The International Diabetes Closed Loop (iDCL) Trial: Clinical Acceptance of the Artificial Pancreas in Pediatrics: A Study of t:Slim X2 With Control-IQ Technology
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Sponsor: University of Virginia

The International Diabetes Closed Loop (iDCL) trial: 
1 
Clinical Acceptance of the Artificial Pancreas in 
2 
Pediatrics 
3 
A Study of t:slim X2 with Control-IQ Technology  
4 
Study Sponsor 
5 
Marc Breton 
6 
University of Virginia 
7 
Center for Diabetes Technology 
8 
 Protocol Chair 
9 
R. Paul Wadwa, MD 
10 
Barbara Davis Center 
11 
University of Colorado 
12 
Participating Institutions 
13 
University of Virginia, Charlottesville, Virginia 
14 
Barbara Davis Center, University of Colorado, Colorado 
15 
Stanford University, California 
16 
Yale University, Connecticut 
17 
Coordinating Center 
18 
Jaeb Center for Health Research 
19 
 
20 
 
21 
 
22 
 
 
Version Number: v2.5 
23 
May 24, 2019 
24 

 
 
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KEY ROLES 
25 
 
Sponsor Chair / IDE Chair 
 
Name, degree 
Marc Breton 
Institution Name 
University of Virginia, Center for Diabetes Technology 
 
 
Protocol Chair/Director 
 
Name, degree 
R. Paul Wadwa, MD 
Institution Name 
Barbara Davis Center, University of Colorado  
 
JCHR Coordinating Center Director 
 
Name, degree 
Katrina Ruedy, MSPH 
Institution Name 
Jaeb Center for Health Research 
 
Medical Monitor 
 
Name, degree 
Roy Beck, M.D., Ph.D. 
Institution Name 
Jaeb Center for Health Research 
 
26 
 
 
27 

 
 
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PROTOCOL VERSION HISTORY 
28 
Version 
Number 
Author(s) 
Approver 
Effective 
Date 
Revision Description 
1.0 
R. Paul Wadwa 
Daniel Cherñavvsky 
Katrina Ruedy 
Roy Beck 
R. Paul Wadwa 
15NOV2018 
Original protocol.   
1.1 
Jessica Rusnak 
Daniel 
Cherñavvsky  
21NOV2018 
 
1.2 
Sarah Borgman 
Katrina Ruedy 
28NOV2018 
 
2.0 
Mary Oliveri 
Daniel 
Cherñavvsky  
10DEC2018 
Modified study design to include extension phase 
to the experimental group 
2.1  
Katrina Ruedy 
Daniel 
Cherñavvsky 
20Dec2018 
Clarifications added for consistency throughout 
protocol 
2.2 
Jessica Rusnak 
Daniel 
Cherñavvsky 
15Jan2019 
Adding inclusion criteria and clarification 
regarding use of Basal IQ feature; updated 
incorrect section references 
2.3 
Jessica Rusnak 
Katrina Ruedy 
4Feb2019 
Removing and adding questionnaires to be 
completed by participants and parents/guardians 
2.4 
Katrina Ruedy 
Daniel 
Cherñavvsky 
01Apr2019 
Correcting discrepancies in revised questionnaire 
descriptions and other minor clarifications.  
2.5 
Katrina Ruedy 
Marc Breton 
01Jun2019 
Corrections to statistical analysis chapter; update 
of Sponsor name from Daniel Cherñavvsky to 
Marc Breton 
 
29 

 
 
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TABLE OF CONTENTS 
30 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 19 
31 
 Introduction .......................................................................................................................... 19 
32 
 Rationale .............................................................................................................................. 22 
33 
 Potential Risks and Benefits of the Investigational Device ................................................. 22 
34 
1.3.1 Known Potential Risks ................................................................................................... 22 
35 
1.3.1.1 Venipuncture Risks ................................................................................................ 22 
36 
1.3.1.2 Fingerstick Risks .................................................................................................... 22 
37 
1.3.1.3 Subcutaneous Catheter Risks (CGM) .................................................................... 22 
38 
1.3.1.4 Risk of Hypoglycemia ........................................................................................... 23 
39 
1.3.1.5 Risk of Hyperglycemia .......................................................................................... 23 
40 
1.3.1.6 Risk of Device Reuse ............................................................................................. 23 
41 
1.3.1.7 Questionnaire ......................................................................................................... 24 
42 
1.3.1.8 Other Risks ............................................................................................................ 24 
43 
1.3.2 Known Potential Benefits .............................................................................................. 24 
44 
1.3.3 Risk Assessment ............................................................................................................ 24 
45 
 General Considerations ........................................................................................................ 25 
46 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 26 
47 
 Participant Recruitment and Enrollment.............................................................................. 26 
48 
2.1.1 Informed Consent and Authorization Procedures .......................................................... 26 
49 
 Participant Inclusion Criteria ............................................................................................... 27 
50 
 Participant Exclusion Criteria .............................................................................................. 28 
51 
 Screening Procedures ........................................................................................................... 28 
52 
2.4.1 Data Collection and Testing........................................................................................... 28 
53 
CHAPTER 3: RUN-IN PHASE ...................................................................................................................... 30 
54 
 Run-in Phase Overview ....................................................................................................... 30 
55 
 Initiation of CGM ................................................................................................................ 30 
56 
 Initiation of Pump ................................................................................................................ 30 
57 
 Blood Glucose and Ketone Testing ..................................................................................... 31 
58 
 Assessment of Successful Completion of the Run-in Phase................................................ 32 
59 
 Optimization of Insulin Pump Settings ................................................................................ 33 
60 
CHAPTER 4: RANDOMIZATION VISIT ....................................................................................................... 34 
61 

 
 
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 Randomization Visit ............................................................................................................ 34 
62 
4.1.1 HbA1c ............................................................................................................................ 34 
63 
4.1.2 Baseline C-Peptide Assessment ..................................................................................... 34 
64 
4.1.3 Randomization ............................................................................................................... 34 
65 
4.1.4 Questionnaires................................................................................................................ 35 
66 
CHAPTER 5: MAIN STUDY PROCEDURES ................................................................................................. 36 
67 
 Procedures for the CLC Group ............................................................................................ 36 
68 
 Study System Training......................................................................................................... 36 
69 
5.2.1 System Initiation ............................................................................................................ 37 
70 
5.2.2 Home Use of the Study System ..................................................................................... 38 
71 
5.2.3 Study Device Download ................................................................................................ 38 
72 
5.2.4 1-Week Phone Contact .................................................................................................. 38 
73 
5.2.5 2-Week Visit (Training Review and Insulin Pump Optimization) ................................ 38 
74 
 Procedures for the SC Group ............................................................................................... 39 
75 
5.3.1 Study Device Data Download ........................................................................................ 39 
76 
5.3.2 1-Week Phone Contact .................................................................................................. 39 
77 
5.3.3 2-Week Visit (Training Review and Insulin Pump Optimization) ................................ 39 
78 
 Follow-up Visits and Phone Contacts for Both Groups ...................................................... 40 
79 
5.4.1 Follow-up Visits............................................................................................................. 40 
80 
5.4.1.1 Procedures at Follow-up Visits .............................................................................. 40 
81 
5.4.2 Phone Contacts............................................................................................................... 40 
82 
5.4.3 Data from Study Devices ............................................................................................... 41 
83 
5.4.4 16-Week Final First Phase Visit .................................................................................... 41 
84 
 Early Termination Visit (If Applicable) .............................................................................. 41 
85 
 Unscheduled Visits .............................................................................................................. 41 
86 
 Participant Access to Study Device at Study Closure ......................................................... 41 
87 
CHAPTER 6: EXTENSION PHASE PROCEDURES ....................................................................................... 42 
88 
 Closed Loop Control Participants ........................................................................................ 42 
89 
 SC Group Participants ......................................................................................................... 42 
90 
 Early Termination Visit (If Applicable) .............................................................................. 43 
91 
 Unscheduled Visits .............................................................................................................. 43 
92 
 Participant Access to Study Device at Study Closure ......................................................... 43 
93 

 
 
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CHAPTER 7: STUDY DEVICES .................................................................................................................... 44 
94 
 Description of the Investigational Device ........................................................................... 44 
95 
7.1.1 Insulin Pump .................................................................................................................. 44 
96 
7.1.2 Continuous Glucose Monitoring .................................................................................... 44 
97 
7.1.3 Blood Glucose Meter and Strips .................................................................................... 44 
98 
7.1.4 Ketone Meter and Strips ................................................................................................ 44 
99 
7.1.5 Study Device Accountability Procedures ...................................................................... 44 
100 
7.1.6 Blood Ketone Testing .................................................................................................... 44 
101 
 Safety Measures ................................................................................................................... 44 
102 
7.2.1 CGM Calibration ........................................................................................................... 44 
103 
7.2.2 System Failure ............................................................................................................... 45 
104 
7.2.3 Hypoglycemia Threshold Alert and Safety Protocol ..................................................... 45 
105 
7.2.4 Hyperglycemia Threshold Alert and Safety Protocol .................................................... 45 
106 
CHAPTER 8: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 47 
107 
 Laboratory Testing ............................................................................................................... 47 
108 
8.1.1 Comprehensive Metabolic Panel (CMP) ....................................................................... 47 
109 
8.1.2 HbA1c: ........................................................................................................................... 47 
110 
8.1.3 Urine Pregnancy: ........................................................................................................... 47 
111 
8.1.4 C-peptide and Glucose ................................................................................................... 47 
112 
 Questionnaires ..................................................................................................................... 47 
113 
8.2.1 Clarke’s Hypoglycemia Awareness Scale – Child and Parent ...................................... 48 
114 
8.2.2 Hypoglycemia Fear Survey (HFS-II)/Low Blood Sugar Survey – 
115 
Child and Parent ...................................................................................................................... 48 
116 
8.2.3 Problem Areas In Diabetes Survey (PAID) – Child and Parent .................................... 48 
117 
8.2.4 PedsQL Diabetes Module – Child and Parent ............................................................... 48 
118 
8.2.5 INSPIRE Survey – Child and Parent ............................................................................. 49 
119 
8.2.6 Pittsburgh Sleep Quality Index (PSQI) – Parent............................................................ 49 
120 
8.2.7 System Usability Scale (SUS) – Closed-Loop participants only ................................... 49 
121 
CHAPTER 9: ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES .............................................. 50 
122 
 Adverse Events .................................................................................................................... 50 
123 
9.1.1 Definitions...................................................................................................................... 50 
124 
9.1.2 Reportable Adverse Events ............................................................................................ 51 
125 
9.1.2.1 Hypoglycemic Events ............................................................................................ 51 
126 

 
 
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9.1.2.2 Hyperglycemic Events/Diabetic Ketoacidosis ....................................................... 51 
127 
9.1.3 Relationship of Adverse Event to Study Device............................................................ 52 
128 
9.1.4 Intensity of Adverse Event............................................................................................. 52 
129 
9.1.5 Coding of Adverse Events ............................................................................................. 53 
130 
9.1.6 Outcome of Adverse Event ............................................................................................ 53 
131 
 Reportable Device Issues ..................................................................................................... 54 
132 
 Pregnancy Reporting............................................................................................................ 54 
133 
 Timing of Event Reporting .................................................................................................. 54 
134 
 Stopping Criteria .................................................................................................................. 55 
135 
9.5.1 Participant Discontinuation of Study Device ................................................................. 55 
136 
9.5.2 Criteria for Suspending or Stopping Overall Study ....................................................... 55 
137 
 Independent Safety Oversight .............................................................................................. 55 
138 
 Risks..................................................................................................................................... 56 
139 
CHAPTER 10: MISCELLANEOUS CONSIDERATIONS ................................................................................. 57 
140 
 Drugs Used as Part of the Protocol .................................................................................... 57 
141 
 Prohibited Medications, Treatments, and Procedures ....................................................... 57 
142 
 Participant Withdrawal ...................................................................................................... 57 
143 
 Confidentiality ................................................................................................................... 57 
144 
CHAPTER 11: STATISTICAL CONSIDERATION ......................................................................................... 58 
145 
 Statistical and Analytical Plans.......................................................................................... 58 
146 
 Statistical Hypotheses ........................................................................................................ 58 
147 
 Sample Size........................................................................................................................ 58 
148 
 Outcome Measures ............................................................................................................ 59 
149 
11.4.1 Primary Efficacy Endpoint .......................................................................................... 59 
150 
11.4.2 Secondary Efficacy Endpoints ..................................................................................... 59 
151 
11.4.2.1 Secondary Efficacy Endpoints Included in Hierarchical Analysis ...................... 59 
152 
11.4.2.2 Other Secondary Efficacy Endpoints ................................................................... 59 
153 
11.4.2.3 Safety Analyses ..................................................... Error! Bookmark not defined. 
154 
11.4.3 CGM Metrics Calculations .......................................................................................... 60 
155 
 Analysis Datasets and Sensitivity Analyses ...................................................................... 61 
156 
11.5.1 Per Protocol Analyses .................................................................................................. 61 
157 
11.5.2 Other Sensitivity Analyses ........................................................................................... 61 
158 
 Analysis of the Primary Efficacy Endpoint ....................................................................... 62 
159 

 
 
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 Analysis of the Secondary Endpoints ................................................................................ 62 
160 
11.7.1 Hierarchical Analyses .................................................................................................. 62 
161 
11.7.2 Other Endpoint Analyses ............................................................................................. 63 
162 
 Safety Analyses.................................................................................................................. 64 
163 
 Intervention Adherence...................................................................................................... 65 
164 
 Adherence and Retention Analyses ................................................................................. 66 
165 
 Baseline Descriptive Statistics ......................................................................................... 66 
166 
 Device Issues ................................................................................................................... 66 
167 
 Planned Interim Analyses ................................................................................................ 67 
168 
 Subgroup Analyses .......................................................................................................... 67 
169 
 Multiple Comparison/Multiplicity ................................................................................... 68 
170 
 Exploratory Analyses ....................................................................................................... 68 
171 
CHAPTER 12: DATA COLLECTION AND MONITORING ............................................................................ 69 
172 
 Case Report Forms and Device Data ................................................................................. 69 
173 
 Study Records Retention ................................................................................................... 69 
174 
 Quality Assurance and Monitoring .................................................................................... 69 
175 
 Protocol Deviations............................................................................................................ 70 
176 
CHAPTER 13: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 71 
177 
 Ethical Standard ................................................................................................................. 71 
178 
 Institutional Review Boards............................................................................................... 71 
179 
 Informed Consent Process ................................................................................................. 71 
180 
13.3.1 Consent Procedures and Documentation ..................................................................... 71 
181 
13.3.2 Participant and Data Confidentiality ............................................................................ 71 
182 
CHAPTER 14: REFERENCES ....................................................................................................................... 73 
183 
184 

 
 
 
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LIST OF ABBREVIATIONS 
185 
ABBREVIATION 
DEFINITION 
AP 
Artificial Pancreas 
BG 
Blood Glucose 
BT/BTLE 
Bluetooth, Bluetooth low energy 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring System  
CLC 
Closed-Loop Control 
CSII 
Continuous Subcutaneous Insulin Injection 
CTR 
Control-to-Range 
DiAs 
Diabetes Assistant 
DKA 
Diabetic Ketoacidosis 
EC 
European Commission 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ID 
Identification 
iDCL 
International Diabetes Closed Loop 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
IQR 
Interquartile Range 
JDRF 
Juvenile Diabetes Research Foundation 
LGS 
Low Glucose Suspend 
PLGS 
Predictive Low Glucose Suspend 
POC 
Point-of-Care 
QA 
Quality Assurance 
QC 
Quality Control 
RBM 
Risk-Based Monitoring 
RCT 
Randomized Control Trial 
SC 
Standard of Care group 
SD 
Standard Deviation 
TDD 
Total Daily Dose 
UI 
User Interface 
 
186 
187 

 
 
 
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Signature Page 
188 
The International Diabetes Closed Loop (iDCL) trial:  
189 
Clinical Acceptance of the Artificial Pancreas in Pediatrics 
190 
A Study of t:slim X2 with Control-IQ Technology 
191 
Protocol Identifying Number: DCLP5 Pediatrics 
192 
IND/IDE Sponsor: University of Virginia 
193 
Version Number: v.2.5 
194 
24MAY2019 
195 
 
Protocol Chair 
 
Name, Institution 
R. Paul Wadwa, M.D./ University of Colorado – Barbara Davis Center 
Signature/Date 
 
 
Sponsor (IDE Holder) 
 
Name/Institution 
Marc Breton/ University of Virginia 
Signature/Date 
 
 
Coordinating Center Director 
 
Name, Institution 
Katrina J. Ruedy, MSPH; Jaeb Center for Health Research 
Signature/Date 
 
 
Medical Monitor 
 
Name, Institution 
Roy Beck, MD, PhD; Jaeb Center for Health Research 
Signature/Date 
 

 
 
 
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CLINICAL CENTER PRINCIPAL INVESTIGATOR STATEMENT OF 
196 
COMPLIANCE 
197 
Protocol Title: The International Diabetes Closed Loop (iDCL) trial: Clinical Acceptance of 
198 
the Artificial Pancreas in Pediatrics- A Study of t:slim X2 with Control-IQ Technology 
199 
Protocol Version/Date: v2.5 / 24MAY2019 
200 
I have read the protocol specified above.  In my formal capacity as a Clinical Center Principal 
201 
Investigator, my duties include ensuring the safety of the study participants enrolled under my 
202 
supervision and providing the Jaeb Center for Health Research, with complete and timely 
203 
information, as outlined in the protocol.  It is understood that all information pertaining to the 
204 
study will be held strictly confidential and that this confidentiality requirement applies to all 
205 
study staff at this clinical center. 
206 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
207 
required by the following: United States (US) Code of Federal Regulations (CFR) applicable to 
208 
clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 
209 
CFR Part 812). 
210 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
211 
will take place without prior agreement from the sponsor and documented approval from the 
212 
Institutional Review Board (IRB), or other approved Ethics Committee, except where necessary 
213 
to eliminate an immediate hazard(s) to the trial participants. 
214 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
215 
completed Human Participants Protection Training and Good Clinical Practice Training.  
216 
Further, I agree to ensure that all staff members involved in the conduct of this study are 
217 
informed about their obligations in meeting the above commitments. 
218 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
219 
 
dd 
mmm 
yyyy 
220 
Investigator’s Name: ____________________________________ 
221 
Clinical Center Name/Number: _____________________________________ 
222 

 
 
 
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PROTOCOL SUMMARY 
223 
PARTICIPANT AREA 
DESCRIPTION 
Title 
The International Diabetes Closed Loop (iDCL) trial: Clinical Acceptance 
of the Artificial Pancreas in Pediatrics- A study of t:slim X2 with Control-
IQ Technology 
Précis 
A randomized controlled trial of at-home closed loop system vs. standard 
of care (defined as either sensor-augmented pump or any kind of low 
predictive low blood glucose suspend [PLGS; LGS] if participant is 
currently using) in youth age 6 to 13 years old. 
Investigational Device 
t:slim X2 with Control-IQ and Dexcom G6 system 
Objectives 
The objective of the study is to assess efficacy and safety of a closed loop 
control (CLC) system (t:slim X2 with Control-IQ Technology) in a 
randomized controlled trial with partial crossover. 
Study Design 
First phase a 16-week parallel group randomized clinical trial with 3:1 
randomization to intervention with the closed loop system vs. standard of 
care (SC); followed by a 12-week period where the Standard of Care (SC) 
group will transition to use CLC and the experimental arm will extend the 
use of CLC for the same period 
Number of Clinical Centers 
Up to 4 US clinical centers 
Endpoint 
The primary outcome for the first phase is time in target range 70-180 
mg/dL measured by CGM in CLC group vs. SC group over 16 weeks 
The primary outcome for the extension phase is improving time in range 
70-180 mg/dL by CGM when SC (control group) transitions to t:slim X2 
with Control-IQ compared with the same group during the Main Phase.  
Population 
Key Inclusion Criteria 
 Type 1 Diabetes 
 Ages ≥ 6 and ≤ 13 years old 
Key Exclusion Criteria  
 Use of any non-insulin glucose-lowering agents except metformin 
 Actively using any other closed-loop system 
Sample Size 
First phase: Up to 150 screened participants with the goal of randomizing 
100 participants in this 16-week randomized trial. 
Extension phase will consist of a partial crossover: All randomized 
participants  will participate in an extension phase for another 12 weeks 
(total 28 weeks).  The SC group (control group) will crossover to use 
Tandem t:slim X2 with Control-IQ for 12 weeks. The experimental arm 
will continue on the Control-IQ for 12 weeks.   
Treatment Groups 
 Intervention Group: t:slim X2 with Control-IQ Technology and 
Study CGM. 
 Control Group: Standard of care (SC) (defined as either sensor-
augmented pump or any kind of low or predictive low blood glucose 
suspend [PLGS; LGS] if participant is currently using), and study 
CGM 
 All participants will be offered to extend the study for 12 weeks and 
the SC group will use the t:slim X2 with Control-IQ System  after 
the first 16-week phase  
Participant Duration 
16-20 weeks (depending on duration of run-in phase) plus ~12-week 
extension phase  

 
 
 
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PARTICIPANT AREA 
DESCRIPTION 
Protocol Overview/Synopsis 
After consent is signed, eligibility will be assessed.  Eligible participants 
not currently using an insulin pump and Dexcom G4, G5 or Dexcom G6 
CGM with minimum data requirements will initiate a run-in phase of 2 to 
4 weeks that will be customized based on whether the participant is 
already a pump or CGM user.  Participants who skip or successfully 
complete the run-in will be randomly assigned 3:1 to the use of closed-
loop control (CLC group) system using Tandem t:slim X2 with Control-
IQ Technology vs SC for 16 weeks. All participants will be provided the 
option of using t:slim X2 with Control-IQ system in a 12 week Extension 
Phase. [Figure 1] 
 
224 
Figure 1: Study Design: Participants Randomized 3:1 Control-IQ Control (CLC) vs. 
225 
Standard of Care (SC) Groups. Extension phase with partial crossover of SC group 
226 
switching to use Control IQ. 
227 

 
 
 
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SCHEMATIC OF STUDY DESIGN 
228 
 
229 
Figure 2: Schematic of Complete Study Design 
230 
 
 
231 
Screening/Enrollment Visit 

Eligibility assessment and informed consent 

HbA1c from local lab or POC device and central lab sample 

Device download and adherence assessment for current CGM user 
CGM Placement/Training; 
Pump Training in Pump-Naïve Participants 
2-4 Week Run-In with home use of study CGM 
(all participants) and study pump (MDI participants) 
Run-in Review Visit 
Reassess Eligibility 
Optimization of Insulin Pump Settings 
Randomization 
16 weeks 
 
Eligible 
To Skip 
Run-In*? 
No 
Yes 
*Current use of insulin pump and Dexcom G4, G5, or G6 CGM with readings captured on at least 
11 out of the previous 14 days 
Extension Phase for all participants using 
Control IQ 
12 weeks 
End of Study 

 
 
 
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232 
Figure 3:  Schematic of Study Design (Post-Randomization) 
233 
Randomization Visit 
Week 2 Visit 
Refresher training on devices 
Phone Contacts Weeks: 1, 4, 6, 10, 12, 14 
Clinic Visits: Weeks 2, 8, 16  
Study system training and home use 
Training immediately after randomization with 
one week of closed-loop system use at home 
Primary Outcome 
 (16 weeks)  
CLC Group 
SC Group 
One week of closed-loop system use 
at home 
One week of SC at home with study CGM 
and personal or study-provided pump 
One week of SC at home with study CGM 
and personal or study-provided pump 
(2-4 weeks of training with provided 
pump training for pump naïve) 
Week 1 Phone Contact 
System data assessment 
Week 1 Phone Contact 
SC data assessment 
Control Participants 
Study system training and home use 
Extension Phase Phone Contacts: Weeks 17, 19, 21, 25 
Extension Phase Clinic Visits: Weeks 16, 23, 28  
Primary Outcome of Extension Phase (28 weeks) 
Experimental Participants 
Study system home use continued 
Extension Phase Phone Contacts: Weeks 20, 24 
Extension Phase Clinic Visits: Week 28  

 
 
 
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234 
 
235 
 
236 
 
237 
 
238 
 
239 
 
240 
 
241 
 
242 
 
243 
 
244 
 
245 
 
246 
Table 1. Schedule of Study Visits and Procedures (Primary Study Phase) 
 
247 
 
Pre 
Pre 
0 
1w 
2w 
4w 
6w 
8w 
10w 
12w 
14w 
16w 
Visit (V) or Phone (P) 
V 
V 
V 
P 
V 
P 
P 
V 
P 
P 
P 
V 
Comment 
Screen/
Enroll 
Run-in 
Rand 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
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) and blood 
glucose assessment 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (females of 
child-bearing potential) 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
Device Data download(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review diabetes management and 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Questionnaires as defined in 
section 8.2 
 
 
X 
 
 
 
 
 
 
 
 
X 

 
 
 
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Experimental  Group 
20w 
24w 
28w 
Visit (V) or Phone (P) 
P 
P 
V 
Comment 
 
 
 
Eligibility Assessment 
 
 
 
HbA1c (DCA Vantage or similar point of care 
device, or local lab) 
 
 
X 
HbA1c (Central lab) 
 
 
X 
C-peptide (Central lab) and blood glucose 
assessment 
 
 
 
Pregnancy test (females of child-bearing potential) 
 
 
X 
Device Data download(s) 
X 
X 
X 
Review diabetes management and AEs 
X 
X 
X 
Questionnaires as defined in section 8.2 
 
 
X 
Table 2: Schedule of Visits and Procedures (Extension Phase for Experimental Group) 
 
248 

 
 
 
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249 
 
250 
 
251 
 
252 
 
253 
 
254 
 
255 
 
256 
 
257 
 
258 
 
259 
 
260 
Table 3: Schedule of Visits and Procedures (Extension Phase for SC Group) 
261 
 
262 
 
263 
Control Group 
17w 
19w 
21w 
23w 
25w 
28w 
Visit (V) or Phone (P) 
P 
P 
P 
V 
P 
V 
Comment 
 
 
 
 
 
 
Eligibility Assessment 
 
 
 
 
 
 
HbA1c (DCA Vantage or similar point of care device, or local 
lab) 
 
 
 
 
 
X 
HbA1c (Central lab) 
 
 
 
 
 
X 
C-peptide (Central lab) and blood glucose assessment 
 
 
 
 
 
 
Pregnancy test (females of child-bearing potential) 
 
 
 
X 
 
X 
Device Data download(s) 
X 
X 
X 
X 
X 
X 
Review diabetes management and AEs 
X 
X 
X 
X 
X 
X 
Questionnaires as defined in section 8.2 
 
 
 
 
 
X 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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Chapter 1: Background Information 
264 
 Introduction 
265 
The Tandem X2 insulin pump with Control-IQ Technology is a third-generation closed-loop 
266 
control (CLC) system retaining the same control algorithm that was initially tested by UVA’s DiAs 
267 
system and then implemented in the inControl system (TypeZero Technologies, Inc.). DiAs is 
268 
described in 13 IDEs (see IDEs 1-12 and 14 in the list below) and inControl is described on the 
269 
rest of IDEs mentioned below (i.e.in IDEs G160097, G160181, G150240, G140169/S010). For 
270 
complete algorithmic and clinical background, we refer to these IDEs and to a number of scientific 
271 
publications that describe glycemic control outcomes and clinical impressions from the use of 
272 
these systems (see list of 25 peer-reviewed papers and scientific presentations under Bibliography). 
273 
Overall, this control algorithm has been implemented in two mobile platforms (DiAs and 
274 
inControl) and has been tested in 30 clinical trials by 450 adults and children with type 1 diabetes 
275 
for over 350,000 hours of use to date in the U.S. and overseas.  
276 
As described in the Background, this project is a result from a sequence of clinical trials that have 
277 
tested extensively the control system and in several centers in the U.S. and overseas. The following 
278 
21 IDEs reflect this progress: 
279 
1. IDE #G110095: Feasibility study of closed loop control in type 1 diabetes using heart rate 
280 
monitoring as an exercise marker, approved 10/08/2011; 
281 
2. IDE #G120032: Early feasibility (pilot) study of outpatient control-to-range; 3/2/2012; 
282 
3. IDE #G120210: Early feasibility study 2 of outpatient control-to-range; 10/12/2012; 
283 
4. IDE #G130118: DiAs control-to-range nocturnal closed-loop camp study; 6/19/2013;  
284 
5. IDE #G130121: Optimizing closed-loop control of type 1 diabetes mellitus in adolescents; 
285 
6/19/2013; 
286 
6. IDE# G130142:  Closed loop control in adolescents using heart rate as exercise indicator; 
287 
7/16/13; 
288 
7. IDE #G130143: Early feasibility study of adaptive advisory/automated (AAA) control of 
289 
type 1 diabetes; 7/19/2013; 
290 
8. IDE #G140066:  Full day and night closed-loop with DiAs platform; 5/9/14. 
291 
9. IDE #G140068: Unified Safety System (USS) Virginia Closed Loop versus sensor 
292 
augmented pump therapy overnight in type 1 diabetes; 5/14/2014; 
293 
10. IDE #G140089: Outpatient control-to-range: Safety and efficacy with day-and-night in-home 
294 
use; 6/6/2014; 
295 
11. IDE #G140169: Unified Safety System (USS) Virginia Closed-Loop versus Sensor 
296 
Augmented Pump (SAP) therapy for hypoglycemia reduction in type 1 diabetes; 10/3/2014. 
297 
12. IDE #G150221: Reducing risks and improving glucose control during extended exercise in 
298 
youth with T1DM: The AP Ski Camp; 11/09/2015;  
299 

 
 
 
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13. IDE #G150240: Project Nightlight: Efficacy and system acceptance of dinner/night vs. 24 hr 
300 
closed loop control; 11/12/2015; 
301 
14. IDE #G160047: Closed-loop in young children 5-8 years old using DiAs platform; 
302 
03/29/2016;  
303 
15. IDE #G160097: Clinical Acceptance of the Artificial Pancreas: the International Diabetes 
304 
Closed-Loop (iDCL) Trial/Research Site Training Protocol; 06/03/16. 
305 
16. IDE#G160181: PROTOCOL 1 for “Clinical Acceptance of the Artificial Pancreas: The 
306 
International Diabetes Closed Loop (iDCL) Trial; 09/21/16 
307 
17. IDE#G170255: Protocol 3 for “Pilot Trial of t:slim X2 with Control-IQ 
308 
Technology”;11/16/17 and IDE#G170255/S001 Protocol 3 for “Training Study of t:slim X2 
309 
with Control-IQ Technology”; 11/16/17 
310 
18. IDE#G170267: “Real-Time Monitoring and Glucose Control During Winter-Sport Exercise 
311 
in Youth with Type 1 Diabetes: The AP Ski Camp Continued”; 11/21/17 
312 
19. IDE#G150240/S008: A long-term home use study, enrolling 18-70 years old TID 
313 
participants since January 2018; it is anticipated that this study will be completed April 2019.  
314 
20. IDE#G170255: A pilot study of 5 adult subjects completed in December 2017.   
315 
21. IDE#G170267: Three 48-hour winter ski camps trial T1D participants; one site enrolled 13-
316 
18 years old participants in January 2018. The other two sites enrolled participants aged 6-12 
317 
years old. At the conclusion of these ski camps, subjects continued with the study device for 
318 
72 hours use at home (March & April 2018). 
319 
In the G170255 pilot study (mean age 52.8 yrs; 3F/2M, mean A1c 6.5%), the system was 
320 
challenged with a variety of scenarios including: Pump disconnection, CGM sensor removal 
321 
without stopping session, CGM sensor change, Basal Rate change, Cartridge Change, Extended 
322 
Bolus, Calibration at non-ideal conditions, Stopping Control-IQ, Reset Sleep Time, Restaurant 
323 
Meals and Exercise (treadmill/walk). The study demonstrated excellent connectivity with 98% 
324 
time in closed-loop control and 94%-time CGM is available during 196 hours of use. [28] 
325 
The results of the home portion of the IDE#G170267/ski camp trial (Table 5) were as follow: The 
326 
Control-IQ significantly improved time in target range 70-180 mg/dL (71.0±6.6 vs. 52.8±13.5%; 
327 
p=0.001) and mean sensor glucose (153.6±13.5 vs. 180.2±23.1 mg/dL; p=0.003) without 
328 
increasing hypoglycemia time <70 mg/dL (1.7 [1.3-2.1] vs. 0.9 [0.3-2.7]%; ns). The HCL system 
329 
was active for 94.4% of the study period. Subjects reported that use of the system was associated 
330 
with less time thinking about diabetes, decreased worry about blood sugars, and decreased burden 
331 
in managing diabetes. [33] 
332 
No AE or SAE happened during these trials related to the equipment used. 
333 
 
 
334 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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METRIC (COMPUTED DURING CLOSED-LOOP USE) 
OVERALL 
DAYTIME 
NIGHTTIME 
Mean glucose (mg/dL) 
129 
135 
121 
Coefficient of variation (median) 
27% 
27% 
21% 
% below 54 mg/dL (median) 
0.7% 
0.0% 
0.0% 
% below 60 mg/dL (median) 
1.1% 
2.0% 
0.0% 
% below 70 mg/dL (median) 
2.9% 
4.1% 
1.0% 
Percent in range 70-180 mg/dL (mean) 
87% 
82% 
94% 
% above 180 mg/dL (median) 
5% 
8% 
6% 
% above 250 mg/dL (median) 
0% 
0% 
0% 
% above 300 mg/dL (median) 
0% 
0% 
0% 
Table 4. Pilot Study results based on time in closed-loop 
335 
 
336 
Table 5. Glycemic Outcomes Measured by CGM: Ski camp and home use trial 
337 
Closed-Loop Control System 
338 
The Closed-Loop Control System contained in t-slim X2 with Control-IQ Technology is described 
339 
in Master File MAF-2032/A008. Control-IQ Technology is derived from inControl previously 
340 
described in IDE# G160097, G160181, G150240 and G140169/S010. The CLC is an “artificial 
341 
pancreas” (AP) application that uses advanced closed loop control algorithms to automatically 
342 
manage blood glucose levels for people with Type 1 Diabetes. The system modulates insulin to 
343 
keep blood glucose in a targeted range. The system components include the t:slim X2 with 
344 
Control-IQ Technology and the Dexcom CGM G6. 
345 
 
OVERALL 
DAYTIME [7AM - 11 PM] 
NIGHTIME [11PM - 7AM] 
 
Control-
IQ 
SAP 
p-
value 
Control-IQ 
SAP 
p-
value 
Control-IQ 
SAP 
p-
value 
70 - 180 mg/dL 
(%) 
71.0 ± 6.6 
52.8 ± 13.5 
0.001 
69.1 ± 10.1 
54.4 ± 14.2 
0.010 
74.9 ± 10.1 
49.6 ± 18.8 
0.001 
< 50 mg/dL (%) 
0 [0-0.1] 
0 [0-0.4] 
ns 
0 [0-0] 
0 [0-0.6] 
ns 
0 [0-0] 
0 [0-0] 
ns 
< 54 mg/dL (%) 
0.2 [0-0.5] 
0.2 [0-0.6] 
ns 
0 [0-0.4] 
0.3 [0-0.9] 
ns 
0 [0-0] 
0 [0-0] 
ns 
< 60 mg/dL (%) 
0.7 [0.2-1] 
0.5 [0-0.9] 
ns 
0.3 [0-1.1] 
0.7 [0-1.3] 
ns 
0 [0-0.2] 
0 [0-0] 
ns 
< 70 mg/dL (%) 
1.7 [1.3-
2.1] 
0.9 [0.3-2.7] 
ns 
1.6 [0.7-2.6] 
1.4 [0.5-3.4] 
ns 
0.7 [0-2.6] 
0 [0-0] 
0.190 
> 180 mg/dL (%) 
26.7 ± 7.2 
44.7 ± 13.8 
0.001 
28.1 ± 11.1 
42 ± 14.4 
0.017 
23.8 ± 9.9 
49.9 ± 19.3 
0.001 
> 250 mg/dL (%) 
7.2 ± 4.5 
16.1 ± 10.3 
0.015 
8.3 ± 6.4 
14.8 ± 11 
0.097 
5.2 ± 8 
18.7 ± 12.9 
0.007 
> 300 mg/dL (%) 
2.9 ± 2.7 
5.3 ± 3.9 
0.102 
3.5 ± 3.9 
4.4 ± 4.5 
ns 
1.8 ± 4 
7.1 ± 6.5 
0.030 
Mean glucose 
(mg/dL) 
153.6 ± 
13.5 
180.2 ± 23.1 
0.003 
157 ± 20.2 
175.7 ± 24.7 
0.064 
147.1 ± 
16.4 
188.8 ± 
30.2 
0.001 
Coefficient of 
Variation (%) 
36.6 ± 4.9 
36.5 ± 5.4 
ns 
35.7 ± 5.3 
36.8 ± 6.1 
0.185 
33.4 ± 7.1 
32.9 ± 6.4 
ns 
Insulin use (U/day) 
33.2 ± 
15.5 
27.8 ± 12.3 
ns 
26.4 ± 12.8 
22.3 ± 9.6 
ns 
6.8 ± 2.8 
5.5 ± 3 
ns 
CHO treatment (g) 
15.5 ± 
16.9 
35.5 ± 55.5 
ns 
14.7 ± 16.7 
34.5 ± 55.7 
ns 
0.9 ± 2 
1.2 ± 2.6 
ns 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
PAGE 22 OF 76 
 
 
346 
Figure 4. t:slim X2 with Control-IQ and Dexcom G6 system 
347 
 Rationale 
348 
The objective of this randomized clinical trial is to assess the efficacy and safety of the Control-
349 
IQ closed loop system over a 16-week period compared with standard of care. In addition, the data 
350 
from this trial may be used for subsequent PMA application for this system. 
351 
The 12-week extension phase will allow for additional exposure time to the Tandem t:slim X2 with Control-
352 
IQ Technology and evaluation of the SC arm when crossover to use Control IQ for 12-week period.  
353 
 Potential Risks and Benefits of the Investigational Device 
354 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are 
355 
handled to minimize this risk.  Hypoglycemia, hyperglycemia and ketone formation are always a 
356 
risk in participants with type 1 diabetes and participants will be monitored for these events. 
357 
 
358 
1.3.1.1 Venipuncture Risks 
359 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws can 
360 
cause some common reactions like pain, bruising, or redness at the sampling site.  Less common 
361 
reactions include bleeding from the sampling site, formation of a small blood clot or swelling of 
362 
the vein and surrounding tissues, and fainting. 
363 
1.3.1.2 Fingerstick Risks 
364 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
365 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital laboratory 
366 
tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount of bleeding 
367 
under the skin will produce a bruise.  A small scar may persist for several weeks.  The risk of local 
368 
infection is less than 1 in 1000.  This should not be a significant contributor to risks in this study 
369 
as fingersticks are part of the usual care for people with diabetes. 
370 
1.3.1.3 Subcutaneous Catheter Risks (CGM) 
371 
Participants using the CGM will be at low risk for developing a local skin infection at the site of 
372 
the sensor needle placement.  If a catheter is left under the skin for more than 24 hours, it is possible 
373 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
PAGE 23 OF 76 
 
to get an infection where it goes into the skin, with swelling, redness and pain.  There may be 
374 
bleeding where the catheter is put in and bleeding under the skin causes a bruise (1 in 10 risk). 
375 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
376 
leave a small portion of the sensor under the skin that may cause redness, swelling or pain at the 
377 
insertion site.  The participant should be further instructed to notify the study coordinator 
378 
immediately if this occurs. 
379 
1.3.1.4 Risk of Hypoglycemia 
380 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a low 
381 
blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and possibly less 
382 
than it would be as part of daily living.  Symptoms of hypoglycemia can include sweating, 
383 
jitteriness, and not feeling well.  Just as at home, there is the possibility of fainting or seizures 
384 
(convulsions) and that for a few days the participant may not be as aware of symptoms of 
385 
hypoglycemia.  A CGM functioning poorly and significantly over-reading glucose values could 
386 
lead to inappropriate insulin delivery. 
387 
1.3.1.5 Risk of Hyperglycemia 
388 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
389 
extended period or if the pump or infusion set is not working properly.  A CGM functioning poorly 
390 
and significantly under-reading glucose values could lead to inappropriate suspension of insulin 
391 
delivery. 
392 
1.3.1.6 Risk of Device Reuse 
393 
The study CGM system is labeled for single use only. The sensor (the component of the system 
394 
that enters the skin) will be single use only. The receiver, if used, is a hand-held device. The 
395 
transmitter and receiver may be reused during the study after cleaning the device using a hospital-
396 
approved cleaning procedure. The transmitter is attached to the sensor but does not enter the skin. 
397 
Participants will be informed that FDA or relevant national authorities have approved these devices 
398 
for single use and that by using them among multiple patients, bloodborne pathogens (i.e. Hepatitis 
399 
B) may be spread through the use of multiple users. 
400 
The study insulin pump is labeled for single-patient use. During the study, this device may be 
401 
reused after cleaning adhering to a hospital-approved cleaning procedure. All infusion set 
402 
equipment will be single patient use only (infusion set insertion kits, tubing, cartridges etc.)  
403 
Participants will be informed that FDA or relevant national authorities typically approve the insulin 
404 
pump device for single use and that by using them among multiple patients, bloodborne pathogens 
405 
(i.e. Hepatitis B) may be spread through the use of multiple users. 
406 
The study blood glucose meter and blood ketone meter are labeled for single-patient use. 
407 
During the study, only one person can use each device as there are rare risks that bloodborne 
408 
pathogens (i.e. Hepatitis B) may be spread through the use of multiple users. 
409 

 
 
 
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1.3.1.7 Questionnaire 
410 
As part of the study, participants (parent and child) will complete questionnaires which include 
411 
questions about their private attitudes, feelings and behavior related to the investigational 
412 
equipment as well as managing diabetes.  It is possible that some people may find these 
413 
questionnaires to be mildly upsetting. Similar questionnaires have been used in previous research 
414 
and these types of reactions have been uncommon. 
415 
1.3.1.8 Other Risks 
416 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
417 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
418 
If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, 
419 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
420 
medication may be required. 
421 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump infusion 
422 
sites are inserted under the skin.  It is possible that any part that is inserted under the skin may 
423 
cause an infection.  These occur very infrequently, but, if an infection was to occur, oral and/or 
424 
topical antibiotics can be used.  The risk of skin problems could be greater if you use a sensor for 
425 
longer than it is supposed to be used.  Therefore, participants (and parents) will be carefully 
426 
instructed about proper use of the sensor. 
427 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be collected 
428 
for the study as measures of diabetes self-management behaviors.  Some people 
429 
may be uncomfortable with the researchers' having such detailed information about their daily 
430 
diabetes habits. 
431 
 
432 
One purpose of this research is to reduce the frequency of hypoglycemia and severe hypoglycemic 
433 
events. Hypoglycemia is the number one fear of many individuals and families with someone who 
434 
has type 1 diabetes and this fear often prevents optimal glycemic control. 
435 
It is expected that this protocol will yield increased knowledge about using an automated 
436 
closed-loop system to control the glucose level and is intended to develop data to support a future 
437 
PMA-application. The individual participant may not benefit from study participation. 
438 
 
439 
Based on the facts that (1) children and adolescents with diabetes experience mild hypoglycemia 
440 
and hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
441 
intervention involves periodic automated insulin dosing that may reduce the likelihood of 
442 
hypoglycemia, and periodic automated attenuation of insulin delivery that may reduce the 
443 
likelihood of hyperglycemia, (3) if any, hypo and/or hyperglycemia occur, mitigations are in place, 
444 
and have been tested in prior studies using the investigational device system in the home setting, 
445 
that limit the likelihood of excessive insulin dosing or prolonged withdrawal of insulin, and (4) 
446 
rapid reversal of hypoglycemia and hyperglycemia can be achieved, it is the assessment of the 
447 
investigators that this protocol falls under DHHS 46.405 which is a minor increase over minimal 
448 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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risk. In addition, it is the belief of the investigators that this study also presents prospect of direct 
449 
benefit to the participants and general benefit to others with diabetes. 
450 
 General Considerations 
451 
The study is being conducted in compliance with the policies described in the study policies 
452 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
453 
protocol described herein, and with the standards of Good Clinical Practice (GCP). 
454 
Whenever possible, data will be directly collected in electronic case report forms, which will be 
455 
considered the source data. 
456 
There is no restriction on the number of participants to be enrolled by each clinical center toward 
457 
the overall recruitment goal. 
458 
The protocol is considered a significant risk device study, due to the fact that the closed loop 
459 
system is experimental.  Therefore, an investigational device exemption (IDE) from the U.S. Food 
460 
and Drug Administration (FDA) is required to conduct the study. 
461 

 
 
 
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Chapter 2: Study Enrollment and Screening 
462 
 Participant Recruitment and Enrollment 
463 
Enrollment will proceed with the goal of having 100 participants randomized for the first 16-week 
464 
phase of this trial.  A maximum of 150 individuals may be enrolled into screening for the study in 
465 
order to achieve this goal considering an approximately 30% withdrawal and screen failure rate. 
466 
For the extension phase, all 100 participants that were randomized and completed the main study 
467 
will complete the 12-week extension phase. The participants randomized to SC in the main study 
468 
will crossover to use t:slim x2 with Control IQ. The interventional arm in the main study will 
469 
continue using the Control IQ system for 12 additional weeks. 
470 
Study participants will be recruited from up to 4 clinical centers in the United States without regard 
471 
to gender, race, or ethnicity.  There is no restriction on the number of participants to be enrolled 
472 
by each clinical center toward the overall recruitment goal. 
473 
The study team will make every effort to have the following minimum numbers of participants 
474 
complete the trial in the specified subgroups at the time of enrollment: 
475 
 At least one-third of participants with HbA1c ≥8.0% and one-third of participants with HbA1c 
476 
<7.9% 
477 
 At least one-third of participants in the age range 6-10 and one-third of participants 11-13 years 
478 
old 
479 
 At least 20% of participants who are on multiple daily injections (MDI) rather than pump 
480 
 At least 20% of  participants who are CGM-naïve (defined as not using a CGM in the prior 3 
481 
months) 
482 
 
483 
Potential eligibility may be assessed as part of a routine-care examination.  Before completing any 
484 
procedures or collecting any data that are not part of usual care, written informed consent and child 
485 
assent will be obtained. 
486 
A parent/legal guardian (referred to subsequently as “parent”) will be provided with the Informed 
487 
Consent Form to read and will be given the opportunity to ask questions.  Potential participants 
488 
meeting the IRB’s minimum age of assent will be given a Child Assent Form to read and discuss 
489 
with his/her parents and study personnel.  If the parent and child agree to participate, the Informed 
490 
Consent Form and Child Assent Form (if applicable) will be signed.  A copy of the consent form 
491 
will be provided to the participant and his/her parent and another copy will be added to the 
492 
participant’s study record. 
493 
As part of the informed consent process, each participant and/or parent/legal guardian will be asked 
494 
to sign an authorization for release of personal information.  The investigator, or his or her 
495 
designee, will review the study-specific information that will be collected and to whom that 
496 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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information will be disclosed.  After speaking with the participant, questions will be answered 
497 
about the details regarding authorization. 
498 
A participant is considered enrolled when the informed consent form and child assent (if 
499 
applicable) has been signed. 
500 
 Participant Inclusion Criteria 
501 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate in 
502 
the study. 
503 
1. Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year 
504 
and using insulin for at least 6 months  
505 
2. Familiarity and use of a carbohydrate ratio for meal boluses. 
506 
3. Age ≥ 6 and ≤ 13 years old 
507 
4. Weight ≥25 kg and ≤140 kg 
508 
5. For females, not currently known to be pregnant 
509 
If female and sexually active, must agree to use a form of contraception to prevent pregnancy 
510 
while a participant in the study.  A negative serum or urine pregnancy test will be required for 
511 
all females of child-bearing potential. Participants who become pregnant will be discontinued 
512 
from the study. Also, participants who during the study develop and express the intention to 
513 
become pregnant within the timespan of the study will be discontinued. 
514 
6. Living with one or more parent/legal guardian knowledgeable about emergency procedures for 
515 
severe hypoglycemia and able to contact emergency services and study staff. 
516 
7. Willingness to suspend use of any personal closed loop system that they use at home for the 
517 
duration of the clinical trial once the study CGM is in use 
518 
8. Investigator has confidence that the participant can successfully operate all study devices and 
519 
is capable of adhering to the protocol 
520 
9. Willingness to switch to lispro (Humalog) or aspart (Novolog) if not using already, and to use 
521 
no other insulin besides lispro (Humalog) or aspart (Novolog) during the study for participants 
522 
using the t:slim X2. This includes: 
523 
o Participants randomized to Control IQ 
524 
o Participants on the SC group on MDI treatment that will be provided a Tandem 
525 
pump to switch to CSII 
526 
o Participates that are already in CSII randomized to SC during the extension phase 
527 
when transition to Control IQ  
528 
10. Total daily insulin dose (TDD) at least 10 U/day 
529 
11. Willingness not to start any new non-insulin glucose-lowering agent during the course of the 
530 
trial (see section 2.3) 
531 

 
 
 
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12. Participant and parent(s)/guardian(s) willingness to participate in all training sessions as 
532 
directed by study staff.  
533 
 Participant Exclusion Criteria 
534 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from study 
535 
participation. 
536 
1. Concurrent use of any non-insulin glucose-lowering agent other than metformin (including 
537 
GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas). 
538 
2. Hemophilia or any other bleeding disorder 
539 
3. A condition, which in the opinion of the investigator or designee, would put the participant or 
540 
study at risk (specified on the study procedure manual) 
541 
4. Participation in another pharmaceutical or device trial at the time of enrollment or during the 
542 
study 
543 
5. Employed by, or having immediate family members employed by Tandem Diabetes Care, Inc., 
544 
or having a direct supervisor at place of employment who is also directly involved in 
545 
conducting the clinical trial (as a study investigator, coordinator, etc.); or having a first-degree 
546 
relative who is directly involved in conducting the clinical trial 
547 
 Screening Procedures 
548 
After informed consent has been signed, a potential participant will be evaluated for study 
549 
eligibility through the elicitation of a medical history, performance of a physical examination 
550 
by study personnel and local laboratory testing if needed to screen for exclusionary medical 
551 
conditions. 
552 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
553 
date per investigator discretion. 
554 
 
555 
A standard physical exam (including vital signs and height and weight measurements) will be 
556 
performed by the study investigator or designee (a physician, research physician, resident, fellow, 
557 
nurse practitioner or a physician assistant). 
558 
The following procedures will be performed/data collected/eligibility criteria checked and 
559 
documented: 
560 
 Inclusion and exclusion criteria assessed 
561 
 Demographics (date of birth, sex, race and ethnicity) 
562 
 Contact information (retained at the clinical center and not entered into study database) 
563 
 Medical history 
564 
 Concomitant medications 
565 

 
 
 
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 Physical examination to include: 
566 
 Weight, height 
567 
 Vital signs including measurement of blood pressure and pulse 
568 
 Comprehensive Metabolic Panel to assess kidney and liver functioning 
569 
Blood draw for:  
570 
 HbA1c level measured using the DCA Vantage or comparable point of care device or local lab 
571 
o Measurement performed as part of usual clinical care prior to obtaining informed consent 
572 
for participation in the trial may be used 
573 
o Measurement must be made within two weeks prior to enrollment 
574 
o Sample to be sent to a central lab 
575 
 Urine or serum pregnancy test for all women of child-bearing potential and sexually active. 
576 
Screening procedures will last approximately 1-2 hours. 
577 

 
 
 
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Chapter 3: Run-In Phase 
578 
 Run-in Phase Overview 
579 
This phase may begin immediately after enrollment is complete or may be deferred for a maximum 
580 
of 28 days. The purpose of this run-in phase is to 1) assess compliance with study procedures, 2) 
581 
to introduce the study CGM to study participants without current use of a CGM and 3) to introduce 
582 
an insulin pump to participants who have not previously used an insulin pump. 
583 
Participants who currently use an insulin pump and a Dexcom G4, G5 or G6 with CGM data 
584 
captured on at least 11 out of the previous 14 days prior to the time of enrollment can skip the run-
585 
in phase. If a participant is using a pump with a Low Glucose Suspend (LGS) feature, they will be 
586 
allowed to continue using this feature. Participants who do not currently use a Dexcom G4, G5, or 
587 
G6 CGM will be required to participate in the CGM run-in phase.  Participants currently using a 
588 
Dexcom G4, G5, or G6 CGM with CGM readings captured on fewer than 11 out of the previous 
589 
14 days prior to time of enrollment will be required to participate in the CGM run-in phase.  During 
590 
the CGM run-in phase, participants will use the study CGM for a minimum of 11 days with a goal 
591 
of at least 14 days.  
592 
All participants and their parent(s) will receive training on the study CGM as detailed below. This 
593 
will be an unblinded use of the study CGM.  
594 
Additionally, MDI and study pump naïve participants will participate in a pump run-in phase that 
595 
will run 2 to 6 weeks before randomization is assigned. If both pump run-in phase and CGM run-
596 
in phase are indicated, they will run concurrently. Training is detailed below.  
597 
 
598 
 Initiation of CGM 
599 
The participant will be provided with sensors and instructed to use the study CGM on a daily basis. 
600 
Training will be provided to participants not experienced with CGM use as to how to use the CGM 
601 
in real-time to make management decisions and how to review the data after an upload for 
602 
retrospective review. Participants using a personal CGM prior to the study will discontinue the 
603 
personal CGM beginning in this period. 
604 
The participant will be observed placing the sensor. The study CGM user’s guide will be provided 
605 
for the participant to take home. 
606 
 Initiation of Pump 
607 
Pump-naïve participants will use the study insulin pump and CGM for up to 4 weeks before 
608 
randomization is assigned.  
609 
Participants who are pump-naïve will be provided with a study pump similar to the pump used 
610 
with the closed-loop system, but with the closed-loop control feature either absent or deactivated 
611 
and will be instructed to use the pump on a daily basis. An initial basal insulin profile will be 
612 

 
 
 
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customized on a per-participant basis. Total daily insulin dose will be reduced by approximately 
613 
20% as a general rule, with a recommended method outlined in a separate procedures’ manual. 
614 
Further adjustments to total daily dose (TDD) and intraday basal rate profile may be made during 
615 
the course of the run-in period that can be concomitant with the CGM run-in phase. 
616 
Participants and parent(s) will complete training on the study pump as detailed below. 
617 
 The participant will be fully instructed on the study insulin pump. A qualified system trainer 
618 
will conduct the training and in particular discuss differences from their home pump in 
619 
important aspects such as calculation of insulin on board (IOB) and correction boluses.  
620 
 The study pump will have the Basal-IQ feature, and participants will be able to use this feature 
621 
at investigator discretion. 
622 
Additional topics are not limited to but may include: infusion site initiation, cartridge/priming 
623 
procedures, setting up the pump, charging the pump, navigation through menus, bolus 
624 
procedures including stopping a bolus, etc. 
625 
 For pump-naïve participants, the study team will assist the participant in study pump infusion 
626 
site initiation and will start the participant on the study pump. The study pump will be 
627 
programmed with the participant’s insulin requirements.  
628 
 The participant will be supervised with the study pump during at least one meal or snack bolus 
629 
to ensure participant understanding of the pump features.  
630 
 The participant will be encouraged to review the literature provided with the pump and infusion 
631 
sets after the training is completed. 
632 
 
633 
Note: For the extension phase, participants in the control group will be trained on the use of the 
634 
Control IQ system.  Follow up phone contacts and in-clinic visits are described in Table 3. 
635 
 
636 
 Blood Glucose and Ketone Testing 
637 
Participants will receive supplies for blood glucose and ketone testing. 
638 
 Blood glucose testing 
639 
o Participants will be provided with a study blood glucose meter, test strips, and standard 
640 
control solution to perform quality control (QC) testing at home per manufacturer guidelines. 
641 
o All study blood glucose meters will be QC tested with control solution if available during 
642 
all office visits.  A tested meter will not be used in a study if it does not read within the target 
643 
range at each concentration per manufacturer labeling.  The participant will be instructed to 
644 
contact study staff for a replacement of the meter, test strips, and control solution if a meter 
645 
fails QC testing at home. 
646 

 
 
 
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o Participants will be reminded to use the study blood glucose meter for all fingerstick BGs 
647 
during the study. 
648 
o Participants will be given guidelines for treatment of low or high blood glucose. 
649 
 Blood ketone testing 
650 
o Participants will be provided with a study blood ketone meter, test strips, and standard 
651 
control solution to perform QC testing at home per manufacturer guidelines. 
652 
o All study blood ketone meters will be QC tested with control solution if available during 
653 
all office visits.  A tested meter will not be used in a study if it does not read within the target 
654 
range at each concentration per manufacturer labeling.  The participant will be instructed to 
655 
contact study staff for a replacement of the meter, test strips, and control solution if a meter 
656 
fails QC testing at home.   
657 
o Participants will be instructed to perform blood ketone testing as described in section 7.1.6. 
658 
o Participants will be given guidelines for treatment of elevated blood ketones 
659 
 Participants will be required to have a home glucagon emergency kit. Participants who 
660 
currently do not have one will be given a prescription for the glucagon emergency kit. 
661 
 Assessment of Successful Completion of the Run-in Phase 
662 
Enrolled participants will return approximately 14 days after the initiation of the run-in phase 
663 
to assess progress or successful completion of the phase.  If needed, one or more interim visits or 
664 
phone contacts may occur to assist the participant with any system use issues. Visit procedures 
665 
will include the following: 
666 
 Assessment of compliance with the use of either or both CGM and/or study pump (if 
667 
applicable) 
668 
 Assessment of compliance with the use of:  
669 
o CGM,  
670 
o study pump,  
671 
o CGM and study pump 
672 
 Assessment of skin reaction in areas where a CGM sensor was worn  
673 
 Assessment of eligibility to continue to the randomized control trial (RCT)  phase of the study 
674 
The appropriate study equipment will be downloaded and reviewed after the first 2 weeks of the 
675 
run-in phase have been completed; participants will be evaluated for compliance and progress. If 
676 
that run-in phase occurred without any major safety issues, participants who are completing only 
677 
the CGM run-in can be randomized. Those completing study pump and CGM may continue the 
678 
run-in phase for another 2-4 weeks at PI discretion. In addition, MDI or study-pump naïve 
679 
participants will be contacted by study staff within approximately 24hrs, 72hrs, and 1 week after 
680 
pump initiation to answer any questions related to device use prior to the 2-week visit. All 
681 
participants may have unlimited contact with the study team as needed.  
682 

 
 
 
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To enter the randomized trial from the run-in phase, participants must have obtained CGM 
683 
readings on at least 11 out of the previous 14 days of the run-in phase (if applicable) and pump-
684 
naïve patients must have successfully used the study pump each day (if applicable).  If a participant 
685 
fails to meet either or both of these criteria, or if it is determined that the participant will benefit 
686 
from additional time with equipment training, then the run-in period may be extended at the 
687 
discretion of the investigator. One or two additional periods may occur, each a minimum of 11 
688 
days with a goal of at least 14 days, with another clinic visit to assess results after each period 
689 
using the same criteria as above. The run-in duration will therefore vary from approximately 2 to 6 
690 
weeks, depending on the participant. Additional visits and phone contacts for further training are 
691 
at investigator discretion. 
692 
An assessment of CGM and pump knowledge will be made and the participant must demonstrate 
693 
sufficient competency to proceed to the RCT. The trainer and participant will review the individual 
694 
items listed on the pump training checklist to ensure competency.   
695 
Participants who are unable to meet the CGM or study pump compliance requirements and those 
696 
who no longer meet all of the inclusion and exclusion criteria will be withdrawn from the study. 
697 
If the participant is eligible to continue in the study, study staff will follow the procedure for insulin 
698 
pump optimization described below in section 3.6. 
699 
 Optimization of Insulin Pump Settings 
700 
 Data-driven optimization of pump settings will occur at the following times: 
701 
 For the first phase: Prior to Randomization: 
702 
o At the Run-in Review Visit 
703 
 Following Randomization visit and initiation of Extension Phase: 
704 
o If needed at the criteria of the physician at each clinical center, optimization may be done 
705 
by phone contacts or in clinic visits. 
706 
o If the study participant contacts the study physician due to concerns about their pump 
707 
settings due to recurring hypo- or hyperglycemia. 
708 
Data will be obtained from CGM and/or pump downloads at the visit. Adjustments to pump 
709 
settings (basal rates, correction factor, insulin-to-carbohydrate ratio, etc.) will be made in response 
710 
to major trends observed in the CGM data, with flexibility for clinicians to adhere to guidelines 
711 
and practices established at each individual practice rather than a fixed set of heuristics for all 
712 
clinical centers. 
713 

 
 
 
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Chapter 4: Randomization Visit 
714 
 Randomization Visit 
715 
The visit may occur on the same day as the Screening or Run-in Review Visit, or on a subsequent 
716 
day. If deferred, the randomization visit should occur no more than 14 days after screening (if Run-
717 
in skipped) or successful completion of the run-in phase. 
718 
A urine pregnancy test will be repeated for all females of child-bearing potential if this visit is not 
719 
on the same day as the Screening Visit. 
720 
 
721 
HbA1c will be measured using DCA Vantage or similar point-of-care (POC) device or local lab if 
722 
this visit is not on the same day as the Screening Visit.  A blood sample also will be drawn to send 
723 
to the central laboratory for baseline HbA1c determination to be used in outcome analyses. 
724 
 
725 
A blood sample will be drawn to send to the central laboratory for a random, non-fasting C-peptide 
726 
determination to characterize baseline residual insulin production. In conjunction, blood glucose 
727 
may be measured using a blood glucose meter or a blood sample may be drawn to send to the 
728 
central laboratory for a blood glucose assessment. 
729 
 
730 
Eligible participants will be randomly assigned to one of two treatment groups in a 3:1 ratio: 
731 
1. Control-IQ Closed-Loop Control (CLC) Group 
732 
2. Standard of Care (SC) Group 
733 
The participant’s randomization group assignment is determined by completing a Randomization 
734 
Visit case report form on the study website. The randomization list will use a permuted block 
735 
design, stratified by clinical center. 
736 
The participant will be included in the data analysis regardless of whether or not the protocol for 
737 
the assigned randomization group is followed.  Thus, the investigator must not randomize a 
738 
participant until he/she is convinced that the participant/parent will accept assignment to either 
739 
of the two groups. 
740 
It was decided that it was more important to stratify randomization by clinical center than by 
741 
factors such as baseline time in range, HbA1c, or device use since these factors will be easier to 
742 
adjust for in analysis than will clinical center in view of the relatively small number at each clinical 
743 
center. 
744 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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745 
Participants will complete a set of baseline questionnaires, described in section 8.2 adapted for 
746 
age, prior to randomization.   
747 

 
 
 
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Chapter 5: Main Study Procedures  
748 
 Procedures for the CLC Group 
749 
Participants assigned to the CLC group will receive study system training. These training 
750 
sessions can occur on the same day or extend to up to one additional day if needed within 1-7 
751 
days from randomization; participants will not take the study system home until training has 
752 
been completed. 
753 
The parent/guardian will be trained on severe hypoglycemia emergency procedures including 
754 
removal of the study pump and administration of glucagon. The parent/guardian will be asked to 
755 
attend any/all of the other training procedures.  
756 
 Study System Training  
757 
Participants will receive study system training by a qualified trainer. The study system includes 
758 
the Tandem t:slim X2 with Control-IQ technology and associated Dexcom G6 CGM. 
759 
CGM training will include: 
760 
 The participant will be instructed and supervised on how to insert the sensor and transmitter. 
761 
 The participant will learn how to calibrate the CGM unit 
762 
 The participant will learn how to access the CGM trace via the t:slim X2 with Control-IQ user 
763 
interface 
764 
 Participants will be asked to perform fingerstick blood glucose measurements in accordance 
765 
with the labeling of the study CGM device 
766 
Pump training will include: 
767 
 The participant will be fully instructed on the study insulin pump. A qualified system trainer 
768 
will conduct the training and in particular discuss differences from their home pump in 
769 
important aspects such as calculation of insulin on board and correction boluses. Additional 
770 
topics not limited to but may include: infusion site initiation, cartridge/priming procedures, 
771 
setting up the pump, charging the pump, navigation through menus, bolus procedures including 
772 
stopping a bolus, etc. 
773 
 The study team will assist the participant in study pump infusion site initiation and will start 
774 
the participant on the study pump. The study pump will be programmed with the participant’s 
775 
usual basal rates and pump parameters. The participant’s personal pump will be removed. 
776 
 The participant will be supervised with the study pump during at least one meal or snack bolus 
777 
to ensure participant understanding of the pump features. 
778 
 The participant will be encouraged to review the literature provided with the pump and infusion 
779 
sets after the training is completed. 
780 
Pump training specific to the Control-IQ Technology functions will include: 
781 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
PAGE 37 OF 76 
 
 How to turn on and off Control-IQ technology. 
782 
 How to understand when Control-IQ is increasing or decreasing basal rates. 
783 
 How to administer a meal or correction bolus on the t:slim X2 with Control-IQ system 
784 
 What to do when exercising while using the system 
785 
 How to enable the sleep function and set the sleep schedule 
786 
 The participant will be assessed for understanding of the system interface and how to react to 
787 
safety/alert messages. 
788 
 The participant will be given a User Guide as a reference. 
789 
 
790 
The participant will be instructed to use the system in closed-loop mode except 1) when no 
791 
calibrated CGM sensor is available or 2) if insulin is delivered by any means other than the 
792 
study pump (e.g. injection of subcutaneous insulin via syringe in the event of infusion site failure). 
793 
If insulin is delivered by any means other than the study pump, participant will be instructed to 
794 
turn off Control-IQ for approximately four hours. 
795 
The participant will also be instructed to contact study staff during periods of illness with an 
796 
elevated temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant 
797 
illness, or during periods of use of medications such as epinephrine for the emergency treatment 
798 
of a severe allergic reaction or asthma attack in addition to use of oral or injectable glucocorticoids 
799 
to determine if closed-loop use should be temporarily discontinued. 
800 
The participant’s parent/legal guardian will be required to attend the training procedures and will 
801 
be trained in all aspects aforementioned. All training will be conducted considering age of 
802 
participant and parent involvement on diabetes treatment.  
803 
Participants will be provided with sufficient supplies to last until the subsequent visit. 
804 
Participants will be provided with contact information and will be asked to call the study 
805 
clinical staff for any health-related issues and for technical issues with t:slim X2 with 
806 
Control-IQ. Participants may use the study pump without Control-IQ activated and study 
807 
CGM during periods of component disconnections or technical difficulties.  Participants will 
808 
also receive study staff contact information to ask any questions they may have during the study. 
809 
Study staff will discuss with the participant that routine contact is required and will make 
810 
arrangements with the participant for the contacts.  If the participant cannot be reached, the 
811 
participant’s other contact methods will be utilized, including the emergency contact.  Participants 
812 
who are not compliant with the arranged contacts on two separate occasions may be discontinued 
813 
at the discretion of the investigator.  
814 
Upon completion of the t:slim X2 with Control-IQ training, study staff will document, using a 
815 
checklist, that the participant is familiar with the function/feature and/or capable of performing 
816 
each of the tasks specified. 
817 

 
 
 
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Participants will be provided Hypoglycemia, Hyperglycemia and Ketone Guidelines (section 7.2) 
818 
for when their glucose levels are >300 mg/dL for more than two hours or >400 mg/dL at any time 
819 
or <70 mg/dL or ketones ≥1.5 mmol/L. 
820 
 
821 
After training on the study system has been completed, participants will proceed with home use 
822 
(meaning free-living use at school, home, etc.) of the t:slim X2 with Control-IQ technology 
823 
system. 
824 
Participants may use available manufacturer-provided software and features of the study CGM 
825 
related to mobile data access or remote monitoring, but will be instructed not to use any third-party 
826 
components for this purpose. 
827 
 
828 
Participants will be instructed to download the study device prior to each phone visit or on at least 
829 
every 3-week basis throughout the remainder of the study. 
830 
 
831 
Study staff will perform a phone call with the participant within 7 (±1) days following 
832 
randomization. 
833 
The following will occur: 
834 
 Assessment of compliance with study device use by review of any available device data 
835 
 Assessment of adverse events, adverse device effects, and device issues 
836 
 Study staff will answer any questions related to device use 
837 
Participants will then complete an additional week of home use with the study system.  Participants 
838 
will return to clinic 14 (±3) days from the date of randomization. 
839 
 
840 
The participant will be offered review training to address any questions on the use of the study 
841 
device including meal bolus strategies and strategies related to pump use and exercise. 
842 
The following will occur: 
843 
 Assessment of compliance with study device use by review of any available device data 
844 
 Assessment of adverse events, adverse device effects, and device issues 
845 
 Study staff will answer any questions related to device use and follow the procedure for insulin 
846 
pump optimization described in section 3.6 using the study CGM available data from the 
847 
previous two weeks. 
848 
 The blood glucose meter and study ketone meter will be downloaded and QC tested with 
849 
control solution. 
850 

 
 
 
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 Procedures for the SC Group 
851 
Participants in the SC group will use an insulin pump that they usually use for the treatment of 
852 
their diabetes or a study pump provided by the study team if they are transitioning from MDI to 
853 
pump for the study, in conjunction with the study CGM, study blood glucose meter, and study 
854 
ketone meter. Study pump training and/or study CGM training will be provided if the participant 
855 
is initiating use of these devices at this point.  
856 
If a participant is using a pump with a LGS feature, he/she will be allowed to continue using this 
857 
feature during the trial. 
858 
Participants may use available manufacturer-provided software and features of the study CGM 
859 
related to mobile data access or remote monitoring, but will be instructed not to use any third-party 
860 
components for this purpose. 
861 
 
862 
Participants will be instructed to upload data from the study CGM using commercially available 
863 
software prior to the 1-week phone contact and prior to the 2-week clinic visit for clinician review.  
864 
Participants will be provided with any software and hardware needed to perform these data 
865 
uploads. 
866 
 
867 
Study staff will perform a phone call with the participant 7(+1) days following randomization. 
868 
The following will occur: 
869 
 Assessment of compliance with study device use by review of any available device data 
870 
 Assessment of adverse events, adverse device effects, and device issues 
871 
 Study staff will answer any questions related to device use 
872 
The participant will continue on SC for a second week, then return to the clinic 14 (±3) days from 
873 
the date of randomization. 
874 
 
875 
The participant will be offered review training on the use of SC during the remainder of the study, 
876 
including meal bolus strategies and strategies related to pump use and exercise. 
877 
The following will occur: 
878 
 Assessment of compliance with study device use by review of any available device data 
879 
 Assessment of adverse events, adverse device effects, and device issues 
880 
 Study staff will review uploaded CGM data, answer any questions related to device use, and 
881 
follow the procedure for insulin pump optimization described in section 3.6. 
882 
 The study blood glucose meter and study ketone meter will be downloaded and QC tested with 
883 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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at least two different concentrations of control solution if available. 
884 
The participant will be instructed to upload data from the CGM at least once every 4 weeks for the 
885 
remainder of the study. 
886 
 Follow-up Visits and Phone Contacts for Both Groups 
887 
The schedule for remaining follow-up visits and phone contacts is the same for both treatment 
888 
groups.  Study staff will discuss with the participant that periodic contact is required and will make 
889 
arrangements with the participant for the contacts.  If the participant or parent/guardian, cannot be 
890 
reached, the participant’s other contact methods will be utilized, including the emergency contact. 
891 
 
892 
Follow-up visits in clinic will occur at:  
893 
 2 week (±3 days) 
894 
 8 weeks (±1 week) 
895 
 16 weeks (+1 week) – end of Main Study Phase 
896 
5.4.1.1 Procedures at Follow-up Visits 
897 
Procedures performed in both groups at each visit, unless otherwise specified below: 
898 
 Assessment of compliance with study device use by review of any available device data 
899 
 Assessment of adverse events, adverse device effects, and device issues 
900 
 Download of device data (study system or personal pump and study CGM, study BG meter, 
901 
study ketone meter) 
902 
 
903 
In addition to the 1-week phone contact described above for the respective treatment groups, the 
904 
following phone contacts will be made: 
905 
 4 weeks (±3 days) 
906 
 6 weeks (±3 days) 
907 
 10 weeks (±3 days) 
908 
 12 weeks (±3 days) 
909 
 14 weeks (±3 days) 
910 
At each phone contact, the following procedures are performed in both treatment groups: 
911 
 Review of available CGM and/or system data to identify any safety issues associated with 
912 
insulin pump settings and current diabetes management approach 
913 
 Assessment of adverse events, adverse device effects, and device issues 
914 

 
 
 
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Additional phone contacts may be performed as needed. 
915 
 
916 
All participants will be asked to upload data from the CGM at least once every 4 weeks during the 
917 
extension phase. The study staff will confirm that the data were received. 
918 
 
919 
All participants will return to the clinic for a 16-Week (+7 days) final clinic visit during which the 
920 
following will occur: 
921 
 HbA1c determination using the DCA Vantage or similar point of care device 
922 
 Collection of a blood sample to send to the central laboratory for HbA1c determination 
923 
 Completion of questionnaires  
924 
 Weight and height measurement will be repeated 
925 
 Assessment of adverse events, adverse device effects, and device issues 
926 
 Download of device data (study system or personal pump and study CGM, study BG meter, 
927 
study ketone meter) 
928 
 Early Termination Visit (If Applicable) 
929 
Participants will be asked to come for an end of study visit in the event of withdrawal or early 
930 
termination. 
931 
 Unscheduled Visits 
932 
Participants may have unscheduled visits during the study period if required for additional device 
933 
training or other unanticipated needs per the study investigator discretion. 
934 
 Participant Access to Study Device at Study Closure 
935 
Participant will return all investigational study devices and supplies (insulin pump, CGM and 
936 
related supplies) at study closure.  Participant may keep the study ketone meter and study 
937 
glucometer if these devices are not marked for investigational use only.  
 
938 

 
 
 
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Chapter 6: Extension Phase Procedures   
939 
At the conclusion of the 16-week visit, all participants will have the option to use of the Control-
940 
IQ closed-loop system.  
941 
 Closed Loop Control Participants 
942 
Participants who have completed the 16-week Main Study Phase will be provided the option to 
943 
continue the use the t:slim with Control-IQ System for an additional 12 weeks.   
944 
The following phone contacts will be made for CLC Group participants in the Extension Phase:  
945 
 20 week (±3 days)  
946 
 24 week (±3 days)  
947 
At each phone contact, the following procedures are performed:  
948 
Review of available CGM and/or system data to identify any safety issues associated with insulin 
949 
pump settings and current diabetes management approach  
950 
 Assessment of adverse events, adverse device effects, and device issues 
951 
 SC Group Participants 
952 
Training on pump (section 5.2) use will be provided and therapy optimization will occur as 
953 
follows: 
954 
 If needed at the criteria of the physician at each clinical center, optimization may be done at 
955 
either phone contacts or in clinic visits.  
956 
 If the study participant contacts the study physician due to concerns about their pump settings 
957 
due to recurring hypo- or hyperglycemia. 
958 
Data will be obtained from CGM and/or pump downloads at the visit. Adjustments to pump 
959 
settings (basal rates, correction factor, insulin-to-carbohydrate ratio, etc.) will be made in response 
960 
to major trends observed in the CGM data, with flexibility for clinicians to adhere to guidelines 
961 
and practices established at each individual practice rather than a fixed set of characteristics for all 
962 
clinical centers. 
963 
The following phone contacts will be made for SC Group participants in the Extension Phase:  
964 
 17 weeks (±3 days)  
965 
 19 weeks (±3 days)  
966 
 21 weeks (±3 days)  
967 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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 25 weeks (±3 days)  
968 
At each phone contact, the following procedures are performed:  
969 
 Review of available CGM and/or system data to identify any safety issues associated with 
970 
insulin pump settings and current diabetes management approach  
971 
 Assessment of adverse events, adverse device effects, and device issues  
972 
Follow-up visits for SC group during the Extension Phase in clinic will occur at:  
973 
 23 Weeks (±1 week) 
974 
 28 Weeks (+1 week) – End of Study 
975 
Procedures Specific to the 28 Week Visit 
976 
 HbA1c determination using the DCA Vantage or similar point of care device 
977 
 Collection of a blood sample to send to the central laboratory for HbA1c determination 
978 
 Completion of questionnaires 
979 
 Weight measurement will be repeated, in addition to height  
980 
 Insulin Pump Optimization as described above 
981 
 Early Termination Visit (If Applicable) 
982 
Participants will be asked to come for an end of study visit in the event of withdrawal or early 
983 
termination. 
984 
 Unscheduled Visits 
985 
Participants may have unscheduled visits during the study period if required for additional device 
986 
training or other unanticipated needs per the study investigator discretion. 
987 
 Participant Access to Study Device at Study Closure 
988 
Participant will return all investigational study devices and supplies (insulin pump, CGM and 
989 
related supplies) at study closure.  Participant may keep the study ketone meter and study 
990 
glucometer if these devices are not marked for investigational use only. 
991 

 
 
 
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Chapter 7: Study Devices 
992 
 Description of the Investigational Device 
993 
 
994 
The study system will include the Tandem t:slim X2 with Control-IQ technology. 
995 
 
996 
The study CGM will include Dexcom G6 transmitter and sensors when using the Tandem t:slim 
997 
X2 with Control-IQ technology.  This may not be an FDA-approved device system at the start of 
998 
the study, but may become approved during the course of the study.  The CGM sensor will be 
999 
replaced at least once every 10 days. 
1000 
 
1001 
Blood glucose levels will be measured using the study’s blood glucose meter (glucometer) and the 
1002 
CGM device will be calibrated if needed using the study glucometer and strips in accordance with 
1003 
the manufacturer’s labeling. 
1004 
 
1005 
Blood ketone levels will be measured using the Abbott Precision Xtra meter and strips in 
1006 
accordance with the manufacturer’s labeling.  The blood glucose meter component of the Precision 
1007 
Xtra device will not be used. 
1008 
 
1009 
Device accountability procedures will be detailed in the clinical center procedures manual. 
1010 
 
1011 
 Participants to perform QC testing at home per manufacturer guidelines. 
1012 
 All study blood ketone meters will be QC tested with control solution if available during all 
1013 
office visits.  A tested meter will not be used in a study if it does not read within the target 
1014 
range at each concentration per manufacturer labeling.  The participant will be instructed to 
1015 
contact study staff for a replacement of the meter, test strips, and control solution if a meter 
1016 
fails QC testing at home. 
1017 
 Participants will be instructed on how to perform blood ketone testing. 
1018 
 Participants will be given guidelines for treatment of elevated blood ketones. 
1019 
 Safety Measures 
1020 
 
1021 
Throughout the study, participants will be instructed to calibrate the study CGM in accordance 
1022 
with manufacturer labelling. 
1023 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
PAGE 45 OF 76 
 
 
1024 
If the CGM signal becomes unavailable for more than 20 minutes consecutively, Control-IQ or 
1025 
closed loop will not operate to automatically adjust insulin. If the CGM is not connected, the 
1026 
system will revert to usual function of the pump and deliver insulin with the insulin dosing 
1027 
parameters programmed in the system for that individual. Resumption of Closed-Loop will 
1028 
occur automatically once CGM signal is available again. 
1029 
If the study system is unable to activate Control-IQ for any reason, the pump will automatically 
1030 
revert to preprogrammed basal insulin delivery without any need for instruction from the user. 
1031 
If the t:slim X2 detects a system error that does not allow the pump to operate, the Malfunction 
1032 
Alarm will display and the participant will be instructed to contact Tandem Technical Support via 
1033 
the study team. 
1034 
 
1035 
During the course of the study, participants will be permitted to change the CGM low glucose 
1036 
threshold alert setting on their device or mobile app, but will be instructed to choose a value no 
1037 
less than 70 mg/dL. 
1038 
The t:slim X2 with Control-IQ system will issue a predictive hypoglycemia alert (Control-IQ Low 
1039 
Alert) when the system predicts BG <70 mg/dL within the next 15 minutes (<80 mg/dL when 
1040 
exercise mode is activated). 
1041 
If the participant receives a Control-IQ Low Alert, a message appears on the user interface (UI) 
1042 
that is accompanied by vibration followed by vibrations and/or sound if not acknowledged by the 
1043 
user in 5 minutes.  This alert remains on the screen until acknowledged by the user. The user is 
1044 
prompted to test blood sugar and treat with carbs. 
1045 
 
1046 
During the course of the study, participants will be permitted to change the CGM high glucose 
1047 
threshold alert setting on their device or mobile app, but will be instructed to choose a value no 
1048 
greater than 300 mg/dL. 
1049 
The t:slim X2 with Control-IQ system will issue a predictive hyperglycemia alert (Control-IQ 
1050 
High Alert) when the system has increased insulin delivery, but detects a CGM value above 200 
1051 
mg/dL and does not predict the value will decrease in the next 30 minutes. 
1052 
If the participant receives a Control-IQ High Alert, a message appears on the UI that is 
1053 
accompanied by vibration followed by vibrations and/or sound if not acknowledged by the user in 
1054 
5 minutes. This alert remains on the screen until acknowledged by the user. The user is prompted 
1055 
to check the site for occlusion and test blood glucose. 
1056 
If a participant’s CGM reading is >300 mg/dL for over 2 hours or ≥400 mg/dL at any point, the 
1057 
participant will be instructed to take the following steps: 
1058 
 Perform a blood glucose meter check. 
1059 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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 If the blood glucose is >300 mg/dL, check for blood ketones with the study ketone meter. 
1060 
 If the ketone level is ≥1.5 mmol/L, take correction insulin, change insulin (pump) infusion site 
1061 
and contact study staff. 
1062 
 If a participant administers correction insulin via insulin syringe, participants will be instructed 
1063 
to turn Control-IQ off for approximately four hours. 
1064 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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Chapter 8: Testing Procedures and Questionnaires 
1065 
 Laboratory Testing 
1066 
 
1067 
A blood sample will be obtained at screening to assess kidney and liver functioning.  
1068 
 
1069 
 Performed locally at the Screening visit, Randomization visit and the 16-week visit.  
1070 
 A blood sample will be obtained and sent to central lab at the Randomization visit, at the 16-
1071 
week visit and at the end of the study visit.  
1072 
 
1073 
Performed locally for females of child-bearing potential at the Screening visit and the 
1074 
Randomization visit. This will also be done anytime pregnancy is suspected. 
1075 
 
1076 
Blood samples will be obtained and sent to the central lab at the Randomization visit. Back-up 
1077 
samples will be stored on-site until all samples are resulted. 
1078 
 Questionnaires 
1079 
Questionnaires are completed at the Randomization Visit and Week 16 Visit for all participants.  
1080 
Participants who complete the Extension Phase will also complete the questionnaires at Week 28. 
1081 
The questionnaires will be family and age appropriate are described briefly below.  The procedures 
1082 
for administration are described in the clinical center procedures manual. 
1083 
The following questionnaires will be completed at the Randomization Visit: 
1084 
 Clarke’s Hypoglycemia Awareness Scale – Child and Parent (Children age 10+ years at the 
1085 
time of consent will complete as well as all Parents) 
1086 
 Fear of Hypoglycemia Survey (HFS-II) – Child and Parent 
1087 
 Problem Areas In Diabetes Survey (PAID) – Child and Parent 
1088 
 Pediatric Quality of Life – Child and Parent  
1089 
 INSPIRE Survey – Child and Parent 
1090 
 Pittsburgh Sleep Quality Index (PSQI) – Parent 
1091 
The following questionnaires will be completed at the Week 16 and Week 28 Visits: 
1092 
 Clarke’s Hypoglycemia Awareness Scale – Child and Parent (Children age 10+ years at the 
1093 
time of consent will complete as well as all Parents) 
1094 

 
 
 
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 Fear of Hypoglycemia Survey (HFS-II) – Child and Parent 
1095 
 Problem Areas In Diabetes Survey (PAID) – Child and Parent 
1096 
 Pediatric Quality of Life – Child and Parent 
1097 
 INSPIRE Post-Assessment Survey – Child and Parent 
1098 
 Pittsburgh Sleep Quality Index (PSQI) – Parent  
1099 
 System Usability Scale (SUS) – Closed-Loop participants only 
1100 
Administration time is approximately 15 minutes. 
1101 
 
1102 
The scale comprises eight questions characterizing the participant's exposure to episodes 
1103 
of moderate and severe hypoglycemia. It also examines the glycemic threshold for, and 
1104 
symptomatic responses to hypoglycemia. A score of four or more on a scale of 0 to 7 implies 
1105 
impaired awareness of hypoglycemia.  
1106 
Administration time is approximately 5 minutes. 
1107 
 
1108 
The Hypoglycemia Fear Survey-II was developed to measure behaviors and worries related to fear 
1109 
of hypoglycemia in adults with type 1 diabetes. It is composed of 2 subscales, the Behavior (HFS-
1110 
B) and Worry (HFS-W). HFS-B items describe behaviors in which patients may engage to avoid 
1111 
hypoglycemic episodes and/or their negative consequences (e.g., keeping blood glucose levels 
1112 
higher, making sure other people are around, and limiting exercise or physical activity). HFS-W 
1113 
items describe specific concerns that patients may have about their hypoglycemic episodes (e.g., 
1114 
being alone, episodes occurring during sleep, or having an accident). HFS-II was adapted for 
1115 
children and parents. Items are rated on a 5-point Likert scale (0=never, 4=always), with higher 
1116 
scores indicating higher fear of hypoglycemia.  
1117 
Administration time is approximately 10 minutes (both versions). 
1118 
 
1119 
The Problem Areas In Diabetes Survey is a measure of diabetes-related emotional distress and 
1120 
consists of a scale of 16 items for the Parent version and 11 items for the Child version. Patients 
1121 
and parents rate the degree to which each item is currently problematic for them on a 6-point Likert 
1122 
scale, from 1 (no problem) to 6 (serious problem). 
1123 
Administration time is approximately 10 minutes. 
1124 
 
1125 
This is a 33-item scale developed and validated for the measurement of diabetes-specific quality 
1126 
of life. Separate forms have been validated for child self-report (5-7 year old; 8-12 year old; and 
1127 
12-18 year old) and parent report for these same age groups. Participants record the extent to 
1128 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
PAGE 49 OF 76 
 
which they (or their child) experienced each of 33 problems related to diabetes in the prior 
1129 
month.  
1130 
Administration time is approximately 15 minutes. 
1131 
 
1132 
The INSPIRE (Insulin Delivery Systems: Perceptions, Ideas, Reflections and Expectations) survey 
1133 
was developed to assess various aspects of a user’s experience regarding automated insulin 
1134 
delivery for both patients and family members. The surveys include various topics important to 
1135 
patients with type 1 diabetes and their family members based upon >200 hours of qualitative 
1136 
interviews and focus groups. The child pre-assessment survey includes 27 items, and the parent 
1137 
pre-assessment survey includes 45 items. The post-assessment child survey includes 17 items, and 
1138 
the parent post-assessment contains 21 items. Response options for all surveys include a 5-point 
1139 
Likert scale from strongly agree to strongly disagree, along with an N/A option. 
1140 
Administration time is approximately 5 minutes. 
1141 
 
1142 
Pittsburgh Sleep Quality Index (PSQI) is a 10-item questionnaire that measures the sleep quality 
1143 
and pattern of sleep in adults. Seven component scores are derived, each scored 0 (no difficulty) 
1144 
to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 
1145 
21). Higher scores indicate worse sleep quality. 
1146 
Administration time is approximately 5 minutes. 
1147 
 
1148 
The System Usability Scale (SUS) is a 10-item questionnaire that measures the overall usability of 
1149 
a system. It is a valid and reliable measure of the perceived usability of a system and is technology-
1150 
agnostic. The questionnaire presents statements with five response options (anchoring the options 
1151 
from strongly disagree to strongly agree) and asks users to rate their agreement to the statements.  
1152 
User scores are transformed into a composite score, from 0 to 100, and this score is taken as an 
1153 
overall measure of the system’s usability; higher scores indicate better perceived usability. 
1154 
Administration time is approximately 5 minutes. 
 
1155 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
PAGE 50 OF 76 
 
Chapter 9: Adverse Events, Device Issues, and Stopping Rules 
1156 
 Adverse Events 
1157 
 
1158 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
1159 
relationship between the adverse event and the device(s) under investigation (see section 9.1.2 for 
1160 
reportable adverse events for this protocol). 
1161 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
1162 
 Results in death. 
1163 
 Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
1164 
become life-threatening, is not necessarily considered a serious adverse event). 
1165 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
1166 
 Results in persistent or significant disability/incapacity or substantial disruption of the ability 
1167 
to conduct normal life functions (sight threatening). 
1168 
 Is a congenital anomaly or birth defect. 
1169 
 Is considered a significant medical event by the investigator based on medical judgment (e.g., 
1170 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
1171 
the outcomes listed above). 
1172 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
1173 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
1174 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
1175 
investigational plan or application (including a supplementary plan or application), or any other 
1176 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare 
1177 
of participants (21 CFR 812.3(s)). 
1178 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which the 
1179 
device may have caused or to which the device may have contributed (Note that an Adverse Event 
1180 
Form is to be completed in addition to a Device Deficiency or Issue Form). 
1181 
Device Complaints and Malfunctions: A device complication or complaint is something that 
1182 
happens to a device or related to device performance, whereas an adverse event happens to a 
1183 
participant.  A device complaint may occur independently from an AE, or along with an AE.  
1184 
An AE may occur without a device complaint or there may be an AE related to a device complaint.  
1185 
A device malfunction is any failure of a device to meet its performance specifications or otherwise 
1186 
perform as intended.  Performance specifications include all claims made in the labeling for the 
1187 
device.  The intended performance of a device refers to the intended use for which the device is 
1188 
labeled or marketed. (21 CFR 803.3).  Note: for reporting purposes, clinical centers will not be 
1189 
asked to distinguish between device complaints and malfunctions. 
1190 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
PAGE 51 OF 76 
 
 
1191 
For this protocol, a reportable adverse event includes any untoward medical occurrence that meets 
1192 
one of the following criteria: 
1193 
1. A serious adverse event 
1194 
2. An Adverse Device Effect as defined in section 9.1.1, unless excluded from reporting in section 
1195 
9.2 
1196 
3. An Adverse Event occurring in association with a study procedure 
1197 
4. Hypoglycemia meeting the definition of severe hypoglycemia as defined below  
1198 
5. Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, a hyperglycemic or 
1199 
ketosis event meeting the criteria defined below 
1200 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
1201 
events unless associated with an Adverse Device Effect.  Skin reactions from sensor placement are 
1202 
only reportable if severe and/or required treatment. 
1203 
Pregnancy occurring during the study will be recorded. 
1204 
9.1.2.1 Hypoglycemic Events 
1205 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
1206 
when the following definition for severe hypoglycemia is met:  the event required assistance of 
1207 
another person due to altered consciousness, and required another person to actively administer 
1208 
carbohydrate, glucagon, or other resuscitative actions.  This means that the participant was 
1209 
impaired cognitively to the point that he/she was unable to treat himself/herself, was unable to 
1210 
verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure or 
1211 
coma.  These episodes may be associated with sufficient neuroglycopenia to induce seizure or 
1212 
coma.  If plasma glucose measurements are not available during such an event, neurological 
1213 
recovery attributable to the restoration of plasma glucose to normal is considered sufficient 
1214 
evidence that the event was induced by a low plasma glucose concentration. 
1215 
9.1.2.2 Hyperglycemic Events/Diabetic Ketoacidosis 
1216 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1217 
event when one of the following 4 criteria is met:  
1218 
 the event involved DKA, as defined by the Diabetes Control and Complications Trial (DCCT) 
1219 
and described below 
1220 
 evaluation or treatment was obtained at a health care provider facility for an acute event 
1221 
involving hyperglycemia or ketosis 
1222 
 blood ketone level ≥1.5 mmol/L and communication occurred with a health care provider at 
1223 
the time of the event 
1224 
 blood ketone level ≥3.0 mmol/L, even if there was no communication with a health care 
1225 
provider 
1226 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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Hyperglycemic events are classified as DKA if the following are present: 
1227 
 Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
1228 
 Serum ketones ≥1.5 mmol/L or large/moderate urine ketones; 
1229 
 Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
1230 
 Treatment provided in a health care facility 
1231 
All reportable Adverse Events—whether volunteered by the participant, discovered by study 
1232 
personnel during questioning, or detected through physical examination, laboratory test, or other 
1233 
means—will be reported on an adverse event form online.  Each adverse event form is reviewed 
1234 
by the Medical Monitor to verify the coding and the reporting that is required. 
1235 
 
1236 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1237 
by determining if there is a reasonable possibility that the adverse event may have been caused by 
1238 
the study device. 
1239 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1240 
following general guideline when determining whether an adverse event is related: 
1241 
Yes 
1242 
There is a plausible temporal relationship between the onset of the adverse event and the study 
1243 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
1244 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of 
1245 
response to the study intervention; and/or the adverse event abates or resolves upon discontinuation 
1246 
of the study intervention or dose reduction and, if applicable, reappears upon re-challenge. 
1247 
No 
1248 
Evidence exists that the adverse event has an etiology other than the study intervention (e.g., 
1249 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1250 
medication); and/or the adverse event has no plausible temporal relationship to study intervention. 
1251 
 
1252 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or (3) 
1253 
severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse event 
1254 
is not necessarily serious.  For example, itching for several days may be rated as severe, but may 
1255 
not be clinically serious. 
1256 
 MILD: Usually transient, requires no special treatment, and does not interfere with the 
1257 
participant’s daily activities. 
1258 
 MODERATE: Usually causes a low level of inconvenience or concern to the participant and 
1259 
may interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
1260 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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 SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug 
1261 
therapy or other treatment. 
1262 
 
1263 
Adverse events will be coded using the MedDRA dictionary.  The Medical Monitor will review 
1264 
the investigator’s assessment of causality and may agree or disagree.  Both the investigator’s and 
1265 
Medical Monitor’s assessments will be recorded.  The Medical Monitor will have the final say in 
1266 
determining the causality. 
1267 
Adverse events that continue after the participant’s discontinuation or completion of the study will 
1268 
be followed until their medical outcome is determined or until no further change in the condition 
1269 
is expected. 
1270 
 
1271 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1272 
 RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae.  
1273 
Record the AE/SAE stop date. 
1274 
 RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
1275 
without change in the event anticipated.  Record the AE/SAE stop date. 
1276 
 FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event that 
1277 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the time of 
1278 
death; however, were not the cause of death, will be recorded as “resolved” at the time of death. 
1279 
 NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as the 
1280 
event was ongoing with an undetermined outcome. 
1281 
o An ongoing outcome will require follow-up by the clinical center in order to determine the 
1282 
final outcome of the AE/SAE. 
1283 
o The outcome of an ongoing event at the time of death that was not the cause of death, will 
1284 
be updated and recorded as “resolved” with the date of death recorded as the stop date. 
1285 
 UNKNOWN – An unknown outcome is defined as an inability to access the participant or the 
1286 
participant’s records to determine the outcome (for example, a participant that was lost to 
1287 
follow-up). 
1288 
All clinically significant abnormalities of clinical laboratory measurements or adverse events 
1289 
occurring during the study and continuing at study termination should be followed by the 
1290 
participant’s physician and evaluated with additional tests (if necessary) until diagnosis of the 
1291 
underlying cause, or resolution.  Follow-up information should be recorded on source documents. 
1292 
If any reported adverse events are present when a participant completes the study, or if a participant 
1293 
is withdrawn from the study due to an adverse event, the participant will be contacted for re-
1294 
evaluation within 2 weeks.  If the adverse event has not resolved, additional follow-up will be 
1295 
performed as appropriate.  Every effort should be made by the Investigator or delegate to contact 
1296 
the participant until the adverse event has resolved or stabilized. 
1297 

 
 
 
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 Reportable Device Issues 
1298 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
1299 
whether an adverse event occurred, except in the following circumstances. 
1300 
The following device issues are anticipated and will not be reported on a Device Issue Form but 
1301 
will reported as an Adverse Event if the criteria for AE reporting described above are met: 
1302 
 Component disconnections 
1303 
 CGM sensors lasting fewer than the number of days expected per CGM labeling 
1304 
 CGM tape adherence issues 
1305 
 Pump infusion set occlusion not leading to ketosis 
1306 
 Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
1307 
 Intermittent device component disconnections/communication failures not leading to system 
1308 
replacement 
1309 
 Device issues clearly addressed in the user guide manual that do not require additional 
1310 
troubleshooting 
1311 
 Skin reactions from CGM sensor placement or pump infusion set placement that do not meet 
1312 
criteria for AE reporting 
1313 
 Pregnancy Reporting 
1314 
If pregnancy occurs, the participant will be discontinued from the study.  The occurrence of 
1315 
pregnancy will be reported on an AE Form. 
1316 
 Timing of Event Reporting 
1317 
SAEs and UADEs must be reported to the Coordinating Center within 24 hours via completion of 
1318 
the online serious adverse event form. 
1319 
Other reportable adverse events, device malfunctions (with or without an adverse event), and 
1320 
device complaints should be reported promptly by completion of an electronic case report form, 
1321 
but there is no formal required reporting period. 
1322 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1323 
serious, related, and unexpected. Notification will be made within 10 days after the Coordinating 
1324 
Center becomes aware of the event. 
1325 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1326 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1327 
Ethics Committee. 
1328 
Upon receipt of a UADE report, the Sponsor will investigate the UADE and if indicated, report 
1329 
the results of the investigation to the clinical centers’ IRBs, and the FDA within 10 working days 
1330 
of the Sponsor becoming aware of the UADE per 21CFR 812.46(b). The Medical Monitor must 
1331 
determine if the UADE presents an unreasonable risk to participants. If so, the Medical Monitor 
1332 
must ensure that all investigations, or parts of investigations presenting that risk, are terminated as 
1333 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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soon as possible but no later than 5 working days after the Medical Monitor makes this 
1334 
determination and no later than 15 working days after first receipt notice of the UADE. 
1335 
In the case of a device system component malfunction (e.g. pump, CGM, control algorithm), 
1336 
information will be forwarded to the responsible company by the clinical center personnel, to be 
1337 
handled by its complaint management system. 
1338 
 Stopping Criteria 
1339 
 
1340 
Rules for discontinuing study device use are described below. 
1341 
 The investigator believes it is unsafe for the participant to continue on the intervention.  This 
1342 
could be due to the development of a new medical condition or worsening of an existing 
1343 
condition; or participant behavior contrary to the indications for use of the device that imposes 
1344 
on the participant’s safety 
1345 
 The participant requests that the treatment be stopped 
1346 
 Participant pregnancy 
1347 
 Two distinct episodes of DKA 
1348 
 Two distinct severe hypoglycemia events as defined in section 9.1.2.1 
1349 
If pregnancy occurs, the participant will be discontinued from the study entirely. Otherwise, even 
1350 
if the study device system is discontinued, the participant will be encouraged to remain in the study 
1351 
through the final study visit. 
1352 
 
1353 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or severe 
1354 
hyperglycemia event (as defined in section 9.1.2.2), use of the study device system will be 
1355 
suspended while the problem is diagnosed. 
1356 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
1357 
study device requires stoppage of device use for safety reasons (e.g. product recall).  The affected 
1358 
study activities may resume if the underlying problem can be corrected by a protocol or system 
1359 
modification that will not invalidate the results obtained prior to suspension. The study Medical 
1360 
Monitor will review all adverse events and adverse device events that are reported during the study 
1361 
and will review compiled safety data at periodic intervals (generally timed to the review of 
1362 
compiled safety data by the DSMB). The Medical Monitor may request suspension of study 
1363 
activities or stoppage of the study if deemed necessary based on the totality of safety data available. 
1364 
 Independent Safety Oversight 
1365 
A Data and Safety Monitoring Board (DSMB) will review compiled safety data at periodic 
1366 
intervals (typically every 6 months). In addition, the DSMB will review all DKA and severe 
1367 
hypoglycemia irrespective of relatedness to study device use, and all serious events (including 
1368 
UADEs) related to study device use at the time of occurrence. The DSMB also will be informed 
1369 
of any ADEs not meeting criteria for a UADE if the Medical Monitor requests the DSMB 
1370 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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review.   The DSMB can request modifications to the study protocol or suspension or outright 
1371 
stoppage of the study if deemed necessary based on the totality of safety data available. Details 
1372 
regarding DSMB review will be documented in a separate DSMB document. 
1373 
 Risks 
1374 
The potential risks associated with use of the study device are described in section 1.3. 
1375 
Additional risks are minor and/or infrequent and include: 
1376 
 Pain, bruising, redness, or infection from blood draws 
1377 
 Loss of confidentiality 
1378 
 Stress from completing quality of life questionnaires
1379 

 
 
 
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Chapter 10: Miscellaneous Considerations 
1380 
 Drugs Used as Part of the Protocol 
1381 
Participants will use either lispro or aspart insulin prescribed by their personal physician. 
1382 
 Prohibited Medications, Treatments, and Procedures 
1383 
Participants using glulisine at the time of enrollment will be asked to contact their personal 
1384 
physician to change their prescribed personal insulin to lispro or aspart for the duration of the trial 
1385 
in the case they are randomized to experimental arm 
1386 
Treatment with any non-insulin glucose-lowering agent (including GLP-1 agonists, Symlin, DPP-
1387 
4 inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas and naturaceuticals) will not be 
1388 
permitted. 
1389 
The investigational study devices (t:slim X2 insulin pump, study CGM systems) must be removed 
1390 
before Magnetic Resonance Imaging (MRI), Computed Tomography (CT) or diathermy treatment. 
1391 
Participants may continue in the trial after temporarily discontinuing use if requiring one of the 
1392 
treatments above.  
1393 
 Participant Withdrawal 
1394 
Participation in the study is voluntary, and a participant may withdraw at any time.  For participants 
1395 
who withdraw, their data will be used up until the time of withdrawal. 
1396 
 Confidentiality 
1397 
For security and confidentiality purposes, participants will be assigned an identifier that will 
1398 
be used instead of their name.  Protected health information gathered for this study will be 
1399 
shared with the coordinating center, the Jaeb Center for Health Research in Tampa, FL.  
1400 
De-identified participant information may also be provided to research sites involved in the study. 
1401 
De-identified participant information may also be provided to Tandem for system evaluation 
1402 
purposes. 
1403 

 
 
 
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Chapter 11: Statistical Consideration 
1404 
 Statistical and Analytical Plans 
1405 
The outcome metrics and the statistical analyses are summarized below.  A detailed statistical 
1406 
analysis plan will be written and finalized prior to the first tabulation of data by treatment group 
1407 
(ie, for DSMB review).  The analysis plan synopsis in this chapter contains the framework of the 
1408 
anticipated final analysis plan. 
1409 
 Statistical Hypotheses 
1410 
This study is an extension to children ages 6-13 years old, of the Main Protocol described in IDE 
1411 
G180053, which includes N=168 children ages 14 and up and adults. Thus, the primary outcome 
1412 
for this study is identical to the Main protocol - CGM-measured % in range 70-180 mg/dL.  
1413 
The hypotheses for the primary outcome are: 
1414 
a. Null Hypothesis: There is no difference in mean CGM-measured % in range 70-180 mg/dL 
1415 
over 16 weeks between SC and CLC  
1416 
b. Alternative Hypothesis: The mean CGM-measured % in range 70-180 mg/dL over 16 
1417 
weeks is different for SC and CLC. 
1418 
 Sample Size 
1419 
Sample size has been computed for the primary outcome (CGM-measured % in range 70-180 
1420 
mg/dL). Data from IDE G170267; Device Name: t:slim X2 with Control-IQ Technology; “Real-
1421 
Time Monitoring and Glucose Control During Winter-Sport Exercise in Youth with Type 1 
1422 
Diabetes: The AP Ski Camp Continued” were used to calculate sample size specific to this age 
1423 
group. In this study, which was completed in the winter of 2018, 24 school-aged children (6-12 
1424 
years) with type 1 diabetes participated in a 3-day ski camp (∼5 h skiing/day), followed by an 
1425 
additional 72 hour at-home phase under parental supervision. Study participants were randomized 
1426 
1:1 to SAP and t:slim X2 with Control-IQ Technology. The data from the 72-hour home phase 
1427 
was used for this sample size calculation – note that the closed-loop control system and the age 
1428 
range of the participants are identical to those proposed in this application: 
1429 
Results from home phase of G170267 
Control IQ 
SAP 
F 
p value 
Percent between 70 and 180mg/dl 
71 ± 6.6 
52.8 ± 13.5 
16.4 
0.001 
From the DCLP1 study using the same algorithm in an older cohort, the effective standard 
1430 
deviation (after adjusting for the correlation between baseline and follow up) for time in range 70-
1431 
180 mg/dL over the course of 6 months was 6% (95% CI 5% to 7%) for the CLC group and 7% 
1432 
(95% CI 6% to 8%) for the SAP group. 
1433 
A total sample size was computed to be N=60 for the following assumptions: (1) 3:1 [CLC:SC] 
1434 
randomization, (2) 90% power, (3) a 10% absolute increase in % time in range 70-180 mg/dL, (4) 
1435 
an effective SD of 10%, and (5) 2-sided type 1 error of 0.05. 
1436 

 
 
 
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The total sample size has been increased to N=100 to account for dropouts and to increase the 
1437 
number of participants who will be exposed to the CLC system for an enhanced safety and 
1438 
feasibility assessment.  
1439 
 Efficacy Outcome Measures 
1440 
 
1441 
 CGM-measured % in range 70-180 mg/dL 
1442 
 
1443 
11.4.2.1 Secondary Efficacy Endpoints Included in Hierarchical Analysis 
1444 
The following secondary endpoints will be tested in a hierarchical fashion as described in 
1445 
section 11.7.1. 
1446 
 CGM-measured % above 180 mg/dL 
1447 
 CGM-measured mean glucose 
1448 
 HbA1c at 16 weeks 
1449 
 CGM-measured % below 70 mg/dL 
1450 
 CGM-measured % below 54 mg/dL 
1451 
 CGM-measured % above 250 mg/dL 
1452 
 Glucose variability measured with the coefficient of variation (CV) 
1453 
11.4.2.2 Other Secondary Efficacy Endpoints 
1454 
The following endpoints are considered exploratory. Type 1 error for these endpoints will be 
1455 
controlled using the false discovery rate (FDR) instead of the familywise error rate (FWER).   
1456 
CGM-Measured: 
1457 
 % in range 70-140 mg/dL 
1458 
 glucose variability measured with the standard deviation (SD) 
1459 
 % <60 mg/dL 
1460 
 low blood glucose index 
1461 
 hypoglycemia events (defined as at least 15 consecutive minutes <70 mg/dL) 
1462 
 % >300 mg/dL  
1463 
 high blood glucose index 
1464 
 % in range 70-180 mg/dL improvement from baseline to 16 weeks ≥5% 
1465 
 % in range 70-180 mg/dL improvement from baseline to 16 weeks ≥10% 
1466 

 
 
 
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HbA1c: 
1467 
 HbA1c <7.0% at 16 weeks 
1468 
 HbA1c <7.5% at 16 weeks 
1469 
 HbA1c improvement from baseline to 16 weeks >0.5% 
1470 
 HbA1c improvement from baseline to 16 weeks >1.0% 
1471 
 HbA1c relative improvement from baseline to 16 weeks >10% 
1472 
 HbA1c improvement from baseline to 16 weeks >1.0% or HbA1c <7.0% at 16 weeks 
1473 
Questionnaires 
1474 
 Fear of Hypoglycemia Survey (HFS-II) – total score, 2 subscales and 4 factor scores: 
1475 
 Behavior (avoidance and maintain high BG) 
1476 
 Worry (helplessness and social consequences) 
1477 
 Clarke Hypoglycemia Awareness Scores 
1478 
 Problem Areas In Diabetes Survey (PAID) 
1479 
 INSPIRE survey scores 
1480 
 PedsQL Diabetes Module – total score and 5 subscales: 
1481 
 Diabetes 
1482 
 Treatment I 
1483 
 Treatment II 
1484 
 Worry 
1485 
 Communication 
1486 
 Pittsburgh Sleep Quality Index (Parent only) 
1487 
 System Usability Scale (SUS) 
1488 
Other: 
1489 
 Insulin 
1490 
 Total daily insulin (units/kg) 
1491 
 Basal: bolus insulin ratio 
1492 
 Weight and Body Mass Index (BMI) 
1493 
 
1494 
Randomization is preceded by two weeks of CGM run-in, which will be used in the calculation 
1495 
of baseline CGM metrics. For participants who are eligible to skip the run-in, comparable 
1496 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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amount of CGM data from their own sensors will be taken before randomization visit to 
1497 
calculate baseline CGM metrics. 
1498 
CGM data starting from randomization visit through the 16-week visit will be included in the 
1499 
calculation of each CGM metric. Percentages in range 70-180 mg/dL (and all other CGM-based 
1500 
metrics) will be calculated giving equal weight to each CGM point for each participant. 
1501 
 Analysis Datasets and Sensitivity Analyses 
1502 
All analyses comparing the CLC arm with SC arm will follow the intention-to-treat (ITT) 
1503 
principle with each participant analyzed according to the treatment assigned by randomization. 
1504 
All randomized participants will be included in the primary and secondary hierarchical analyses. 
1505 
Safety outcomes will be reported for all enrolled participants, irrespective of whether the 
1506 
participants was randomized or the study was completed. 
1507 
 
1508 
Per-protocol analyses will be performed for primary outcome and secondary hierarchical 
1509 
outcomes only if >5% of participants will be excluded: 
1510 
 CLC arm: Closed loop mode active for at least 80% of the time 
1511 
 SC arm: CGM use for at least 80% of the time 
1512 
 
1513 
Confounding 
1514 
The primary analysis described below will include a pre-specified list of covariates.  As an 
1515 
additional sensitivity analysis, any baseline demographic or clinical characteristics observed to 
1516 
be imbalanced between treatment groups will be added as covariates to the analyses of the 
1517 
primary endpoint. The determination of a meaningful baseline imbalance will be based on 
1518 
clinical judgement and not a p-value. 
1519 
Exclude First 2 Weeks of CGM Data 
1520 
As noted above in Section 11.4.3, calculation of CGM metrics will include all available post-
1521 
randomization CGM data.  As a sensitivity analysis, CGM metrics will be recalculated by 
1522 
excluding the first two weeks of CGM data following the randomization visit.  The primary 
1523 
analysis will be replicated based on the recalculated outcome.  
1524 
Missing Data 
1525 
It is worth emphasizing that any statistical method for handling missing data makes a number of 
1526 
untestable assumptions.  The goal will be to minimize the amount of missing data in this study so 
1527 
that results and conclusions will not be sensitive to which statistical method is used. To that end, 
1528 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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sensitivity analyses will be performed to explore whether results are similar for primary analysis 
1529 
when using different methods.  The following methods will be applied: 
1530 
 Direct likelihood (primary analysis described below) 
1531 
 Rubin’s multiple imputation 
1532 
 Multiple imputation with pattern mixture model  
1533 
 Available cases only  
1534 
 Analysis of the Primary Efficacy Endpoint 
1535 
Summary statistics (mean ± SD or median (quartiles)) will be reported for the CGM-measured % 
1536 
in range 70-180 mg/dL and for differences from pre-randomization by treatment group. 
1537 
Changes from run-in pre-randomization CGM wear to the 16-week post-randomization period in 
1538 
CGM-measured % in range 70-180 mg/dL between two treatment arms will be compared using a 
1539 
linear mixed effects regression model while adjusting for baseline CGM-measured % in range 
1540 
70-180 mg/dL, age, prior CGM and pump use, and clinical center (random effect). Missing data 
1541 
will be handled using direct likelihood. Residual values will be examined for an approximate 
1542 
normal distribution.  If residuals are highly skewed, then a transformation or robust statistical 
1543 
method (e.g., non-parametric or MM estimation) will be used instead. It is expected that the 
1544 
residual values for CGM-measured % in range 70-180 mg/dL will follow an approximate normal 
1545 
distribution. 
1546 
 Analysis of the Secondary Endpoints 
1547 
Point estimated and confidence intervals for the treatment arm differences will be presented for 
1548 
all secondary metrics. The models will adjust for the corresponding baseline metric, age, prior 
1549 
CGM and pump use, and clinical center (random effect). 
1550 
 
1551 
To preserve the overall type 1 error for selected key secondary endpoints, a hierarchical testing 
1552 
procedure will be used. If the primary analysis for time in range described above results in a 
1553 
statistically significant result (p < 0.05), then testing (similar with the model described above 
1554 
for the primary outcome) will proceed to the next outcome metric in the following order: 
1555 
 CGM-measured % in range 70-180 mg/dL (primary outcome) 
1556 
 CGM-measured % above 180 mg/dL  
1557 
 CGM-measured mean glucose 
1558 
 HbA1c at 16 weeks 
1559 
 CGM-measured % below 70 mg/dL 
1560 
 CGM-measured % below 54 mg/dL 
1561 
 CGM-measured % above 250 mg/dL 
1562 

 
 
 
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 Glucose variability measured with the coefficient of variation (CV) 
1563 
This process continues iteratively moving to the next variable down on the list until a non-
1564 
significant result (p ≥ 0.05) is observed, or all eight variables have been tested.  If a non-
1565 
significant result is encountered, then formal statistical hypothesis testing is terminated and 
1566 
any variables below on the list are not formally tested. 
1567 
For example, in the hypothetical scenario depicted in the table below, the first four outcome 
1568 
variables all have a significant result so testing continues to the fifth variable (CGM % below 70 
1569 
mg/dL).  The result is not significant for that fifth variable (p = 0.06) so testing stops.  No formal 
1570 
hypothesis test is conducted for the last three variables on the list in this example scenario.  
1571 
HIERARCHICAL 
ORDER 
OUTCOME 
VARIABLE 
TREATMENT 
ARM P-VALUE 
SIGNIFICANT? 
ACTION 
1st 
CGM % 70-180 mg/dL 
(primary outcome) 
0.001 
Yes 
Test next variable 
2nd 
CGM % above 180 mg/dL 
0.02 
Yes 
Test next variable 
3rd 
CGM mean glucose 
0.007 
Yes 
Test next variable 
4th 
HbA1c at 16 weeks 
0.03 
Yes 
Test next variable 
5th 
CGM % below 70 mg/dL 
0.06 
No 
Stop formal testing 
6th 
CGM % below 54 mg/dL 
Not tested 
Unknown 
N/A 
7th  
CGM % above 250 mg/dL 
Not tested 
Unknown 
N/A 
8th  
Glucose CV 
Not tested 
Unknown 
N/A 
Table 6. Example Hypothetical Hierarchical Test Results 
1572 
Regardless of the results of the hierarchical testing, summary statistics appropriate to the 
1573 
distribution will be tabulated by treatment arm for each hierarchical outcome.  A 95% confidence 
1574 
interval for the treatment arm difference will also be calculated for all seven secondary 
1575 
hierarchical outcomes listed above.  However, a confidence interval that excludes zero will not 
1576 
be considered a statistically significant result if an outcome variable higher on the hierarchical 
1577 
list failed to reach statistical significance. 
1578 
 
1579 
CGM-Measured Outcomes 
1580 
The analyses for the secondary CGM-measured outcomes will parallel those mentioned above 
1581 
for the primary outcome. For the binary CGM outcomes, risk-adjusted percentages by treatment 
1582 
group will be calculated from a logistic regression model. 
1583 
HbA1c 
1584 
Summary statistics (mean ± SD) will be reported for the central lab HbA1c at baseline, 16 weeks 
1585 
and for differences from pre-randomization by treatment group. 
1586 

 
 
 
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Change in HbA1c from baseline to 16 weeks will be compared between the two treatment arms 
1587 
using a linear model while adjusting for baseline HbA1c, age, prior CGM and pump use, and 
1588 
clinical center (random factor). 
1589 
For extension phase, efficacy of the AP will be compared by using the final 12 weeks of the 
1590 
control period vs. the 12-week AP extension phase. Each participant will be their own control.   
1591 
Missing data will be handled using direct likelihood in a regression model including all available 
1592 
central laboratory HbA1c measurements at baseline and 16-week visits. When available, the 
1593 
local HbA1c measurement will be included in the regression model as an auxiliary variable.  
1594 
For the binary HbA1c outcomes listed above, risk-adjusted percentages by treatment group will 
1595 
be computed from a logistic regression model.  The logistic regression will adjust for the same 
1596 
factors mentioned above for the analysis with HbA1c as a continuous factor (i.e., baseline 
1597 
HbA1c, age, prior CGM and pump use, and clinical center as a random effect). 
1598 
Questionnaires and Other Outcomes 
1599 
For questionnaires administered to both randomization groups, comparisons will be made using 
1600 
similar linear models as described above for the primary outcomes. Separate models will be run 
1601 
for the total score and each of the subscales listed above. 
1602 
Similarly, for insulin, weight and BMI metrics comparisons will be made using similar linear 
1603 
models as described above for the primary HbA1c analysis. 
1604 
 Safety Analyses 
1605 
All randomized participants will be included in these analyses and all their post-randomization 
1606 
safety events will be reported.   
1607 
Safety analyses of the main study (randomized trial phase) will include events occurring on or 
1608 
after randomization until and including the 16-week visit or Day 126 from randomization, 
1609 
whichever occurs first. Safety analyses of the extension phase will include subsequent events 
1610 
until the last visit date or the last event date (whichever is later). 
1611 
Any pre-randomization adverse events will be tabulated separately and will include all 
1612 
participants even if never randomized. 
1613 
For the following outcomes, mean ± SD or summary statistics appropriate to the distribution will 
1614 
be tabulated by treatment group and formal statistical comparisons (main study phase only) will 
1615 
be performed if there are enough events (at least 5 events combined between the two treatment 
1616 
groups): 
1617 
 Number of SH events and SH event rate per 100 person-years 
1618 
 Number of DKA events and DKA event rate per 100 person-years 
1619 
 Any adverse event’ rate per 100 person-years 
1620 

 
 
 
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 Number of calendar days with any ketone level ≥1.0 mmol/L 
1621 
 CGM-measured hypoglycemic events (≥15 minutes with glucose concentration <54 mg/dL) 
1622 
 CGM-measured hyperglycemic events (≥15 minutes with glucose concentration >300 
1623 
mg/dL) 
1624 
 
1625 
If enough events, the numbers of SH/DKA events will be compared between the two treatment 
1626 
arms during the main study phase using a robust Poisson regression. The regression will adjust 
1627 
for the participant-reported number of events prior to the start of the study and clinical center as 
1628 
random effect. The amount of follow up will be included as an offset covariate to compare the 
1629 
rates. Similar analyses will be done for comparing any adverse event and number of calendar 
1630 
days with ketone events between the two treatment groups, except that clinical center will be the 
1631 
only covariate to be adjusted in the model.  
1632 
For CGM-measured hypoglycemia/hyperglycemia events, event rates per week will be compared 
1633 
using similar linear mixed effects regression models as described above for the primary outcome. 
1634 
 
1635 
For both the main study and extension phases, the following safety outcomes will be tabulated by 
1636 
treatment group without a formal statistical comparison: 
1637 
 Other serious adverse events (SAE) 
1638 
 BG-measured hypoglycemic events (days with at least one BG record <54 mg/dL) 
1639 
 BG-measured hyperglycemic events (days with at least one BG record >350 mg/dL)  
1640 
 Worsening of HbA1c from baseline to 16 weeks by >0.5% 
1641 
 Investigational device related (intervention group only): 
1642 
o Adverse device effects (ADE) 
1643 
o Serious adverse device events (SADE) 
1644 
o Unanticipated adverse device effects (UADE) 
1645 
 
1646 
 Intervention Adherence 
1647 
The following tabulations and analyses will be performed by treatment group to assess 
1648 
intervention adherence for the study: 
1649 
 Sensor use –percent time of use, overall and by 4-weekly 
1650 
 The daily frequency of downloaded BGM use overall and by 4-weekly 
1651 
For CLC arm only, the following will be tabulated to assess adherence: 
1652 
 % time in different operational modes - overall and by 4-weekly 
1653 

 
 
 
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 Adherence and Retention Analyses 
1654 
The following tabulations and analyses will be performed by treatment group to assess protocol 
1655 
adherence for the study: 
1656 
 Number of protocol and procedural deviations per participant along with the number and 
1657 
percentage of participants with each number of deviations 
1658 
 Number of protocol and procedural deviations by severity with brief descriptions listed 
1659 
 Flow chart accounting for all participants at all scheduled visits and phone contacts post 
1660 
treatment initiation to assess visit and phone completion rates 
1661 
 Number of and reasons for unscheduled visits and phone calls 
1662 
 Number of participants who stopped treatment and reasons 
1663 
 Baseline Descriptive Statistics 
1664 
Baseline demographic and clinical characteristics of the cohort of all randomized participants 
1665 
will be summarized in a table using summary statistics appropriate to the distribution of each 
1666 
variable. Descriptive statistics will be displayed by treatment group. 
1667 
Will include: 
1668 
 Age 
1669 
 HbA1c 
1670 
 Gender 
1671 
 Race/Ethnicity 
1672 
 Family income, education, and/or insurance status 
1673 
 Insulin method before enrollment (pump vs. MDI) 
1674 
 CGM use before enrollment 
1675 
 Diabetes duration 
1676 
 BMI (height and weight) 
1677 
 C-peptide 
1678 
 Participant-reported number of SH and DKA 12 months prior to the start of the study 
1679 
 Device Issues 
1680 
The following tabulations and analyses will be performed by treatment group to assess device 
1681 
issues: 
1682 
 Device malfunctions requiring study team contact and other reported device issues 
1683 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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 Sensor performance metrics (difference, absolute relative difference, and International 
1684 
Organization for Standardization criteria) – if applicable, by sensor version. 
1685 
 Rate of different failure events and alarms per 24 hours recorded by the Control-IQ system – 
1686 
overall and by month 
1687 
 Planned Interim Analyses 
1688 
All above efficacy and safety analyses will be conducted after all subjects completed the primary 
1689 
study phase. No sample size re-estimation will be needed for the extension phase. The data may 
1690 
be used for PMA, with no interruption on the extension phase.  
1691 
In addition, the DSMB will review safety data at intervals, with no formal stopping rules other 
1692 
than the guidelines provided in the participant-level and study-level stopping criteria (as defined 
1693 
in Section 9.5 of the protocol). 
1694 
 Subgroup Analyses 
1695 
In exploratory analyses, the primary outcome (time 70-180 mg/dL), % time <70 mg/dL and HbA1c 
1696 
at 16 weeks will be assessed separately in various subgroups and for continuous variables 
1697 
according to the baseline value as defined below. Tests for interaction with treatment group will 
1698 
be performed and further explored if an interaction will be found in the first place. 
1699 
Interpretation of subgroup analyses will depend on whether the overall analysis demonstrates a 
1700 
significant treatment group difference. In the absence of such an overall difference and if 
1701 
performed, subgroup analyses will be interpreted with caution. For continuous variables, results 
1702 
will be displayed in subgroups based on cutpoints although the analysis will utilize the variable as 
1703 
continuous, except for age which will be analyzed both as a continuous variable and in two age 
1704 
groups. If there is insufficient sample size in a given subgroup, the cutpoints for continuous 
1705 
measures may be adjusted per the observed distribution of values. Cutpoint selection for display 
1706 
purposes will be made masked to the outcome data. 
1707 
 Baseline HbA1c  
1708 
 Baseline CGM time spent <70 mg/dL 
1709 
 Baseline CGM time spent >180 mg/dL 
1710 
 Baseline CGM time 70-180 mg/dL 
1711 
 Device use before the enrollment: pump/MDI, CGM/no CGM, and combinations of both 
1712 
 Age 
1713 
 Sex 
1714 
 Race/ Ethnicity 
1715 
 Clinical center 
1716 
 BMI (Height and weight) 
1717 
 Family income, education, and/or insurance status 
1718 

 
 
 
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 C-peptide level 
1719 
 Multiple Comparison/Multiplicity 
1720 
Primary Analysis 
1721 
Since there will be a single comparison for the primary outcome (CGM-measured % 70-180 
1722 
mg/dL), no adjustment is needed. 
1723 
Secondary Hierarchical Analyses 
1724 
The hierarchical testing procedure described above in section 11.7.1 will be used to control the 
1725 
overall type 1 error for the primary outcome plus seven key secondary outcomes identified above. 
1726 
All Other Secondary Analyses 
1727 
For all above-mentioned secondary analyses, the false discovery rate will be controlled using the 
1728 
adaptive Benjamini-Hochberg procedure. 
1729 
 Exploratory Analyses 
1730 
In addition to the analysis for the CGM-measured endpoints described earlier, separate analyses 
1731 
will be conducted for daytime and nighttime. 
1732 
The CGM-measured analyses will be replicated with only CGM data when the closed-loop was 
1733 
active for the CLC group. The CGM data for the SC group will be the same as mentioned above 
1734 
in the CGM Metrics Calculation section 11.4.3. 
1735 

 
 
 
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Chapter 12: Data Collection and Monitoring 
1736 
 Case Report Forms and Device Data 
1737 
The main study data are collected through a combination of electronic case report forms 
1738 
(CRFs) and electronic device data files obtained from the study software and individual hardware 
1739 
components.  These electronic device files and electronic CRFs from the study website are 
1740 
considered the primary source documentation. 
1741 
When data are directly collected in electronic case report forms, this will be considered the source 
1742 
data.  Each participating clinical center will maintain appropriate medical and research records for 
1743 
this trial, in compliance with ICH E6 and regulatory and institutional requirements for the 
1744 
protection of confidentiality of participants. 
1745 
 Study Records Retention 
1746 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
1747 
application in an ICH region and until there are no pending or contemplated marketing applications 
1748 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
1749 
development of the investigational product.  These documents should be retained for a longer 
1750 
period, however, if required by local regulations.  No records will be destroyed without the written 
1751 
consent of the sponsor, if applicable.  It is the responsibility of the sponsor to inform the 
1752 
investigator when these documents no longer need to be retained. 
1753 
 Quality Assurance and Monitoring 
1754 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1755 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1756 
conducted and data are generated, documented and reported in compliance with the protocol, Good 
1757 
Clinical Practice (GCP) and the applicable regulatory requirements.  Adverse events will be 
1758 
prioritized for monitoring. 
1759 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1760 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations 
1761 
— A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and monitoring will 
1762 
conform with 21 Code of Federal Regulations (CFR) 812. 
1763 
The data of most importance for monitoring at the clinical center are participant eligibility and 
1764 
adverse events.  Therefore, the RBM plan will focus on these areas.  As much as possible, remote 
1765 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the verity 
1766 
and completeness of the key clinical center data.  Elements of the RBM may include: 
1767 
 Qualification assessment, training, and certification for clinical centers and clinical center 
1768 
personnel 
1769 
 Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1770 
 Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1771 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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review of entered data and edits, statistical monitoring, study closeout 
1772 
 On-site monitoring (site visits): source data verification, site visit report 
1773 
 Agent/Device accountability 
1774 
 Communications with clinical center staff 
1775 
 Participant retention and visit completion 
1776 
 Quality control reports 
1777 
 Management of noncompliance 
1778 
 Documenting monitoring activities 
1779 
 Adverse event reporting and monitoring 
1780 
Coordinating Center representatives or their designees may visit the study facilities at any time 
1781 
in order to maintain current and personal knowledge of the study through review of the records, 
1782 
comparison with source documents, observation and discussion of the conduct and progress of the 
1783 
study. 
1784 
 Protocol Deviations 
1785 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1786 
requirements.  The noncompliance may be either on the part of the participant, the investigator, or 
1787 
the clinical center staff.  As a result of deviations, corrective actions are to be developed by the 
1788 
clinical center and implemented promptly. 
1789 
The clinical center PI/study staff is responsible for knowing and adhering to the IRB requirements.  
1790 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1791 

 
 
 
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Chapter 13: Ethics/Protection of Human Participants 
1792 
 Ethical Standard 
1793 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1794 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
1795 
CFR Part 56, and/or the ICH E6. 
1796 
 Institutional Review Boards 
1797 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1798 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1799 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1800 
require review and approval by the IRB before the changes are implemented to the study.  All 
1801 
changes to the consent form will be IRB approved; a determination will be made regarding whether 
1802 
previously consented participants need to be re-consented. 
1803 
 Informed Consent Process 
1804 
 
1805 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
1806 
study and continues throughout the individual’s study participation.  Extensive discussion of risks 
1807 
and possible benefits of participation will be provided to the participants and their families.  
1808 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
1809 
document.  The investigator will explain the research study to the participant and answer any 
1810 
questions that may arise.  All participants will receive a verbal explanation in terms suited to their 
1811 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1812 
research participants.  Participants will have the opportunity to carefully review the written consent 
1813 
form and ask questions prior to signing. 
1814 
The participants should have the opportunity to discuss the study with their surrogates or think 
1815 
about it prior to agreeing to participate.  The participant will sign the informed consent and child 
1816 
assent documents prior to any procedures being done specifically for the study.  The participants 
1817 
may withdraw consent at any time throughout the course of the trial.  A copy of the informed 
1818 
consent and child assent documents will be given to the participants for their records.  The rights 
1819 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
1820 
medical care will not be adversely affected if they decline to participate in this study. 
1821 
 
1822 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
1823 
device company supplying study product may inspect all documents and records required to be 
1824 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
1825 
hospital) for the participants in this study.  The clinical center will permit access to such records. 
1826 

 
 
 
DCLP5 V2.5_PEDIATRIC_CLINICAL PROTOCOL_CLEAN_09OCT2019 
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The study participant’s contact information will be securely stored at each clinical center for 
1827 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1828 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
1829 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
1830 
will be transmitted to and stored at the Jaeb Center for Health Research and the University of 
1831 
Virginia Center for Diabetes Technology.  This will not include the participant’s contact or 
1832 
identifying information.  Rather, individual participants and their research data will be identified 
1833 
by a unique study identification number.  The study data entry and study management systems 
1834 
used by clinical centers and by Jaeb research staff will be secured and password protected.  At the 
1835 
end of the study, all study databases will be de-identified and archived at Jaeb Center for Health 
1836 
Research and the University of Virginia Center for Diabetes Technology. Permission to transmit 
1837 
data will be included in the informed consent. 
1838 

 
 
 
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Chapter 14: References 
1839 
1. Kovatchev, B.P., Breton, M.D., Keith-Hynes, P.T., Patek, S.D. The Diabetes Assistant (DiAs) 
1840 
– Unified platform for monitoring and control of blood glucose levels in diabetic patients; 
1841 
PCT/US12/43910, 2012. 
1842 
2. Keith Hynes, P., Guerlain, S., Mize, L.B., Hughes Karvetski, C., Khan, M., McElwee Malloy, 
1843 
M. & Kovatchev, B.P. DiAs user interface: A patient-centric interface for mobile artificial 
1844 
pancreas systems. J Diabetes Sci Technol, 7, 1416–1426 (2013). PMID: 24351168 
1845 
3. Place, J., Robert, A., Ben Brahim, N., Keith Hynes, P., Farret, A., Pelletier, M.J., Buckingham, 
1846 
B., Breton, M., Kovatchev, B.P. & Renard, E. DiAs web monitoring: A real-time remote 
1847 
monitoring system designed for artificial pancreas outpatient trials. J Diabetes Sci Technol, 7, 
1848 
1427–1435. (2013). PMID: 24351169 
1849 
4. Keith-Hynes, P., Mize, B., Robert, A., Place, J. The Diabetes Assistant: A smartphone-based 
1850 
system for real-time control of blood glucose. Electronics 2014, 3, 609-623; 
1851 
doi:10.3390/electronics3040609 
1852 
5. Kovatchev, B.P., Renard, E., Cobelli, C., Zisser, H., Keith-Hynes, P., Anderson, S.M. Brown, 
1853 
S.A. Chernavvsky, D.R., Breton, M.D., Farret, A., Pelletier, M.J., Place, J., Bruttomesso, D., 
1854 
Del Favero, S., Visentin, R., Filippi, A., Scotton, R., Avogaro, A. & Doyle III, F.J. Feasibility 
1855 
of outpatient fully integrated closed-loop control: First studies of wearable artificial pancreas. 
1856 
Diabetes Care, 36, 1851-1858 doi: 10.2337/dc12-1965 (2013). PMID: 23801798, PMCID: 
1857 
PMC3687268 
1858 
6. Kovatchev, B.P., Renard, E., Cobelli, C., Zisser, H., Keith-Hynes, P., Anderson, S.M., Brown, 
1859 
S.A., Chernavvsky, D.R., Breton, M.D., Mize, L.B., Farret, A., Place, J., Bruttomesso, D., Del 
1860 
Favero, S., Boscari, F., Galasso, S., Avogaro, A., Magni, L., Di Palma, F., Toffanin, C., 
1861 
Messori, M., Dassay, E., Doyle, F. III. Safety of outpatient closed-loop control: First 
1862 
randomized crossover trials of a wearable artificial pancreas. Diabetes Care, 37, 1789-1796 
1863 
doi: 10.2337/dc13-2076 (2014). PMID: 24929429, PMCID: PMC4067397 
1864 
7. DeSalvo, D., Keith-Hynes, P., Peyser, T., Place, J., Caswell, K., Wilson, D., Harris, B., 
1865 
Clinton, P., Kovatchev, B.P., Buckingham, B.A. Remote glucose monitoring in camp setting 
1866 
reduces the risk of prolonged nocturnal hypoglycemia. Diabetes Technol Ther, 16, 1-7 
1867 
doi:10.1089/dia.2013.0139 (2013). PMID: 24168317 
1868 
8. Ly, T.T., Breton, M.D., Keith-Hynes, P., De Salvo, D., Clinton, P., Benassi, K., Mize, L.B., 
1869 
Chernavvsky, D.R., Place, J., Wilson, D.M., Kovatchev, B.P., Buckingham, B.A. Overnight 
1870 
glucose control with an automated, unified safety system in children and adolescents with type 
1871 
1 diabetes at diabetes camp. Diabetes Care, 37, doi: 10.2337/dc14-0147 (2014). PMID: 
1872 
24879841, PMCID: PMC4179507 
1873 
9. Kropff, J., Del Favero, S., Place, J., Toffanin, C., Visentin, R., Monaro, M., Messori, M., 
1874 
Di Palma, F., Lanzola, G., Farret, A., Boscari, F., Galasso, S., Magni, P., Avogaro, A., 
1875 
Keith-Hynes, P., Kovatchev, B.P., Bruttomesso, D., Cobelli, C.,  DeVries, J.H., Renard, E., 
1876 
Magni, L., for the AP@home consortium. 2 month evening and night closed-loop glucose 
1877 
control in patients with Type 1 Diabetes under free-living conditions: A randomised crossover 
1878 

 
 
 
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trial. Lancet Diabetes Endocrinol, 3(12):939-47 dx.doi.org/10.1016/S2213-8587(15)00335-6 
1879 
(2015). 
1880 
10. Renard, E et al. Reduction of hyper- and hypoglycemia during two months with a wearable 
1881 
artificial pancreas from dinner to breakfast in patients with type 1 diabetes. 2015-A-3083-
1882 
Diabetes. American Diabetes Association 75th Scientific Sessions, Boston, MA, poster 940-P. 
1883 
11. Anderson, S et al. First New Year’s Night on closed-loop control (CLC) at home: Case reports 
1884 
from a multi-center international trial of long-term 24/7 CLC. 2015-A-4763-Diabetes. 
1885 
American Diabetes Association 75th Scientific Sessions, Boston, MA, presentation 223–OR. 
1886 
12. Kovatchev BP. JDRF Multi-Center 6-Month Trial of 24/7 Closed-Loop Control. Advanced 
1887 
Technologies and Treatments for Diabetes (ATTD), Plenary Session, Milan, Italy, 2016. 
1888 
13. Kovatchev, B.P. Closed-loop control modalities in type 1 diabetes: Efficacy and system 
1889 
acceptance. Advanced Technologies and Treatments for Diabetes (ATTD), Paris, France, 
1890 
2015. 
1891 
14. Del Favero S. A multicenter randomized cross-over Italian pediatric summer camp: AP vs SAP 
1892 
in 5-8 year old children. Advanced Technologies and Treatments for Diabetes (ATTD), 
1893 
Plenary Session, Milan, Italy, 2016. 
1894 
15. Cherñavvsky, D. et al. Closed-loop control during extended winter-sport exercise in youth with 
1895 
T1DM: Results from the first AP ski camp. ATTD Data Club Session, Milan, (2016). 
1896 
16. Chernavvsky, D.R., DeBoer, M.D., Keith-Hynes, P., Mize, B., McElwee, M., Demartini, S., 
1897 
Dunsmore, S.F., Wakeman, C., Kovatchev, B.P., Breton, M.D. Use of an artificial pancreas 
1898 
among adolescents for a missed snack bolus and an underestimated meal bolus. Pediatric 
1899 
Diabetes, doi:10.1111/pedi.12230 (2014). PMID: 25348683 
1900 
17. Brown, S.A., Kovatchev, B.P., Breton, M.D., Anderson, S.M., Keith-Hynes, P., Patek, S.D., 
1901 
Jiang, B., Ben Brahim, N., Vereshchetin, P., Bruttomesso, D., Avogaro, A., Del Favero, S., 
1902 
Boscari, F., Galasso, S., Visentin, R., Monaro, M., Cobelli, C. Multinight “bedside” 
1903 
closed-loop control for patients with type 1 diabetes. Diabetes Technol Ther 17(3), 
1904 
doi:10.1089/dia.2014.0259 (2015). PMID: 25594434, PMCID: PMC4346235 
1905 
18. Kovatchev BP, Tamborlane WV, Cefalu WT, Cobelli C. The Artificial Pancreas in 2016: 
1906 
A Digital Treatment Ecosystem for Diabetes. Diabetes Care 2016; 39:1123-27. PMID: 
1907 
27330124 
1908 
19. Del Favero S, Boscari F, Messori M, Rabbone I, Bonfanti R, Sabbion A, IaFusco D, Schiaffini 
1909 
R, Visentin R, Calore R, Moncada YL, Galasso S, Galderisi A, Vallone V, Di Palma F, Losiouk 
1910 
E1, Lanzola G1, Tinti D, Rigamonti A, Marigliano M, Zanfardino A, Rapini N, Avogaro A, 
1911 
Chernavvsky D, Magni L, Cobelli C, Bruttomesso D. Randomized Summer Camp Crossover 
1912 
Trial in 5- to 9-Year-Old Children: Outpatient Wearable Artificial Pancreas Is Feasible and 
1913 
Safe. Diabetes Care. 2016;39:1180-5. PMID: 27208335 
1914 
20. Renard E, Farret A, Kropff J, Bruttomesso D, Messori M, Place J, Visentin R, Calore R, 
1915 
Toffanin C, Di Palma F, Lanzola G, Galasso S, Avogaro A, Keith-Hynes P, Kovatchev BP, 
1916 
Del Favero S., Cobelli C, Magni L, DeVries HJ. AP@home Consortium. Day and night closed 
1917 
loop glucose control in patients with type 1 diabetes under free-living conditions: comparison 
1918 

 
 
 
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of a single-arm, 1-month experience to results of a previously reported feasibility study of 
1919 
evening and night at home. Diabetes Care 2016; 39:1151-60. PMID: 27208331 
1920 
21. Anderson SM, Raghinaru D, Pinsker JE, Boscari F, Renard E, Buckingham BA, Nimri R, 
1921 
Doyle FJ III, Brown SA, Keith-Hynes P, Breton MD, Chernavvsky D, Bevier WC, Bradley 
1922 
PK, Bruttomesso D, Del Favero S, Calore R, Cobelli C, Avogaro A, Farret A, Place J, Ly TT, 
1923 
Shanmugham S, Phillip M, Dassau E, Dasanayake IS, Kollman C, Lum JW, Beck RW, and 
1924 
Kovatchev BP. Multinational home use of closed-loop control is safe and effective. 
1925 
Diabetes Care 2016; 39:1143-1150. PMID: 27208316 
1926 
22. DeBoer MD, Cherñavvsky DR, Topchyan K, Kovatchev BP, Francis GL, Breton MD. Heart 
1927 
rate informed artificial pancreas system enhances glycemic control during exercise in 
1928 
adolescents with T1D. Pediatr Diabetes. 2016; doi: 10.1111/pedi.12454. PMID: 27734563 
1929 
23. Kovatchev BP, Cheng P, Anderson SM, Pinsker JE, Boscari F, Buckingham BA, Doyle FJ. 
1930 
III, Hood KK, Brown SA. Breton MD, Chernavvsky DR, Bevier WC, Bradley PK, 
1931 
Bruttomesso D, Del Favero S, Calore R, Cobelli C, Avogaro A, Ly TT, Shanmugham S, 
1932 
Dassau E, Kollman C, Lum JW, Beck RW, for the Control to Range Study Group. Feasibility 
1933 
of Long-Term Closed-Loop Control: A Multicenter 6-Month Trial of 24/7 Automated Insulin 
1934 
Delivery. Diabetes Technol Ther 2017; 19: 18-24. doi:10.1089/dia.2016.0333. PMID: 
1935 
27982707 
1936 
24. DeBoer MD, Breton MD, Wakeman CA, Schertz EM, Emory EG, Robic JL, Kollar LL, 
1937 
Kovatchev BP, Chernavvsky DR. Performance of an Artificial Pancreas System for Young 
1938 
Children with Type 1 Diabetes. Diabetes Technol Ther 2017; 19, DOI: 10.1089/dia.2016.0424. 
1939 
PMID: 28426239 
1940 
25. Breton MD, Cherñavvsky DR, Forlenza GP, DeBoer MD, Robic J, Wadwa RP, Messer LH,  
1941 
Kovatchev BP, Maahs DM. Closed Loop Control During Intense Prolonged Outdoor Exercise 
1942 
in Adolescents With Type 1 Diabetes: The Artificial Pancreas Ski Study. Diabetes Care 2017 
1943 
Aug; dc170883. https://doi.org/10.2337/dc17-0883 
1944 
26. Ly TT, Gallego PH, Davis EA, Jones TW: Impaired Awareness of Hypoglycemia in a 
1945 
Population-Based Sample of Children and Adolescents With Type 1 Diabetes. Diabetes Care 
1946 
32(10):1802-1806, 2009 
1947 
27. Shepard JA, Vajda KA, Nyer M, Clarke WL, Gonder-Frederick LA, : Understanding the 
1948 
Construct of Fear of Hypoglycemia in Pediatric Type 1 Diabetes. J Pediatr Psychol 39(10): 
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1115-1125, 2014 
1950 
28. Markowitz JT, Volkening LK, Butler DA, Antisdel-Lomaglio J, Anderson BJ, Laffel LM. Re-
1951 
examining a measure of diabetes-related burden in parents of young people with Type 1 
1952 
diabetes: the Problem Areas in Diabetes Survey - Parent Revised version (PAID-PR). Diabet 
1953 
Med. 2012;29(4):526–530. doi:10.1111/j.1464-5491.2011.03434. 
1954 
29. Varni, J. W., Delamater, A.M., Hood, K.K., Raymond, J.K., Chang, N.T., Driscoll, K.A., 
1955 
Wong, J.C., Yi-Frazier, J.P., Grishman, E.K., Faith, M.A., Corathers, S.D., Kichler, J.C., 
1956 
Miller, J.L., Doskey, E.M., Aguirre, V.P., Heffer, R.W., & Wilson, D. P. (in press). Pediatric 
1957 
Quality of Life Inventory (PedsQL) 3.2 Diabetes Module for youth with Type 2 diabetes: 
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Reliability and validity. Diabetic Medicine. 
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30. J. Weissberg-Benchell, J.B. Shapiro, K. Hood, L.M. Laffel, D. Naranjo, K. Miller, K. Bernard:  
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Assessing patient‐reported outcomes for automated insulin delivery systems: the psychometric 
1961 
properties of the INSPIRE measures. Diabet. Med. 00: 1– 9 ( 2019) 
1962 
31. Buysse DJ1, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ: The Pittsburgh Sleep 
1963 
Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 
1964 
May;28(2):193-213 
1965 
32. Brown S, Raghinaru D, Emory E, Kovatchev B: First Look at Control-IQ: A New-Generation 
1966 
Automated Insulin Delivery System. Diabetes Care Oct 2018, dc181249; DOI: 10.2337/dc18-
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1249. PMID: 30305346 
1968 
33. Ekhlaspour L, Wadwa RP, Chernavvsky D, Forlenza GP, Messer L, Town M, Swanson V, 
1969 
Maahs DM, Kovatchev B, Buckingham B, Breton M: Artificial Pancreas (AP) Ski Camp 2018: 
1970 
Successful Use of the Tandem Control-IQ AP System in Adolescents and Children During 
1971 
Winter Sports and at Home (abstract). Pediatric Diabetes 2018;17 
1972