. Hepatitis B) may be spread through 
1402 
the use of multiple users. 
1403 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
42 
 
 
 
 
 
1404 
The study blood glucose meter and blood ketone meter are labeled for single-patient use. During the 
1405 
study, only one person can use each device as there are rare risks that bloodborne pathogens (i.e. 
1406 
Hepatitis B) may be spread through the use of multiple users. 
1407 
 
1408 
 Psychosocial Questionnaires 
1409 
As part of the study, subjects will complete psychosocial questionnaires which include questions about 
1410 
their private attitudes, feelings and behavior related to diabetes.  It is possible that some people may 
1411 
find these questionnaires to be mildly upsetting. Similar questionnaires have been used in previous 
1412 
research and these types of reactions have been uncommon. 
1413 
 
1414 
 Other Risks 
1415 
Some subjects may develop skin irritation or allergic reactions to the adhesives used to secure the 
1416 
CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  If these 
1417 
reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, etc.) will be 
1418 
tried, sites will be rotated frequently, and a mild topical steroid cream or other medication may be 
1419 
required. 
1420 
 
1421 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump infusion sites 
1422 
are inserted under the skin.  It is possible that any part that is inserted under the skin may cause an 
1423 
infection.  These occur very infrequently, but, if an infection was to occur, oral and/or topical 
1424 
antibiotics can be used.  The risk of skin problems could be greater if you use a sensor for longer than 
1425 
it is supposed to be used.  Therefore subjects will be carefully instructed about proper use of the 
1426 
sensor. 
1427 
 
1428 
Data downloaded from the CGM, pump, and blood glucose and ketone meters will be collected for the 
1429 
study as measures of diabetes self-management behaviors.  Some people may be uncomfortable with 
1430 
the researchers' having such detailed information about their daily diabetes habits. 
1431 
 
1432 
 Risk Assessment 
1433 
Based on the facts that (1) adults and adolescents with diabetes experience mild hypoglycemia and 
1434 
hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
1435 
intervention involves periodic automated insulin dosing that may increase the likelihood of 
1436 
hypoglycemia, and periodic automated attenuation of insulin delivery that may increase the likelihood 
1437 
of hyperglycemia, (3) mitigations are in place, and have been tested in prior studies using the 
1438 
investigational device system in the home setting, that limit the likelihood of excessive insulin dosing 
1439 
or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and hyperglycemia can be 
1440 
achieved, it is the assessment of the investigators that this protocol falls under DHHS 46.405 which is 
1441 
a minor increase over minimal risk. In addition, it is the belief of the investigators that this study also 
1442 
presents the prospect of direct benefit to the subjects and general benefit to others with diabetes. 
1443 
 
1444 
 Study Stopping Criteria 
1445 
 Subject Discontinuation of Study Treatment 
1446 
Rules for discontinuing closed-loop use (if randomized to CTR group) or study CGM use (if 
1447 
randomized to the SAP group) are as follows: 
1448 
1. The investigator believes it is unsafe for the subject to continue on the intervention. This could 
1449 
be due to the development of a new medical condition or worsening of an existing condition; or 
1450 
subject behavior contrary to the indications for use of the device that imposes on the subject’s 
1451 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
43 
 
 
 
 
safety—e.g., SAP subject with recurring hypoglycemia due to large correction boluses based 
1452 
on CGM values without confirmatory fingerstick (assuming contraindicated by CGM 
1453 
labelling); or CTR subject with recurring hypoglycemia due to over-boluses in closed-loop with 
1454 
the expectation that the system will prevent hypoglycemia  
1455 
2. The subject requests that the treatment be stopped  
1456 
3. Subject pregnancy 
1457 
 
1458 
In addition, closed-loop use will be discontinued if either of the following occurs: 
1459 
1. Two distinct episodes of severe hypoglycemia as defined in section 7.1 related to automated 
1460 
insulin delivery  
1461 
2. Two distinct episodes of DKA as defined in section 7.1 related to automated attenuation of 
1462 
insulin delivery  
1463 
 
1464 
 
1465 
Even if study treatment is discontinued, the subject will remain in the study and will be encouraged to 
1466 
participate in study activities such as scheduled phone calls, clinic visits, device downloads, blinded 
1467 
CGM use, and HbA1c measurements, with priority given to trying to have the subject complete the 13-
1468 
week visit. 
1469 
 
1470 
 Criteria for Suspending/Stopping Overall Study 
1471 
In the case of a system malfunction resulting in a severe hypoglycemia or severe hyperglycemia event 
1472 
(as defined in Section 7.1) during closed-loop control either due to excess insulin administration or 
1473 
inappropriate suspension that occurs more than one time, enrollment visits, randomization visits, and 
1474 
all use of the closed-loop system in the study will be suspended while the problem is diagnosed.  In 
1475 
addition, study activities could be similarly suspended if the manufacturer of any constituent study 
1476 
device requires stoppage of device use for safety reasons (e.g. product recall). The affected study 
1477 
activities may resume if the underlying problem can be corrected by a protocol or system modification 
1478 
that will not invalidate the results obtained prior to suspension. 
1479 
 
1480 
As stated in Section 7.6, the study DSMB will be informed of all serious adverse events and any 
1481 
unanticipated adverse device events that occur during the study and will review compiled safety data at 
1482 
periodic intervals.  The DSMB will request suspension of study activities or stoppage of the study if 
1483 
deemed necessary based on the totality of safety data available. 
1484 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  2-9-2018 
44 
 
 
 
 
 MISCELLANEOUS CONSIDERATIONS 
1485 
 
1486 
 Benefits 
1487 
One purpose of this research is to reduce the frequency of hypoglycemia and severe hypoglycemic 
1488 
events. Hypoglycemia is the number one fear of many individuals and families with someone who has 
1489 
type 1 diabetes and this fear often prevents optimal glycemic control.  
1490 
 
1491 
It is expected that this protocol will yield increased knowledge about using an automated closed-loop 
1492 
to control the glucose level.  This research is a definitive step on the path towards development of a 
1493 
fully closed-loop system.  In addition, it is the belief of the investigators that this study also presents 
1494 
prospect of direct benefit to the subjects and general benefit to others with diabetes. 
1495 
 
1496 
 Subject Compensation 
1497 
Subjects will be compensated $50 (or local equivalent) for each separate clinic visit during the study. 
1498 
 
1499 
 Subject Withdrawal 
1500 
Participation in the study is voluntary, and a subject may withdraw at any time.  For subjects who 
1501 
withdraw, their data will be used up until the time of withdrawal. 
1502 
 
1503 
 Confidentiality 
1504 
For security and confidentiality purposes, subjects will be assigned an identifier that will be used 
1505 
instead of their name.  Protected health information gathered for this study will be shared with the 
1506 
coordinating center, the Jaeb Center for Health Research in Tampa, FL.  De-identified subject 
1507 
information may also be provided to research sites involved in the study. 
1508 
1509 
1510 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 45 
 STATISTICAL CONSIDERATIONS 
1511 
 
1512 
The approaches to sample size and statistical analyses are summarized below. A detailed statistical 
1513 
analysis plan will be written and finalized prior to the completion of the study.  
1514 
 
1515 
The co-primary outcomes for this study are CGM-measured % below 70 mg/dL and % above 180 
1516 
mg/dL over a 3-month period. The intervention will be considered effective if both of the following 
1517 
comparisons between two treatment arms (SAP vs. CTR) are statistically significant (p < 0.05): 
1518 
• superiority test for % time CGM values below 70 mg/dL and 
1519 
• non-inferiority test for % time CGM values above 180 mg/dL (non-inferiority limit = 5%). 
1520 
 
1521 
 Sample Size 
1522 
Sample size has been computed using co-primary outcomes of time <70 mg/dL (superiority) and time 
1523 
>180 mg/dL (non-inferiority). Data from the CGM arm of the JDRF CGM RCT from subjects meeting 
1524 
the eligibility criteria for the current trial were used to project the distribution of % below 70 and above 
1525 
180 mg/dL over 3 months as measured by CGM for the SAP group in the proposed study.  
1526 
 
1527 
The  total sample size was computed to be 110 for the following assumptions: (1) 1:1 randomization,  
1528 
(2) 90%  power, with adjustment to account for the two co-primary analyses, (3) a 50% relative 
1529 
reduction in time <70 mg/dL (or absolute reduction of 2.0% assuming baseline of 4.0%) with an 
1530 
effective SD of 2.8% and 2-sided type 1 error of 5%, and (4) a non-inferiority limit of 5% for the 
1531 
treatment group comparison of time >180 mg/dL and assuming there is a true difference of 2.5% 
1532 
favoring the CTR group, with an effective standard deviation of 11% and a 1-sided type 1 error of 
1533 
2.5%.  The sample size was increased to 126 to account for subjects with insufficient data to include in 
1534 
the primary analysis (see section 9.2). 
1535 
 
1536 
The Appendix provides further details of the sample size assumptions and computations. 
1537 
 
1538 
 Calculation of Outcome Metrics and Handling of Missing Data 
1539 
CGM Metrics 
1540 
Randomization is preceded by two weeks of blinded CGM run-in or by presenting at least three weeks 
1541 
of personal CGM data. The two weeks of blinded run-in or the last two weeks of personal CGM data 
1542 
will be used in the calculation of baseline CGM metrics.  
1543 
 
1544 
Per protocol design, the first two weeks following the randomization visit involve a training schedule 
1545 
for both groups. CGM data during this time will not be included in the calculation of the outcome 
1546 
CGM metrics. Unblinded CGM data starting from Week 3 post-randomization through the 3 month 
1547 
visit will be included in the calculation of each CGM metric. Missing (or less than 168 hours) post-
1548 
randomization unblinded sensor data will be imputed using all available post-randomization blinded 
1549 
data. Subjects with any amount of post-randomization unblinded or blinded data will be included in 
1550 
CGM analyses. Percentages <70 and >180 mg/dL will be calculated giving equal weight to each CGM 
1551 
point for each subject.  
1552 
 
1553 
The two weeks of blinded CGM data collected after 9 weeks will not be used for the primary outcome; 
1554 
except for imputations as mentioned above.  
1555 
 
1556 
HbA1c 
1557 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 46 
If the 3-month visit is completed but an HbA1c measurement from the central laboratory is not 
1558 
available, a local HbA1c measurement made at the clinical site at the 3-month visit will be used if 
1559 
available. In such cases the HbA1c value used in the analysis will be computed from a regression line 
1560 
using the available lab-local HbA1c pairs. A similar imputation will be done for any missing lab 
1561 
HbA1c values at baseline or other visits. If neither measurement at 3 months is available, then the 
1562 
HbA1c value will be considered missing and the subject will be excluded from all HbA1c analyses. 
1563 
 
1564 
 Primary Analyses 
1565 
The primary analysis will follow the intention-to-treat principle. It will include all randomized 
1566 
subjects, the data from whom will be analyzed in the group to which the subjects were assigned 
1567 
through randomization.     
1568 
 
1569 
The intervention will be declared effective only if a statistically significant result (p-value<0.05) is 
1570 
obtained for both co-primary outcomes.  The type 1 error is therefore not inflated by two co-primary 
1571 
outcomes. 
1572 
 
1573 
 Changes in CGM-Measured % below 70 mg/dL from Run-in to 3-Months Post-
1574 
Randomization Period between the Two Treatment Arms  
1575 
Summary statistics (median, quartiles) will be reported for the CGM % <70 mg/dL by treatment group.  
1576 
 
1577 
Changes from run-in pre-randomization CGM wear (data generated as described above) to the 3-month 
1578 
post-randomization period in CGM-measured % <70 mg/dL between two treatment arms will be 
1579 
compared using a linear mixed effects regression model with a log(x+0.005) transformation while 
1580 
adjusting for the baseline CGM % <70 mg/dL and clinical center (random effect). Residual values will 
1581 
be examined for an approximate normal distribution.  If values are highly skewed even after the 
1582 
transformation, then an alternate transformation or robust statistical method (e.g., non-parametric or 
1583 
MM estimation) will be used instead. 
1584 
 
1585 
 Changes in CGM-Measured % above 180 mg/dL from Run-in to 3-Months Post-
1586 
Randomization Period between the Two Treatment Arms 
1587 
Summary statistics (median, quartiles) will be reported for the CGM % >180 mg/dL by treatment 
1588 
group.  
1589 
 
1590 
Changes from run-in pre-randomization to over 3-months post-randomization in CGM-measured % 
1591 
>180 mg/dL between two treatment arms will be compared using a linear mixed effects regression 
1592 
model; while adjusting for % >180 during run-in, and clinical center (random effect). A 2-sided 95% 
1593 
confidence interval for the difference between treatment arms will be generated.  Separate two-sided p-
1594 
values will be calculated to test non-inferiority and superiority. Since non-inferiority is often denoted 
1595 
in terms of a one-sided test, it is worth noting that a two-sided test at alpha = 0.05 gives the same 
1596 
rejection region in the right tail as a one-sided test at alpha = 0.025.  It is also worth noting that the 
1597 
additional hypothesis test for superiority does not inflate the overall alpha since a type 1 error can only 
1598 
occur if the two-sided 95% confidence interval fails to contain the true difference. Residual values will 
1599 
be examined for an approximate normal distribution.  If values are highly skewed then a 
1600 
transformation or robust statistical method (e.g., non-parametric or MM estimation) will be used 
1601 
instead. 
1602 
 
1603 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 47 
 Secondary Efficacy Analyses 
1604 
In secondary analyses, treatment group differences will be assessed for additional CGM metrics and 
1605 
HbA1c.  For all secondary analyses (including sections 9.5, 9.6, and 9.7), the false discovery rate will 
1606 
be controlled using the adaptive Benjamini-Hochberg procedure with <0.10 as the threshold for 
1607 
statistical significance.  
1608 
 
1609 
Secondary glycemic metrics based on CGM data will include the following outcomes: 
1610 
 
1611 
CGM Metrics Related to Overall Control 
1612 
- 
mean glucose  
1613 
- 
% in range of 70-180 mg/dL 
1614 
- 
% in range 70-140 mg/dL  
1615 
- 
glucose variability measured with the coefficient of variation  
1616 
 
1617 
CGM Metrics Related to Hypoglycemia 
1618 
- 
% <60 mg/dL 
1619 
- 
% <54 mg/dL  
1620 
- 
low blood glucose index 
1621 
- 
hypoglycemia events (defined as at least 15 consecutive minutes <70mg/dL) 
1622 
 
1623 
CGM Metrics Related to Hyperglycemia 
1624 
- 
% >250 mg/dL 
1625 
- 
% >300 mg/dL  
1626 
- 
high blood glucose index  
1627 
 
1628 
The analyses for the above CGM will parallel those mentioned above for the primary % below 70 
1629 
mg/dL outcome, with the exception that a transformation will not be used for those metrics with a 
1630 
distribution that is approximately normally distributed.  Summary statistics will be reported mean ± SD 
1631 
or median (quartiles) as appropriate to the distribution. 
1632 
 
1633 
A comparison of primary and secondary results during the daytime and overnight will be made.  
1634 
 
1635 
HbA1c 
1636 
Change in HbA1c from baseline to 13 weeks will be compared between the two treatment arms using a 
1637 
linear model while adjusting for baseline HbA1c and clinical center (random factor).  
1638 
 
1639 
Several binary outcomes will be compared between treatment groups using central lab HbA1c values. 
1640 
• HbA1c <7.0% at 13 weeks 
1641 
• HbA1c <7.5% at 13 weeks 
1642 
• HbA1c improvement from baseline to 13 weeks >0.5% 
1643 
• HbA1c improvement from baseline to 13 weeks >1.0% 
1644 
• HbA1c relative improvement from baseline to 13 weeks >10% 
1645 
• HbA1c improvement from baseline to 13 weeks >1.0% or HbA1c <7.0% at 13 weeks  
1646 
 
1647 
Our goal is to minimize the amount of missing data and it is worth noting that all statistical methods 
1648 
for handling missing data rely on untestable assumptions and there is no one correct way to handle 
1649 
missing data. If some HbA1c data will be missing, in addition to the completer-only analyses 
1650 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 48 
mentioned above, sensitivity analyses will be perform in order to confirm that the conclusions do not 
1651 
rely on the statistical methods employed for handling missing data. Replication of the HbA1c analyses 
1652 
with imputed data for subjects with missing both local and central lab HbA1c at 13 weeks will be done 
1653 
using two methods: 
1654 
- 
Rubin’s multiple imputation and 
1655 
- 
Direct likelihood 
1656 
 
1657 
 Additional Treatment Group Comparisons 
1658 
• Insulin 
1659 
o Total daily insulin (units/kg)  
1660 
o Basal: bolus insulin ratio 
1661 
• Weight and Body Mass Index 
1662 
• Clarke Hypoglycemia Awareness Scores 
1663 
• INSPIRE survey scores 
1664 
 
1665 
The analyses for the above metrics will parallel those mentioned above for the secondary efficacy 
1666 
outcomes.  
1667 
 
1668 
 Quality of Life Questionnaires 
1669 
The following questionnaires will be completed at baseline and at 13 weeks: 
1670 
• Fear of Hypoglycemia Survey (HFS-II) – total score and 3 subscales: 
1671 
o Behavior (avoid) 
1672 
o Behavior (maintain high BG) 
1673 
o Worry 
1674 
• Hyperglycemia Avoidance Scale – total score and 4 subscales: 
1675 
o Immediate action 
1676 
o Worry 
1677 
o Low BG preference 
1678 
o Avoid extremes 
1679 
• Diabetes Distress Scale – total score and 4 subscales: 
1680 
o Emotional burden 
1681 
o Physician-related distress 
1682 
o Regimen-related distress 
1683 
o Interpersonal distress 
1684 
• Hypoglycemia Confidence Scale – total score  
1685 
 
1686 
For each questionnaire, mean ± SD values or percentiles appropriate to the distribution will be given 
1687 
by randomization group for the total score and each subscale. For questionnaires administered to both 
1688 
randomization groups comparisons will be made using similar linear models as described above for the 
1689 
primary outcomes. Separate models will be run for the total score and each of the subscales listed 
1690 
above.    
1691 
 
1692 
 Subgroup Analyses 
1693 
In exploratory analyses, the two primary outcomes (% <70 and >180 mg/dL) will be assessed 
1694 
separately in various subgroups and for continuous variables according to the baseline value as defined 
1695 
below. Tests for interaction with treatment group will be performed and further explored if an 
1696 
interaction will be found in the first place.  
1697 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 49 
 
1698 
Interpretation of subgroup analyses will depend on whether the overall analysis demonstrates a 
1699 
significant treatment group difference. In the absence of such an overall difference and if performed, 
1700 
subgroup analyses will be interpreted with caution. For continuous variables, results will be displayed 
1701 
in subgroups based on cutpoints although the analysis will utilize the variable as continuous, except for 
1702 
age which will be analyzed both as a continuous variable and in two age groups. If there is insufficient 
1703 
sample size in a given subgroup, the cutpoints for continuous measures may be adjusted per the 
1704 
observed distribution of values. Cutpoint selection for display purposes will be made masked to the 
1705 
outcome data.  
1706 
- 
Baseline HbA1c (as continuous variable and in the two subgroups >7.5% and <7.5%) 
1707 
- 
Baseline CGM time spent <70 mg/dL 
1708 
- 
Baseline CGM time spent >180 mg/dL 
1709 
- 
Age: As a continuous variable and in these subgroups 
1710 
o <25 
1711 
o ≥25 
1712 
- 
Gender 
1713 
o Female 
1714 
o Male 
1715 
- 
Race 
1716 
o White 
1717 
o Non-White (split if sample size allows) 
1718 
- 
Clinical site 
1719 
 
1720 
Additional analyses may be performed for subgroups defined based on the following baseline 
1721 
demographic/clinical characteristics.   
1722 
- 
body mass index,  
1723 
- 
income, education, and/or insurance status, 
1724 
- 
baseline scores for quality of life, hypoglycemia awareness and fear questionnaires 
1725 
- 
C-peptide level 
1726 
 
1727 
 Safety Analyses 
1728 
All randomized subjects will be included in these analyses and all their post-randomization safety 
1729 
events will be reported.    
1730 
 
1731 
The circumstances of all reportable cases of the following will be summarized and tabulated by 
1732 
treatment group: 
1733 
- 
Severe hypoglycemia (as defined in Section 7.1) 
1734 
- 
Diabetic ketoacidosis (as defined in Section 7.1) 
1735 
- 
Other serious adverse events (SAE) and serious adverse device events (SADE) 
1736 
- 
Unanticipated adverse device effects (UADE) 
1737 
  
1738 
For the following outcomes, mean ± SD or summary statistics appropriate to the distribution will be 
1739 
tabulated by treatment group:  
1740 
- 
Number of SH events and SH event rate per 100 person-years 
1741 
- 
Number of DKA events and DKA event rate per 100 person-years 
1742 
- 
Any adverse event’ rate per 100 person-years 
1743 
 
1744 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 50 
The numbers will be compared between the two treatment arms using robust Poisson regression and 
1745 
the percentage of subjects with at least one event will be compared using Fisher’s exact test. 
1746 
 
1747 
Any pre-randomization adverse events will be tabulated separately and will include subjects who were 
1748 
never randomized.  
1749 
 
1750 
 Additional Tabulations and Plots 
1751 
The following tabulations will be performed according to treatment group without statistical testing:  
1752 
- 
baseline demographics and clinical characteristics, including Diabetes Specific Personality 
1753 
Questionnaire score  
1754 
- 
flow chart accounting for all subjects for all visits  
1755 
- 
visit and phone contact completion rates for each follow-up visit  
1756 
- 
number and reasons for unscheduled visits and phone calls  
1757 
- 
number of subjects who stopped treatment and reasons 
1758 
- 
sensor use – hours of use and days with any sensor use per week - overall and by month 
1759 
- 
The daily frequency of downloaded BGM use - overall and by month 
1760 
- 
Sensor performance metrics (difference, absolute relative difference, and International 
1761 
Organization for Standardization criteria) – if applicable, by sensor version.   
1762 
- 
% time CGM data available 
1763 
- 
protocol deviations  
1764 
- 
device malfunctions requiring study team contact and other reported device issues 
1765 
- 
24 hours plots with median line and IQR bands for % CGM <70 mg/dL, >180 mg/dL, mean, 
1766 
70-180 mg/dL, and coefficient of variation 
1767 
 
1768 
 Tabulations in CTR Arm Only 
1769 
The following tabulations will be performed for the CTR arm only: 
1770 
- 
performance metrics, describing the inControl system and its components  
1771 
- 
% time CGM data were available to the inControl System 
1772 
- 
hours of different CL mode use per week - overall and by month  
1773 
- 
Technology Expectations Survey score at baseline and Technology Acceptance Survey score at 
1774 
13 weeks 
1775 
 
1776 
 Sensitivity Analyses 
1777 
If more than 5% of subjects have fewer than 168 hours of post-randomization CGM data, the two co-
1778 
primary analyses will be replicated excluding such subjects. 
1779 
 
1780 
 Other Analyses 
1781 
Additional analyses that will be detailed in the Statistical Analysis Plan will include the following: 
1782 
• Blinded CGM data 
1783 
o Treatment group comparisons paralleling the unblinded CGM data analyses 
1784 
o Comparison of blinded and unblinded CGM data from the same time periods 
1785 
o Comparison of unblinded CGM data from the blinded time periods versus the unblinded 
1786 
CGM data from the rest of the follow-up period 
1787 
• Effect of menstrual cycle to glycemic control and comparison of treatment groups during 
1788 
different menstrual cycle periods. 
1789 
 
1790 
 
1791 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 51 
 DATA COLLECTION AND MONITORING 
1792 
 
1793 
 Case Report Forms and Device Data 
1794 
The main study data are collected through a combination of electronic case report forms (CRFs) and 
1795 
electronic device data files obtained from the study software and individual hardware components.  
1796 
These electronic device files and electronic CRFs from the study website are considered the primary 
1797 
source documentation. 
1798 
 
1799 
 Quality Assurance and Monitoring 
1800 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1801 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1802 
conducted and data are generated, documented and reported in compliance with the protocol, Good 
1803 
Clinical Practice (GCP) and the applicable regulatory requirements. Adverse events will be prioritized 
1804 
for monitoring. 
1805 
 
1806 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course of the 
1807 
study, consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations — A Risk-
1808 
Based Approach to Monitoring” (August 2013).  Study conduct and monitoring will conform to 21 
1809 
Code of Federal Regulations (CFR) 812. 
1810 
 
1811 
The data of most importance for monitoring at the site are subject eligibility and adverse events.  
1812 
Therefore, the RBM plan will focus on these areas.  As much as possible, remote monitoring will be 
1813 
performed in real-time with on-site monitoring performed to evaluate the verity and completeness of the 
1814 
key site data.  Elements of the RBM may include: 
1815 
• Qualification assessment, training, and certification for sites and site personnel 
1816 
• Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1817 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol review 
1818 
of entered data and edits, statistical monitoring, study closeout 
1819 
• On-site monitoring (site visits): source data verification, site visit report 
1820 
• Device accountability 
1821 
• Communications with site staff 
1822 
• Patient retention and visit completion 
1823 
• Quality control reports 
1824 
• Management of noncompliance 
1825 
• Documenting monitoring activities 
1826 
• Adverse event reporting and monitoring 
1827 
 
1828 
Coordinating Center representatives or their designees may visit the study facilities at any time in order 
1829 
to maintain current and personal knowledge of the study through review of the records, comparison 
1830 
with source documents, observation and discussion of the conduct and progress of the study.  
1831 
 
1832 
 
 
1833 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 52 
 APPENDIX: Sample Size Estimation for the iDCL Trial  
1834 
 
1835 
The  objective of this clinical trial is assess the efficacy and safety of home use of a standard Control-
1836 
to-Range (sCTR) closed-loop (CL) system with minimal central safety monitoring compared with 
1837 
sensor augmented pump therapy (SAP) in subjects with type 1 diabetes. The CL system was primarily 
1838 
designed to reduce hypoglycemia while also keeping hyperglycemia under control. Given this design, 
1839 
a co-primary of superiority in hypoglycemia along with a non-inferiority in hyperglycemia are 
1840 
proposed for the study.  
1841 
 
1842 
Major eligibility criteria are:  
1843 
- 
Clinical diagnosis of type 1 diabetes 
1844 
- 
Use of an insulin infusion pump for at least 6 months 
1845 
- 
Age ≥14.0 years old  
1846 
 
1847 
Primary Analyses 
1848 
The primary analysis in this study will be a combination of two different hypothesis tests comparing the 
1849 
two treatment arms: 
1850 
• CGM percent time below 70 mg/dl (superiority) 
1851 
• CGM time above 180 mg/dl (non-inferiority)  
1852 
 
1853 
1. Using JDRF CGM RCT data to estimate sample size 
1854 
The JDRF CGM RCT was a parallel group 12-months randomized trial comparing open loop CGM 
1855 
use and self-monitoring of blood glucose (SMBG) versus SMBG alone. Data from the treatment 
1856 
/CGM group in the JDRF CGM RCT were used to estimate CGM data in the control group of the 
1857 
proposed study. CGM data for the first 2 weeks were used to simulate a mock run-in phase, the next 2 
1858 
weeks were discarded, and the next 13 weeks were used to estimate time below 70 mg/dl and time 
1859 
above 180 mg/dl means and variances.  
1860 
 
1861 
There were N=125 subjects randomized to open-loop CGM use who met the following criteria: 
1862 
• using a pump for at least 6 months, 
1863 
• age ≥14.0 years, 
1864 
• at least 168 hours of CGM data (i.e. at least 50%) during the 2-week mock run-in phase. 
1865 
 
1866 
2. Primary Analysis  
1867 
The co-primary outcomes are: 
1868 
• superiority in CGM-measured time below 70 mg/dl, and  
1869 
• non-inferiority in CGM-measured time above 180 mg/dl over 3 months (non-inferiority limit 
1870 
of 5%).  
1871 
 
1872 
The study will be declared a success only if both tests listed above reject the null hypothesis. 
1873 
 
1874 
CGM time below 70 mg/dl 
1875 
Among all 125 subjects in the JDRF data, the mean % below 70 mg/dl over 13 weeks = 4.0%, the 
1876 
mean % below 70 mg/dl during the 2 weeks run-in phase = 3.7%, and the correlation between the two 
1877 
= 0.74. The SD for % below 70 mg/dl over 13 weeks = 3.3% (95% CI: 2.9%, 3.8%). A more 
1878 
conservative correlation of 0.5 was used for an effective SD = 2.8% (95% CI: 2.5%, 3.3%). 
1879 

iDCL Protocol 1_v10.0_2-9-2018_ clean.docx  
 
 53 
 
1880 
CGM time above 180 mg/dl 
1881 
Among all 125 subjects in the JDRF data, the mean % above 180 mg/dl over 13 weeks = 27%, the 
1882 
mean % above 180 mg/dl during the 2 weeks run-in phase = 27%, and the correlation between the two 
1883 
= 0.80. The SD for % above 180 mg/dl over 13 weeks = 13% (95% CI: 11%, 15%). A more 
1884 
conservative correlation of 0.5 was used for an effective SD = 11% (95% CI: 10%, 13%). 
1885 
 
1886 
Combined inference 
1887 
For the primary analysis, the intervention will be considered effective only if both co-primary 
1888 
outcomes are found to be statistically significant. Instead of inflating the type 1 error, requiring both 
1889 
comparisons to be statistically significant slightly inflates type 2 error. The lower bound for the overall 
1890 
combined power to reject both null hypothesis will be computed using Bonferroni adjustments. 
1891 
 
1892 
The total sample size was computed to be 110 for the following assumptions: 
1893 
- 
1:1 randomization scheme, 
1894 
- 
90% overall power that accounts for the two co-primary analyses, 
1895 
- 
A 50% relative reduction in time <70 mg/dL of (i.e., 4.0% vs. 2.0% absolute time)  with an 
1896 
effective SD of 2.8% and 2-sided type I error of 5%, 
1897 
- 
A non-inferiority limit of 5% for the treatment group comparison of time >180 mg/dL and 
1898 
assuming there is a true difference of 2.5% favoring the CTR group, with an effective standard 
1899 
deviation of 11% and a 1-sided type I error of 2.5%. 
1900 
 
1901 
The assumptions above with a sample size of N=110 give statistical power: 
1902 
− 96% for the hypoglycemia comparison (superiority) and  
1903 
− 94% power for the hyperglycemia comparison (non-inferiority).   
1904 
 
1905 
Using a Bonferroni bound, the overall power that both tests will reject the null hypothesis is at least 
1906 
94% + 96% - 100% = 90%. 
1907 
 
1908 
4. Summary 
1909 
For the primary analysis, the intervention will be considered effective if a statistically significant 
1910 
reduction in % below 70 mg/dl along with an equivalence in % above 180 mg/dl over 3 months (with a 
1911 
non-inferiority limit of 5%) will be found (co-primary outcomes). Assuming an overall power >90%,  
1912 
an effective SD of 2.8% and a 50% relative reduction in % below 70 mg/dl (or absolute reduction of 
1913 
2.0% assuming baseline of 4%) along with an effective SD of 11%, an improvement of 2.5%, and a 
1914 
non-inferiority limit of 5% in % above 180mg/dl, a minimum total sample size of 110 is needed. 
1915 
 
1916 
The final sample size was selected to be 126 to account for possible non-compliance or dropout. 
1917 

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 54 
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1919 
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